Subscribe
  • Original Article
  • OPEN ACCESS

An Overview of the Role of Peroxisome Proliferator-activated Receptors in Liver Diseases

  • Zahra Changizi1 ,
  • Forough Kajbaf2 and
  • Azam Moslehi1,* 
 Author information
Journal of Clinical and Translational Hepatology 2023;11(7):1542-1552

DOI: 10.14218/JCTH.2023.00334

Abstract

Peroxisome proliferator-activated receptors (PPARs) are a superfamily of nuclear transcription receptors, consisting of PPARα, PPARγ, and PPARβ/δ, which are highly expressed in the liver. They control and modulate the expression of a large number of genes involved in metabolism and energy homeostasis, oxidative stress, inflammation, and even apoptosis in the liver. Therefore, they have critical roles in the pathophysiology of hepatic diseases. This review provides a general insight into the role of PPARs in liver diseases and some of their agonists in the clinic.

Keywords

Liver, Endoplasmic reticulum stress, Nonalcoholic fatty liver disease, PPARα, PPAR, PPARβ/δ

Introduction

Nuclear receptors and transcriptional regulators called peroxisome proliferator-activated receptors (PPARs) have key roles in many physiological and pathological processes, especially energy homeostasis.1 PPARs have three different subtypes: PPARα, PPARβ/δ, and PPARγ, which are located in chromosomes 22q13.31, 3p25.2, and 6q21.31 respectively.2 PPARα (also called NR1C1( is present in tissues that catabolize fatty acids and it regulates inflammation and lipid metabolism.3 PPARβ/δ (also called NR1C2) is less well known and is expressed in the heart, liver, kidneys, skeletal muscle, fat, skin, and gastrointestinal tract.4,5 The PPARγ subtype (also called NR1C3) improves skeletal muscle insulin sensitivity while causing fat storage and lipogenesis in both white and brown adipose tissue. It is also expressed in hepatic stellate cells (HSCs).6 Target genes for the three PPAR alpha, beta/delta, and gamma receptor isoforms are distinct but also overlapping.7 Although PPARs naturally and primarily appear in the nucleus, they actively shuttle between the nucleus and cytoplasm, regulated by different PPAR ligands.8

Notwithstanding their roles in lipid and glucose metabolism,9 growing findings suggest that PPARs function in the modulation of other processes such as inflammation and innate immunity.10 Fatty acids (FAs), eicosanoids, and phospholipids produced by cellular FA metabolism or dietary lipids are natural ligands of PPARs.11 Upon ligand binding, PPARs and retinoid X receptors (RXRs) as major coactivators, create heterodimers, bind to peroxisome proliferator response elements, and influence the expression of downstream target genes.12,13

The liver is the main organ responsible for regulating lipid and glucose homeostasis through controlled biochemical, signaling, and cellular pathways.14 The production of plasma proteins, clotting factors, bile, and the excretion of metabolic waste products are some other liver functions.15,16 Liver diseases imply a broad range of liver disorders, involving over 2 million individuals worldwide each year and affecting other body-system functions, lifestyle, and lifespan.17 Given that PPARs are currently considered important factors in hepatic physiological and pathological processes, investigation of their role in liver diseases seems very useful. Therefore, the objective of this review is to present an overview of PPAR functions in health and in liver diseases.

Physiological function and regulation of PPARs

PPARs are one of the main sensors and regulators of lipid metabolism. In this regard, PPARα is a significant target for fibrate hypolipidemic drugs, implicated mainly in the catabolism of FAs and their oxidation in the heart, muscle, liver, kidney, small and large intestine.18 It also causes glucose homeostasis and insulin resistance. PPARα agonists reduce renal blood pressure by interfering in the renin angiotensin system and provide renal vasodilatation by promoting the expression of endothelial nitric oxide synthase (commonly known as eNOS) in endothelium.19,20 PPARα participates in cardiomyocyte metabolism and protects against cardiac inflammation and infarction.21 In the liver, PPARα activation promotes FA oxidation and thermogenesis and PPARγ promotes energy storage by increasing lipogenesis and adipogenesis. PPARα is a nutrient-sensing nuclear receptor that has important effects in fasting. Food restriction increases PPARα expression,22 and in fasting, PPARα is upregulated and induces some transcription factors such as fasting induced adipose factor (commonly known as FIAF) and fibroblast growth factor (commonly known as FGF) 21, which increase circulating free FAs and ketone bodies to supply energy and prevent hypoglycemia.23–25 Adipose triglyceride lipase (commonly known as ATGL) is a key enzyme here and its absence leads to a decrease in PPARα production.26 In feeding, PPARα increases the maturation of the transcription factor sterol regulatory-element binding protein (SREBP) 1c.27 PPARs are involved in glycerol metabolism as an important substrate for hepatic glucose synthesis. Accordingly, PPARα controls glycerol metabolism in the liver, and PPARγ regulates glycerol metabolism in adipose tissue.28 Additionally, PPARα activates Vanin-1, which is a prominent PPARα-dependent regulated gene in the liver and decreases hepatic steatosis through change in inflammation and oxidative stress pathways.29 PPARα also regulates bile acid metabolism and excretion.30

PPAR-β/δ subtype is involved in FA oxidation, keratinocyte differentiation, wound cure, and adipogenesis.31 The PPAR-β/δ is mainly expressed in the macrophages and skeletal muscle.32 Following activation, PPARβ/δ inhibits interleukin 6 (commonly known as IL6) induced insulin resistance by inhibiting the signal transducer and activator of the transcription 3 (commonly known as STAT3) pathway in adipocytes. However, this pathway is overactivated in PPARβ/δ-null mice compared with wild-type animals.33 PPARδ controls the diurnal expression of lipogenic genes in the dark/feeding cycle that peaks with nocturnal feeding and leads to muscle lipid oxidation. This results from coordination between the liver and muscle in metabolic functions. PPARβ activation is accompanied by an increase in circulating high-density lipoprotein (HDL) levels and chemoattractant signaling suppression in the aorta, which reduces atherosclerotic lesion formation.34 The overexpression of PPARβ/δ in cardiac cells also leads to an increase of glucose metabolism and a decrease of lipid accumulation, and it is associated with cardiac endothelial dysfunction via reducing oxidative stress.35

PPARγ expression is often observed in the spleen, the large intestine, and brown and white adipose tissue. Of the two PPARγ isoforms, PPARγ1is expressed in the liver and other tissues. The PPARγ2 isoform is expressed exclusively in adipose tissue, where it controls adipogenesis and lipogenesis. The PPARγ2 isoform can inhibit lipotoxicity by promoting adipose tissue extension and expanding lipid-buffering size in peripheral organs.36 PPARγ activity in adipocytes directly regulates adipocytokine secretion in peripheral tissues,37 and in PPARγ1 and 2-knockout mouse adipocytes, fat accumulation decreases and glucose tolerance improves.38 The PPARγ1 isoform is expressed in many dendritic cells where it has a role in memory and cognition.39 It has been shown that the macrophage activation of PPARγ suppressed the production of pro-inflammatory cytokines, such as tumor necrosis factor alpha (commonly known as TNFα), IL1β and IL6.40 PPARγ was also shown to increase gastrin secretion in the stomach.20 The physiological range of sex hormones, including testosterone, estradiol, and dihydrotestosterone, also downregulates PPARγ expression and function.41 Escandon et al.42 reported that PPARs have important roles in ocular homeostasis (Fig. 1).

Function of PPARs in different tissues in physiological conditions.
Fig. 1  Function of PPARs in different tissues in physiological conditions.

PPARs, peroxisome proliferator-activated receptors.

PPARs and other transcription factors

As shown in Figure 2, RXRs are the main nuclear receptor to react with PPARs. After ligand binding, PPARs form heterodimers with nuclear RXR. This compound adheres to the peroxide proliferator response element in DNA and changes gene expression and synthesis of new proteins in the cells.43 Another nuclear receptor that reacts with PPARs is the P65 subunit of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB). The PPAR/NF-κB interaction orchestrates some metabolic-based inflammatory responses.44 In the heart, PPARs attenuate NF-κB activity and have antifibrotic and cardiac remodeling effects.45,46

Interactions of PPARs and other transcription factors.
Fig. 2  Interactions of PPARs and other transcription factors.

FXR, Farnesoid X receptor; LXR, Liver X receptor; PCG-1, PPARγ coactivator-1; KLF, Krüppel-like factor; RXR, Retinoid X receptor; TFEB, transcription factor EB; NF-κB, nuclear factor kappa light-chain enhancer of activated B cells; SREBP, sterol regulatory-element binding protein.

The Krüppel-like factor (KLF) family includes zinc finger-containing transcription factors that are involved in many cell processes, including metabolic homeostasis.47 A recent study in skeletal muscle showed that KLF15 had a critical role in metabolic reinforcement through its interactions with PPARδ, suggesting that KLF15 facilitated PPARδ-mediated transcription.48 The antimycobacterial responses of PPARα are another important function of this transcription factor that follows activation of transcription factor EB (commonly known as TFEB). TFEB is a protein coding gene associated with various diseases, such as renal cell carcinoma, Xp11.2 translocation and pycnodysostosis.49 Kim et al.50 reported that during mycobacterial infection, PPARα deficiency resulted in an exaggerated inflammatory response and increased bacterial load. PPARα activation during mycobacterial infection promoted FA β-oxidation and lipid catabolism in macrophages.50

Liver X receptors (LXRs) and SREBP-1c are two other factors that interact with PPARs and are key regulators of liver normal functions.51,52 LXRs are as orphan nuclear receptors that control intracellular cholesterol levels and bile acids. Yoshikawa et al.53 showed that LXRs activation led to signaling repression by decreasing PPAR/RXR heterodimerization in the liver.53 The SREBP-1c transcription factor also regulates de novo lipogenesis in the liver in response to increases of insulin.54 SREBP-1c enhances the transcription and activity of PPARγ.55 On the other hand, PPARα represses SREBP-1c/LXR activity.56

Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) is a family of transcriptional coactivators that interact with PPARs. For example, PGC-1α activates PPARα in mitochondrial FA oxidation, and PGC-1α/PPARγ interaction promotes the expression of encoding aP2, uncoupling protein-1 (UCP1), and glycerol kinase genes.57 Farnesoid X receptor (commonly known as FXR) is a transcriptional factor that interacts with PPARs, especially PPARα. FXR is an upstream protein that activates PPARα expression. They both activate FA oxidation and triglyceride metabolism and decrease the expression of SREBP-1c. They also induce liver autophagy in mice with steatohepatitis.58,59

PPARs in liver diseases

Role of PPARs in nonalcoholic fatty liver

In Western countries, nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease.60 NAFLD includes a broad spectrum of liver disorders such as simple steatosis, nonalcoholic steatohepatitis (NASH) and liver fibrosis.61 It may progress to cirrhosis and hepatocellular cancer.62 All PPAR isotypes control the activation of HSCs and inflammation and are closely related to glucolipid metabolism in NAFLD.63 Because of the association of NAFLD with obesity and hyperglycemia and the important role of PPAR in the transcriptional regulation of glucose and lipid metabolism, their ligands are good options as therapeutic agents.64 It has been demonstrated that PPAR activation prevented NASH development by increasing the release of adipokines such as adiponectin and stimulating the expression of genes related to beta oxidation and decreasing inflammation and oxidative stress.63,65,66 As PPARα is a nutritional sensor and enables the modification of FA oxidation, lipogenesis, and ketone body synthesis rates in response to feeding and fasting, its hepatic expression falls when dietary lipid intake is excessive.67 After PPARα/RXR dimerization and entrance into the nucleus, beta-oxidases, including carnitine palmitoyltransferase 1 (commonly known as CPT-1), a key enzyme in lipolysis, were upregulated and allowed FAs to move to the mitochondrial matrix for further metabolism.58 PPARα also induced FA binding protein 1 (commonly known as FABP) expression and thereby inhibited HSCs activation, resulting in NASH improvement.68 Deficient mice (i.e. PPAR−/−) in either the whole body or only hepatocytes, developed steatosis and gained weight with overexpression of lipid synthesis-related genes, and increased inflammation with both control and high-fat diets.22,69 This could well confirm the unique role of PPARα in lipid catabolism both in the hepatocytes and extra-hepatic cells. Fibrates are considered weak PPARα agonists and some studies have demonstrated an improvement in the biochemical or histological parameters affected by fibrates in NAFLD patients.70,71 Although there is no doubt about the beneficial effects of PPARα in attenuating NAFLD, their agonists have some side effects and their clinical application in NAFLD should be further studied.

In addition to hepatocytes, PPARβ/δ is expressed in Kupffer cells and HSCs, suggesting its potential role in inflammation and fibrosis. Hepatic PPARβ/δ activation not only improves NAFLD through lipolysis related pathways but also reduces hepatic steatosis through autophagy-mediated FA oxidation.72 GW501516 and GW0742 are PPARβ/δ agonists that were shown to ameliorate obesity and insulin resistance and reduce serum triglycerides and low-density lipoprotein cholesterol (LDL-C) in rats and humans.73 According to the available clinical trials for the safety of PPARβ/δ agonists, it has been determined that short-term treatment with these drugs in humans is safe and generally tolerable.74

As previously mentioned, PPARγ is significantly expressed in latent HSCs; nevertheless, it is repressed during the fibrosis process, prevents the activation of the HSCs, and lowers the amount of collagen deposition during liver fibrogenesis. Therefore, PPARγ might be a useful target for the treatment of liver fibrosis.75 Despite its role in hepatic fibrosis attenuation, PPARγ is involved in de novo lipogenesis and FFA import. In hepatocytes, PPARγ induced adipocyte protein 2 and a cluster of differentiation (CD) 36-mediated FFA uptake and promoted FA synthase (commonly known as FAS) and acetyl-CoA carboxylase 1 (commonly known as ACC1) activity.76 PPARγ has additional roles in NAFLD-related processes, including insulin resistance, inflammation, oxidative stress, and endoplasmic reticulum (ER) stress.77 in NAFLD patients and laboratory animals, the expression levels of hepatic PPARγ are higher64 and are significantly associated the initiation of NAFLD and hepatocyte-specific PPARγ expression.78 However, partial PPARγ activation has benefits, mostly brought about by increased adiponectin levels, decreased leptin levels, and insulin resistance improvement.64 Pioglitazone is a PPARγ agonist that can raise the plasma adiponectin levels by acting as an anti-inflammatory and antifibrotic agent (Fig. 3).79 Overall, all types of PPARs have important roles in NASH improvement and steatosis and inflammation restriction. Nevertheless, the effect of PPARα is exclusive. However, it needs more appropriate agonists in patients with NAFLD.

Role of PPARs in different liver diseases.
Fig. 3  Role of PPARs in different liver diseases.

ER, endoplasmic reticulum; HCC, hepatocarcinoma cancer; NASH, nonalcoholic steatohepatitis; PPARs, peroxisome proliferator-activated receptors.

Role of PPARs in ER stress

The ER is a large, dynamic structure with numerous roles in the cell, including lipid metabolism, protein synthesis, and calcium storage.80 After disturbance in the ER, ER stress occurs and correct protein folding is disrupted.81,82 The evidence shows that prolonged ER stress is linked to the development and progression of various diseases, including neurodegeneration, type 2 diabetes, atherosclerosis, cancer, and liver diseases.83 Inhibition and activation role of PPARα has been shown to be involved in ER stress.66 PPARα is a key molecule in the functional conversion of ER stress. PPARα inhibition by small interfering RNA (commonly known as siRNA)-promoted cell injury in mild ER stress, and PPARα activation reduced cell apoptosis in severe ER stress.84 Recently, Van der Krieken et al.85 reported a link between ER stress, PPARα activation, and inhibition of apolipoprotein A-I Transcription. They showed that activating PPARα increased apoA-I transcription and bromodomain and extra-terminal domain (commonly known as BET) protein inhibitors, worsened ER stress, and decreased apoA-I transcription. ER-stress-mediated reduction in apoA-I transcription was most likely partly mediated via the inhibition of PPARα mRNA expression. In addition, BET inhibition increased apoA-I transcription.

In a study by Zarei et al.86 PPARβ/δ knockout led to hepatic ER stress, the induction of activating transcription factor 4 (AFT4) and eukaryotic initiation factor 2 alpha (eIF2α) expression, upregulation of ER stress-induced very low-density lipoprotein receptor, and liver steatosis in mice. Magnesium lithospermate B, a biological agonist of PPARβ/δ, suppressed liver ER stress and increased insulin level and insulin receptor substrate-1 (commonly known as IRS-1).87 In hepatic ER stress, increased proline-rich, extensin-like receptor kinase expression (an important sensor of ER stress) led to eIF2α downregulation and decreased PPARγ through CCAAT-enhancer-binding protein (commonly known as C/EBP)/PPARγ signaling.88 PPARγ also attenuated ER stress by activation of the PPARγ/Nogo-B receptor (commonly known as NGBR) pathway, which improved liver insulin sensitivity.89 These studies demonstrate that at least one of the pathways through which both PPARβ/δ and PPARγ ameliorate liver ER stress is the downregulation of eIF2α and C/EBP, thereby promoting liver function and insulin sensitivity. Several studies (Fig. 3) have shown that PPARα/γ agonists improved liver function via lowered ER stress.90,91

Role of PPARs in infectious hepatitis

Infectious hepatitis is one of the most common causes of hepatitis and results from viral and bacterial infection.92 Hepatitis A, B, C, D, and E are the five primary hepatitis virus subtypes. Each kind of viral hepatitis is caused by a distinct virus.93 According to an old report, PPARγ can block hepatitis B virus (HBV) replication, hepatitis B surface antigen, and hepatitis B e antigen in vitro.94 However, there are also conflicting newer findings. It was shown that bezafibrate, fenofibrate, and rosiglitazone promoted HBV replication. It has been recommended that HBV viral load be managed and regimens might need to be altered, with the addition of an antiviral medication when HBV-infected individuals are treated with PPAR agonists for metabolic illnesses.95 In addition, PPARγ causes hepatic steatosis by activating the HBV X protein.94 Overexpression of the FABP1 gene, which is controlled by PPARα, C/EBPα, and hepatocyte nuclear factor (HNF) 3β, causes the hepatic fat accumulation brought on by HBVx.96 It has been demonstrated that during bacterial hepatitis, PPARα activates and leads to a shift from glucose to lipid utilization, and an increase of ketone bodies, as a result helping in survival promotion.97 This effect is produced through hepatic FGF21 overexpression, which maintains thermogenesis, energy expenditure, and cardiac function. However, the opposite occurs in influenza infection.98,99

On the other hand, hepatitis C virus (commonly known as HCV) infection impairs PPARα and PPARγ mRNA expression,100 and coinfection with human immunodeficiency virus (commonly known as HIV) significantly reduces the expression of the mRNA both receptors through IL1β and decreases HSC activation. However, black patients experienced significantly less suppressive effects of viruses.101,102 Other studies showed that via PPARγ, genotype 3a of the HCV core protein elevated suppressor of cytokine signaling (SOCS) 7 expression in Huh-7 cells. In contrast to other members of the SOCS1 and SOCS3 under study, whose expression is controlled by STAT3 activation, SOCS7 expression seems to be controlled by PPARγ.103,104 another study found that PPARα formed a complex with heat shock protein 90 and X-associated protein 2 (commonly known as XAP2), and that XAP2 was active as a repressor. PPARα is consistently linked to other proteins in tissue extracts and is the nuclear receptor that associates with XAP2 hepatitis virus B (Fig. 3).105 In this context, there are contradictory results about PPARs effects and further studies are required.

Role of PPARs in liver toxicity

Synthetic chemicals and environmental pollutants can interrupt normal liver homeostasis and provide hepatotoxicity. Hepatotoxicity relates to different roles of PPARα, PPARγ, and PPARβ.106 Studies have shown that PPARα activation prevents acute liver toxicity.106,107 Cell death might be prevented by the activation of PPARα, thereby inducing resistance in hepatocytes and/or induction of death protein inhibitors in the dead or dying cells.108 Another study reported that fibrates (PPARα activators) prevented acetaminophen hepatotoxicity in mice.109 Acetaminophen-induced hepatic hypoxia also inhibits PPARα expression to amplify hepatotoxicity and oxidative stress.110 Peraza et al.111 reported that activation of PPARα modulated liver toxicity by interfering with aryl hydrocarbon receptor (commonly known as AhR)-dependent signaling. Ernst et al.112 reported that amiodarone-induced hepatic steatosis in mice was associated with an upregulation of target genes modulated by PPARα. As amiodarone does not stimulate PPARα directly, target-gene induction may reflect a compensatory reaction countering some harmful effects of amiodarone. The protective influence of PPARα on reducing amiodarone-induced hepatic toxicity was shown with the aforementioned results.112 PPARα activation was also shown to protect against carbon tetrachloride and cadmium-induced liver toxicity.113 The aforementioned and similar studies have demonstrated the amelioration of PPARα of hepatotoxicity mediated by diverse anti-inflammatory pathways.

PPARγ activation induces mild liver toxicity but attenuates liver fibrogenesis.106 Troglitazone and rosiglitazone are PPARγ agonists that is reported to induce mild liver toxicity in patients.114 Despite the PPARγ activation in hepatotoxicity, PPARγ ligand treatment attenuates fibrogenesis. The attenuation of PPARγ inhibits the activation of HSCs and it results in a decrease in fibrogenic gene expression, including collagen and α-smooth muscle actin.115 Hepatotoxicity is one of the most studied activities of PPARγ agonists.111 Although one PPARγ ligand can cause liver toxicity, recent findings suggest that another PPARγ ligand can protect against liver damage.111 Although, thiazolidinediones, which are PPARγ agonists, can cause hepatotoxicity,106 it was shown that the induced orchestrated activation of PPARα and PPARγ reprogrammed hepatic macrophage polarization, thereby affecting lipid homeostasis in mice’s liver.116 Lipid droplets emerge when PPARγ is ectopically overexpressed in hepatocytes. For example, the overexpression of PPARγ2 following adenovirus exposure increased hepatosteatosis in mice.117 Bruno et al.118 reported that methoxy eugenol, a molecule found in nutmeg and Brazilian red propolis, attenuated carbon tetrachloride-induced liver fibrosis through the activation of PPARγ. Despite the positive role of PPARα in the attenuation of hepatic toxicity, activation has dual effects of promoting liver toxicity on one hand and attenuates liver fibrosis through HSC suppression on the other. Further studies are needed to clarify the aforementioned effects. PPARβ/δ preventive or therapeutic role for alcoholic liver disease might be similar in hepatotoxicity. In the liver, PPARβ/δ might influence the inflammatory activity of Kupffer cells. The PPARβ/δ subtype, possibly by downregulating expression of proinflammatory genes, is protective against liver toxicity induced by environmental chemicals.119 Nevertheless, PPARβ activation promotes the progression of liver fibrosis (Fig. 3).106

Role of PPARs in liver cancer

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma are the two main kinds of primary liver cancer. Less common malignancies include angiosarcoma, hemangiosarcoma, and hepatoblastoma. HCC develops from hepatocytes, and intrahepatic cholangiocarcinoma starts in the bile ducts.120,121 It should be noted that primary liver cancer therapy and prognosis are greatly influenced by the severity of underlying liver cirrhosis.122 As PPARs targets have been identified in liver disorders, study of new therapeutic alternatives in liver cancer has taken a big step.52 PPARs regulate the cell cycle and metabolism, thus they have special role in carcinogenesis, However, it is not yet apparent which PPAR subunits promote or inhibit cancer.123

Although in HCC, the nuclear expression of PPARα is lower than in normal liver tissue and HCC patients who have a higher nuclear and cytoplasmic expression of PPARα have longer lifespans.124 When a PPARs agonist (e.g., nafenopin) was administered to mice or rats for an extended period, it was observed that hepatocellular cancer or hepatomegaly developed.125 It has been reported that by eliminating PPARα, HCC caused by fatty liver and hepatomegaly was inhibited in HCV core transgenic mice.126 Vacca et al.127 reported that Hepa1-6 hepatoma cell proliferation was decreased by the PPARβ/δ agonist GW501516.127 Adenomatous polyposis coli (commonly known as APC) is a tumor suppressor that inhibits PPARβ/δ transcription by controlling the β-catenin/Tcf-4 pathway. Therefore, PPARβ/δ activity might be elevated as a result of APC/β-catenin mutations.4 Sorafenib-resistant HCC cell metabolic programming was reversed by inhibiting PPARβ/δ activity, a crucial regulator of glutamine metabolism. Eventually, these cells developed sorafenib sensitivity.128

In early cancers, PPARγ expression is markedly downregulated in tumor tissue relative to nontumor tissue.129 It has been determined that PGC-1α’s metastasis suppressor action is dependent on PPARγ because PGC-1α inhibits the Warburg effect via regulating the WNT/β-catenin/PDK1 axis.130 Additionally, the intrinsic and extrinsic cell interactions in HCC have demonstrated the interaction between PPARγ, HSCs, and the fibrogenic microenvironment. In the premalignant milieu, these interactions induce growth arrest, cell senescence, and cell clearance.109 Contrary to the above findings, patients with promoted HCC highly express PPARγ, which can be used as a prognostic indicator.131 PPARγ is intrinsically active in tumor cells, elevates vascular endothelial growth factor A (commonly known as VEGF-A) transcription, and results in promoting myeloid-derived suppressor cell proliferation and CD8+ cell dysfunction. In orthotopic and spontaneous HCC models, a specific PPARγ antagonist (pembrolizumab) changed the suppressive tumor microenvironment into an immunostimulatory one and made tumors more responsive to anti- programmed death-ligand 1 (commonly known as PD-L1) therapy.132 Finally, it is generally stated that as an adjunctive therapy, activation of PPARα and PPARγ sensitizes tumor cells to traditional anticancer therapies used in HCC.52

Feng et al.133 demonstrated that simvastatin blocked the hypoxia inducible factor-1 alpha (commonly known as HIF-1α)/PPARγ/pyruvate kinase muscle 1 (commonly known as PKM2) axis, reducing PKM2-mediated glycolysis and boosting the expression of apoptotic markers in HCC cells, making them more susceptible to sorafenib treatment. Similarly, telmisartan, a partial agonist of PPARγ, increased tumor sensitivity to sorafenib by modulating the extracellular signal-regulated kinase 1/2 (commonly known as ERK1/2), transforming growth factor-β activated kinase 1 (commonly known as TAK1), and NF-κB signaling axis.134 Another study found that the cyclic isoprenoid β-ionone (βI), which has been proposed as a possible chemotherapeutic drug when combined with sorafenib, controlled the expression of PPARγ via RXR.135 PPAR activity in hepatic cancers differ. PPARα usually has a promoting action but PPARγ and PPARδ have mostly tumor suppressive activity. Overall, PPARs promote or suppress liver cancers depending on the PPAR type, cancer type, and tumor stage (Fig. 3).

Role of PPARs in liver cholestasis

Reduced bile formation causes a condition called cholestasis. This leads to a reduction in membrane fluidity and an increase in membrane cholesterol content. Cholestasis biochemical features reflect the maintenance of bile ingredients in the serum, such as bilirubin, bile acids, and cholesterol.136 There are limited studies to investigate the mechanism of the protection of PPARs against cholestasis. Currently, PPARs, owing to their expression in different hepatic parenchymal and nonhepatic parenchymal cell compartments, are of great interest for the treatment of cholestasis. PPAR agonists also have benefits in cholestasis (e.g., bezafibrate and fenofibrate). Bezafibrate has a similar affinity for the PPARα, PPARγ, and PPARδ. Fenofibrate is a PPARα-specific agonist.137

PPARα effectively reduces cholestatic liver injury, thereby improving patient physiological status by the anti-inflammatory effects. During cholestasis, the activation of PPARα has emerged as a novel goal for controlling the transport and synthesis of bile acids.136 Potential treatments for cholestasis by PPARα mainly involve the reduction of the bile acid pool size in the liver and regulation of damage caused by cholestasis.136 Li et al.138 showed that a deficiency of PPARα exacerbated liver injury in cholic acid-induced cholestasis and the activation of PPARα signaling suggested that it protected against cholestatic liver damage. A recent study revealed that fenofibrate, which activates PPARα reversed bile acid metabolism disorders, improved mitochondrial FA beta oxidation (commonly known as β-FAO), and decreased the inflammation and oxidative stress of cytokines in alpha-naphthyl isothiocyanate (commonly known as ANIT)-induced cholestasis.139 The results collectively confirm that PPARα agonists have potential as therapeutic agents for cholestatic liver damage. The importance of PPARα in controlling bile acid balance and treating inflammation during cholestasis has led to new ideas for managing the condition, although its primary physiological function is to regulate the metabolism of glucose and other energy sources.136 Fenofibrate protection against cholestasis-induced liver damage depends on the fenofibrate dose and PPARα, and is mediated by inhibiting c-Jun N-terminal kinase (JNK) signaling.141 It was demonstrated that formononetin inhibited the ANIT-induced inflammatory response by PPARα-dependently inactivating the JNK inflammatory pathway.141 Dai et al.142 reported that PPARα activity effectively protected mice against cholestasis-induced liver injury via inhibiting JNK signaling. In the aforementioned studies, JNK signaling is supported as a pathway for the attenuation of cholestasis-induced liver injury.

PPARγ protects against injury from cholestatic liver disease. The activation of PPARγ by tectorigenin also inhibits hepatic inflammation and bile accumulation and alleviates intrahepatic cholestasis.143 A recent study showed that a PPARγ agonist (formononetin) improved intrahepatic cholestasis and cholestasis associated dyslipidemia induced by α-naphthyl isocyanate.144 In intrahepatic cholestasis of pregnancy, the production of reactive oxygen species could be inhibited by PPARγ and lead to a decrease in the level of inflammation through NF-κB downregulation, which might be a mechanism for intrahepatic cholestasis of pregnancy (Fig. 3).145 The results of the above studies show the potential ability of PPARγ and PPARα to ameliorate hepatic cholestasis and therefore to limit disease development.

Role of PPARs in liver ischemia-reperfusion

Hepatic ischemia-reperfusion injury (IRI) is a major side effect of liver surgery and liver transplantation and a significant contributor to liver dysfunction.146 Hepatic ischemia-reperfusion-induced acute inflammation resulted in the production of reactive oxygen species and release of inflammatory cytokines that damaged liver cells and caused organ failure.147 The interactions of hepatocytes, Kupffer cells, neutrophils, macrophages, sinusoidal endothelial cells, and platelets are among the many intricate and varied mechanisms that make up the pathophysiology of hepatic IRI.148

By activating PPARα and PPARγ, it has been shown that PGC-1 protects the liver against hepatic IRI.149 Additionally, curcumin has been shown to increase PPARα/γ and cyclic adenosine monophosphate (commonly known as CAMP)-responsive element binding protein (commonly kmown as CREB) 1, which are both involved in hepatic ischemia/reperfusion.150,151 Increase in the expression of antioxidant enzymes and decrease in NF-κB activity caused by the administration of WY-14643, a specific agonist of PPARα, improved the antioxidant and anti-inflammatory defense system, it may have potential as a clinical treatment of liver IRI.152 Massip-Salcedo et al.153 reported that activation of PPARα in rats with steatotic livers and undergoing IRI, reduced the harmful effects of adiponectin. In liver IRI, N-3 polyunsaturated FA supplementation induced PPARα activation and PPARα interaction that had anti-inflammatory consequences.154 PPARγ protection against hepatic IRI was reported to be mediated by the NF-κB pathway.155 In general, the protective effects of PPARγ have been widely reported and include reducing oxidative stress, inhibiting inflammatory responses, and antagonizing apoptosis.156 PPARγ is associated with various physiological pathways and has an important role in acute IRI of the liver through the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (commonly known as mTOR)/autophagy pathway. PPARγ is thus a regulator and potential therapeutic target that can reduce liver damage in IRI.157 PPARγ activation decreases IRI and pro-inflammatory NO+ Kupffer cells by attenuating the pro-inflammatory character of Kupffer cells and IRI; therefore it can become a significant strategy to modify outcomes in liver surgery (Fig. 3).158 Interaction between CREB1 and PPARα seems to have the main role in the improvement of IRI. However, PPARγ uses AMPK and mTOR signaling pathways. Nevertheless, in both PPARs, NF-κB is a common transcription factor.

Role of clinical PPAR agents in liver disease

Fibrates are considered the most prevalent PPARα agonists. In a randomized clinical trial, pemafibrate, which is a selective PPARα agonist, did not reduce liver fat in patients with NAFLD, but significantly reduced liver stiffness based on magnetic resonance elastography (MRE).159 In another clinical study, pemafibrate was assessed in NAFLD and atherosclerosis (AS), and was reported that pemafibrate was superior to conventional fibrates and might even be used for chronic kidney disease.160

The clinical use of fibrates has been associated with side effects, including liver damage and elevated creatinine levels.161,162 Although a clinical trial on fibrates has shown negative results for the prevention of atherosclerotic cardiovascular disease,163 another clinical trial conducted in Japan confirmed the superior effects of pemafibrate on lowering triglycerides and increasing HDL-cholesterol (HDL-C).162 A review reported that combination therapy with fenofibrate, another PPARα agonist, and a statin in individuals with cardiovascular disease was safe and reduced dyslipidemia.164 Generally, in individuals at risk for cardiovascular disease, fibrate medication decreases nonfatal coronary events, atherostatic plaque, and dyslipidemia, but often does not decrease death.165 Another trial revealed a decrement of hepatocellular ballooning grade without changes in steatosis, lobular inflammation, and fibrosis in nonalcoholic fatty liver patients treated with fenofibrate.166

We did not find significant clinical studies of the effects of PPARβ/δ agonists (i.e. GW501516 and GW0742) on the liver. Although there are few clinical trials evaluating the safety of PPARβ/δ agonists in other tissues, these medications appear to be safe and well-tolerated when administered to humans, at least for brief periods.167 It is interesting that AMPK activation is a key component of the majority of PPAR β/δ agonist antidiabetes activities.74,168 It is also reported that growth differentiation factor 15 (commonly known as GDF15) activated AMPK to mediate the metabolic effects of PPARβ/δ.169 Although, there are some positive results on ameliorative effects of fibrates in liver diseases, it needs to more studies to confirm.

Thiazolidinediones, which are selective agonists for the PPARγ, are currently used therapeutically.170 Thiazolidinediones have been shown to alter several mediators in insulin-sensitive tissues to affect glucose and lipid metabolism, leading to a reduction in liver fat.171 Although thiazolidinediones have been demonstrated to lower blood glucose levels in patients with type 2 diabetes,172 some reports have reported liver damage and death from acute liver failure in patients with thiazolidinedione administration.173,174 Troglitazone, neotroglitazone, pioglitazone, and rosiglitazone are thiazolidinedione derivatives. Troglitazone was the first thiazolidinedione approved for use in the USA in 1997.175 However, it has been reported that troglitazone causes cytotoxicity by degrading the active protein of PPARγ.176 Because neotroglitazone use was linked to an increased risk of liver failure, it was eventually withdrawn in the USA.177 Nevertheless, studies show pioglitazone is effective in patients with NAFLD/NASH and that it continuously improves histological parameters and normalizes liver transaminases. However, the use of this drug has side effects such as weight gain.178 Taking rosiglitazone for 24 weeks, also stabilized the level of LDL-C, reduced LDL-C, induced AS, and increased HDL-C level.179 According to clinical trials evaluating liver function in individuals with type 2 diabetes, evidence shows that rosiglitazone does not cause hepatic impairment.180 Although there are several other agonists and antagonists for PPARs, they have not been used in clinical studies.181 Overall, it seems that thiazolidinediones derivatives are better drugs for improving liver diseases through their effects on PPARs.

Conclusion

Accumulating evidence from human and animal studies demonstrates that PPARs have multiple functions in the both health and disease that are not limited to the metabolic effects. They change the expression of numerous genes by interaction with other transcriptional factors and affect metabolism, inflammation, infection, circulation, and cancer in the liver. Although there are some side effects associated with the clinical use of PPAR agents, it is hoped that more effective PPAR-based drugs with fewer side effects will be developed in the future.

Abbreviations

FAs: 

fatty acids

FXR: 

farnesoid X receptor

HBV: 

hepatitis B virus

HDL: 

high-density lipoprotein

KLF: 

Krüppel-like factor

LXR: 

liver X receptor

NAFLD: 

nonalcoholic fatty liver disease

NASH: 

nonalcoholic steatohepatitis

NF-κB: 

nuclear factor kappa light-chain enhancer of activated B cells

PCG-1: 

PPARγ coactivator-1

PPARs: 

peroxisome proliferator-activated receptors

RXR: 

retinoid X receptor

SREBP: 

sterol regulatory-element binding protein

TFEB: 

transcription factor EB

UCP1: 

uncoupling protein-1

Declarations

Funding

None to declare.

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

Study conception and design, and revision of the draft manuscript (AM), searching of the literature and drafting of the manuscript and figures (ZC), searching of the literature and drafting of the manuscript (FK). All authors made significant contributions to the study and approved the final manuscript.

References

  1. Berthier A, Johanns M, Zummo FP, Lefebvre P, Staels B. PPARs in liver physiology. Biochim Biophys Acta Mol Basis Dis 2021;1867(5):166097 View Article PubMed/NCBI
  2. Muzio G, Barrera G, Pizzimenti S. Peroxisome Proliferator-Activated Receptors (PPARs) and Oxidative Stress in Physiological Conditions and in Cancer. Antioxidants (Basel) 2021;10(11):1734 View Article PubMed/NCBI
  3. Lin Y, Wang Y, Li PF. PPARα: An emerging target of metabolic syndrome, neurodegenerative and cardiovascular diseases. Front Endocrinol (Lausanne) 2022;13:1074911 View Article PubMed/NCBI
  4. Wagner N, Wagner KD. PPAR Beta/Delta and the Hallmarks of Cancer. Cells 2020;9(5):1133 View Article PubMed/NCBI
  5. Sun C, Mao S, Chen S, Zhang W, Liu C. PPARs-Orchestrated Metabolic Homeostasis in the Adipose Tissue. Int J Mol Sci 2021;22(16):8974 View Article PubMed/NCBI
  6. Crossland H, Constantin-Teodosiu D, Greenhaff PL. The Regulatory Roles of PPARs in Skeletal Muscle Fuel Metabolism and Inflammation: Impact of PPAR Agonism on Muscle in Chronic Disease, Contraction and Sepsis. Int J Mol Sci 2021;22(18):9775 View Article PubMed/NCBI
  7. Burri L, Thoresen GH, Berge RK. The Role of PPARα Activation in Liver and Muscle. PPAR Res 2010;2010:542359 View Article PubMed/NCBI
  8. Peng L, Yang H, Ye Y, Ma Z, Kuhn C, Rahmeh M, et al. Role of Peroxisome Proliferator-Activated Receptors (PPARs) in Trophoblast Functions. Int J Mol Sci 2021;22(1):433 View Article PubMed/NCBI
  9. Monsalve FA, Pyarasani RD, Delgado-Lopez F, Moore-Carrasco R. Peroxisome proliferator-activated receptor targets for the treatment of metabolic diseases. Mediators Inflamm 2013;2013:549627 View Article PubMed/NCBI
  10. Grabacka M, Pierzchalska M, Płonka PM, Pierzchalski P. The Role of PPAR Alpha in the Modulation of Innate Immunity. Int J Mol Sci 2021;22(19):10545 View Article PubMed/NCBI
  11. Tan CK, Zhuang Y, Wahli W. Synthetic and natural Peroxisome Proliferator-Activated Receptor (PPAR) agonists as candidates for the therapy of the metabolic syndrome. Expert Opin Ther Targets 2017;21(3):333-348 View Article PubMed/NCBI
  12. Wagner N, Wagner KD. The Role of PPARs in Disease. Cells 2020;9(11):2367 View Article PubMed/NCBI
  13. Tyagi S, Gupta P, Saini AS, Kaushal C, Sharma S. The peroxisome proliferator-activated receptor: A family of nuclear receptors role in various diseases. J Adv Pharm Technol Res 2011;2(4):236-240 View Article PubMed/NCBI
  14. Shimizu K, Nishimuta S, Fukumura Y, Michinaga S, Egusa Y, Hase T, et al. Liver-specific overexpression of lipoprotein lipase improves glucose metabolism in high-fat diet-fed mice. PLoS One 2022;17(9):e0274297 View Article PubMed/NCBI
  15. Zaefarian F, Abdollahi MR, Cowieson A, Ravindran V. Avian Liver: The Forgotten Organ. Animals (Basel) 2019;9(2):63 View Article PubMed/NCBI
  16. Zhang YY, Meng ZJ. Definition and classification of acute-on-chronic liver diseases. World J Clin Cases 2022;10(15):4717-4725 View Article PubMed/NCBI
  17. Gao E, Hercun J, Heller T, Vilarinho S. Undiagnosed liver diseases. Transl Gastroenterol Hepatol 2021;6:28 View Article PubMed/NCBI
  18. Saha L. Role of peroxisome proliferator-activated receptors alpha and gamma in gastric ulcer: An overview of experimental evidences. World J Gastrointest Pharmacol Ther 2015;6(4):120-126 View Article PubMed/NCBI
  19. Psilopatis I, Vrettou K, Fleckenstein FN, Theocharis S. The Role of Peroxisome Proliferator-Activated Receptors in Preeclampsia. Cells 2023;12(4):647 View Article PubMed/NCBI
  20. Lachal S, Ford J, Shulkes A, Baldwin GS. PPARalpha agonists stimulate progastrin production in human colorectal carcinoma cells. Regul Pept 2004;120(1-3):243-251 View Article PubMed/NCBI
  21. Christofides A, Konstantinidou E, Jani C, Boussiotis VA. The role of peroxisome proliferator-activated receptors (PPAR) in immune responses. Metabolism 2021;114:154338 View Article PubMed/NCBI
  22. Montagner A, Polizzi A, Fouché E, Ducheix S, Lippi Y, Lasserre F, et al. Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut 2016;65(7):1202-1214 View Article PubMed/NCBI
  23. Kersten S, Mandard S, Tan NS, Escher P, Metzger D, Chambon P, et al. Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene. J Biol Chem 2000;275(37):28488-28493 View Article PubMed/NCBI
  24. Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest 1999;103(11):1489-1498 View Article PubMed/NCBI
  25. Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, et al. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab 2007;5(6):415-425 View Article PubMed/NCBI
  26. Fougerat A, Schoiswohl G, Polizzi A, Régnier M, Wagner C, Smati S, et al. ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity. Cell Rep 2022;39(10):110910 View Article PubMed/NCBI
  27. Iroz A, Montagner A, Benhamed F, Levavasseur F, Polizzi A, Anthony E, et al. A Specific ChREBP and PPARα Cross-Talk Is Required for the Glucose-Mediated FGF21 Response. Cell Rep 2017;21(2):403-416 View Article PubMed/NCBI
  28. Patsouris D, Mandard S, Voshol PJ, Escher P, Tan NS, Havekes LM, et al. PPARalpha governs glycerol metabolism. J Clin Invest 2004;114(1):94-103 View Article PubMed/NCBI
  29. van Diepen JA, Jansen PA, Ballak DB, Hijmans A, Hooiveld GJ, Rommelaere S, et al. PPAR-alpha dependent regulation of vanin-1 mediates hepatic lipid metabolism. J Hepatol 2014;61(2):366-372 View Article PubMed/NCBI
  30. Kim KH, Moore DD. Regulation of Liver Energy Balance by the Nuclear Receptors Farnesoid X Receptor and Peroxisome Proliferator Activated Receptor α. Dig Dis 2017;35(3):203-209 View Article PubMed/NCBI
  31. Magadum A, Engel FB. PPARβ/δ: Linking Metabolism to Regeneration. Int J Mol Sci 2018;19(7):2013 View Article PubMed/NCBI
  32. Chen M, Jing D, Ye R, Yi J, Zhao Z. PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy. Stem Cell Res Ther 2021;12(1):566 View Article PubMed/NCBI
  33. Liu S, Brown JD, Stanya KJ, Homan E, Leidl M, Inouye K, et al. A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use. Nature 2013;502(7472):550-554 View Article PubMed/NCBI
  34. Chinetti-Gbaguidi G, Staels B. PPARβ in macrophages and atherosclerosis. Biochimie 2017;136:59-64 View Article PubMed/NCBI
  35. d’Uscio LV, Das P, Santhanam AV, He T, Younkin SG, Katusic ZS. Activation of PPARδ prevents endothelial dysfunction induced by overexpression of amyloid-β precursor protein. Cardiovasc Res 2012;96(3):504-512 View Article PubMed/NCBI
  36. Wu L, Song Y, Zhang Y, Liang B, Deng Y, Tang T, et al. Novel Genetic Variants of PPARγ2 Promoter in Gestational Diabetes Mellitus and its Molecular Regulation in Adipogenesis. Front Endocrinol (Lausanne) 2020;11:499788 View Article PubMed/NCBI
  37. Laganà AS, Vitale SG, Nigro A, Sofo V, Salmeri FM, Rossetti P, et al. Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors (PPARs) in Dysregulated Metabolic Homeostasis, Inflammation and Cancer: Current Evidence and Future Perspectives. Int J Mol Sci 2016;17(7):999 View Article PubMed/NCBI
  38. Hu W, Jiang C, Kim M, Xiao Y, Richter HJ, Guan D, et al. Isoform-specific functions of PPARγ in gene regulation and metabolism. Genes Dev 2022;36(5-6):300-312 View Article PubMed/NCBI
  39. Alhowail A, Alsikhan R, Alsaud M, Aldubayan M, Rabbani SI. Protective Effects of Pioglitazone on Cognitive Impairment and the Underlying Mechanisms: A Review of Literature. Drug Des Devel Ther 2022;16:2919-2931 View Article PubMed/NCBI
  40. Hernandez-Quiles M, Broekema MF, Kalkhoven E. PPARgamma in Metabolism, Immunity, and Cancer: Unified and Diverse Mechanisms of Action. Front Endocrinol (Lausanne) 2021;12:624112 View Article PubMed/NCBI
  41. Sato H, Ishikawa M, Sugai H, Funaki A, Kimura Y, Sumitomo M, et al. Sex hormones influence expression and function of peroxisome proliferator-activated receptor γ in adipocytes: pathophysiological aspects. Horm Mol Biol Clin Investig 2014;20(2):51-61 View Article PubMed/NCBI
  42. Escandon P, Vasini B, Whelchel AE, Nicholas SE, Matlock HG, Ma JX, et al. The role of peroxisome proliferator-activated receptors in healthy and diseased eyes. Exp Eye Res 2021;208:108617 View Article PubMed/NCBI
  43. Sharma S, Shen T, Chitranshi N, Gupta V, Basavarajappa D, Sarkar S, et al. Retinoid X Receptor: Cellular and Biochemical Roles of Nuclear Receptor with a Focus on Neuropathological Involvement. Mol Neurobiol 2022;59(4):2027-2050 View Article PubMed/NCBI
  44. Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol 2009;1(4):a000034 View Article PubMed/NCBI
  45. Duhaney TA, Cui L, Rude MK, Lebrasseur NK, Ngoy S, De Silva DS, et al. Peroxisome proliferator-activated receptor alpha-independent actions of fenofibrate exacerbates left ventricular dilation and fibrosis in chronic pressure overload. Hypertension 2007;49(5):1084-1094 View Article PubMed/NCBI
  46. Doi T, Sakoda T, Akagami T, Naka T, Mori Y, Tsujino T, et al. Aldosterone induces interleukin-18 through endothelin-1, angiotensin II, Rho/Rho-kinase, and PPARs in cardiomyocytes. Am J Physiol Heart Circ Physiol 2008;295(3):H1279-H1287 View Article PubMed/NCBI
  47. McConnell BB, Yang VW. Mammalian Krüppel-like factors in health and diseases. Physiol Rev 2010;90(4):1337-1381 View Article PubMed/NCBI
  48. Fan L, Sweet DR, Fan EK, Prosdocimo DA, Madera A, Jiang Z, et al. Transcription factors KLF15 and PPARδ cooperatively orchestrate genome-wide regulation of lipid metabolism in skeletal muscle. J Biol Chem 2022;298(6):101926 View Article PubMed/NCBI
  49. Zhu Y, Xia C, Ou Y, Zhang C, Li L, Yang D. TFEB-associated renal cell carcinoma: A case report and literature review. Medicine (Baltimore) 2022;101(50):e31870 View Article PubMed/NCBI
  50. Kim YS, Lee HM, Kim JK, Yang CS, Kim TS, Jung M, et al. PPAR-α Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism. J Immunol 2017;198(8):3283-3295 View Article PubMed/NCBI
  51. Lekstrom-Himes J, Xanthopoulos KG. Biological role of the CCAAT/enhancer-binding protein family of transcription factors. J Biol Chem 1998;273(44):28545-28548 View Article PubMed/NCBI
  52. Monroy-Ramirez HC, Galicia-Moreno M, Sandoval-Rodriguez A, Meza-Rios A, Santos A, Armendariz-Borunda J. PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases. Int J Mol Sci 2021;22(15):8298 View Article PubMed/NCBI
  53. Ide T, Shimano H, Yoshikawa T, Yahagi N, Amemiya-Kudo M, Matsuzaka T, et al. Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. II. LXRs suppress lipid degradation gene promoters through inhibition of PPAR signaling. Mol Endocrinol 2003;17(7):1255-1267 View Article PubMed/NCBI
  54. Ruiz R, Jideonwo V, Ahn M, Surendran S, Tagliabracci VS, Hou Y, et al. Sterol regulatory element-binding protein-1 (SREBP-1) is required to regulate glycogen synthesis and gluconeogenic gene expression in mouse liver. J Biol Chem 2014;289(9):5510-5517 View Article PubMed/NCBI
  55. Kim JB, Wright HM, Wright M, Spiegelman BM. ADD1/SREBP1 activates PPARgamma through the production of endogenous ligand. Proc Natl Acad Sci U S A 1998;95(8):4333-4337 View Article PubMed/NCBI
  56. Knight BL, Hebbachi A, Hauton D, Brown AM, Wiggins D, Patel DD, et al. A role for PPARalpha in the control of SREBP activity and lipid synthesis in the liver. Biochem J 2005;389(Pt 2):413-421 View Article PubMed/NCBI
  57. Finck BN, Kelly DP. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Invest 2006;116(3):615-622 View Article PubMed/NCBI
  58. Lee JM, Wagner M, Xiao R, Kim KH, Feng D, Lazar MA, et al. Nutrient-sensing nuclear receptors coordinate autophagy. Nature 2014;516(7529):112-115 View Article PubMed/NCBI
  59. Jiao Y, Lu Y, Li XY. Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis. Acta Pharmacol Sin 2015;36(1):44-50 View Article PubMed/NCBI
  60. Pouwels S, Sakran N, Graham Y, Leal A, Pintar T, Yang W, et al. Non-alcoholic fatty liver disease (NAFLD): a review of pathophysiology, clinical management and effects of weight loss. BMC Endocr Disord 2022;22(1):63 View Article PubMed/NCBI
  61. Hamidi-Zad Z, Moslehi A, Rastegarpanah M. Attenuating effects of allantoin on oxidative stress in a mouse model of nonalcoholic steatohepatitis: role of SIRT1/Nrf2 pathway. Res Pharm Sci 2021;16(6):651-659 View Article PubMed/NCBI
  62. Petrelli F, Manara M, Colombo S, De Santi G, Ghidini M, Mariani M, et al. Hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis: HCC and Steatosis or Steatohepatitis. Neoplasia 2022;30:100809 View Article PubMed/NCBI
  63. Komeili-Movahhed T, Bassirian M, Changizi Z, Moslehi A. SIRT1/NFκB pathway mediates anti-inflammatory and anti-apoptotic effects of rosmarinic acid on in a mouse model of nonalcoholic steatohepatitis (NASH). J Recept Signal Transduct Res 2022;42(3):241-250 View Article PubMed/NCBI
  64. Liss KH, Finck BN. PPARs and nonalcoholic fatty liver disease. Biochimie 2017;136:65-74 View Article PubMed/NCBI
  65. Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol 2015;62(3):720-733 View Article PubMed/NCBI
  66. Komeili Movahhed T, Moslehi A, Golchoob M, Ababzadeh S. Allantoin improves methionine-choline deficient diet-induced nonalcoholic steatohepatitis in mice through involvement in endoplasmic reticulum stress and hepatocytes apoptosis-related genes expressions. Iran J Basic Med Sci 2019;22(7):736-744 View Article PubMed/NCBI
  67. Choudhary NS, Kumar N, Duseja A. Peroxisome Proliferator-Activated Receptors and Their Agonists in Nonalcoholic Fatty Liver Disease. J Clin Exp Hepatol 2019;9(6):731-739 View Article PubMed/NCBI
  68. Sun X, Yu Q, Kang B, Zhao X, Li H, Liu H, et al. Diethyldithiocarbamate inhibits the activation of hepatic stellate cells via PPARα/FABP1 in mice with non-alcoholic steatohepatitis. Biochem Biophys Res Commun 2023;641:192-199 View Article PubMed/NCBI
  69. Régnier M, Polizzi A, Smati S, Lukowicz C, Fougerat A, Lippi Y, et al. Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity. Sci Rep 2020;10(1):6489 View Article PubMed/NCBI
  70. El-Haggar SM, Mostafa TM. Comparative clinical study between the effect of fenofibrate alone and its combination with pentoxifylline on biochemical parameters and liver stiffness in patients with non-alcoholic fatty liver disease. Hepatol Int 2015;9(3):471-479 View Article PubMed/NCBI
  71. Boeckmans J, Natale A, Rombaut M, Buyl K, Rogiers V, De Kock J, et al. Anti-NASH Drug Development Hitches a Lift on PPAR Agonism. Cells 2019;9(1):37 View Article PubMed/NCBI
  72. Tong L, Wang L, Yao S, Jin L, Yang J, Zhang Y, et al. PPARδ attenuates hepatic steatosis through autophagy-mediated fatty acid oxidation. Cell Death Dis 2019;10(3):197 View Article PubMed/NCBI
  73. Lee MY, Choi R, Kim HM, Cho EJ, Kim BH, Choi YS, et al. Peroxisome proliferator-activated receptor δ agonist attenuates hepatic steatosis by anti-inflammatory mechanism. Exp Mol Med 2012;44(10):578-585 View Article PubMed/NCBI
  74. Palomer X, Barroso E, Pizarro-Delgado J, Peña L, Botteri G, Zarei M, et al. PPARβ/δ: A Key Therapeutic Target in Metabolic Disorders. Int J Mol Sci 2018;19(3):913 View Article PubMed/NCBI
  75. Wu L, Guo C, Wu J. Therapeutic potential of PPARγ natural agonists in liver diseases. J Cell Mol Med 2020;24(5):2736-2748 View Article PubMed/NCBI
  76. Skat-Rørdam J, Højland Ipsen D, Lykkesfeldt J, Tveden-Nyborg P. A role of peroxisome proliferator-activated receptor γ in non-alcoholic fatty liver disease. Basic Clin Pharmacol Toxicol 2019;124(5):528-537 View Article PubMed/NCBI
  77. Chen H, Tan H, Wan J, Zeng Y, Wang J, Wang H, et al. PPAR-γ signaling in nonalcoholic fatty liver disease: Pathogenesis and therapeutic targets. Pharmacol Ther 2023;245:108391 View Article PubMed/NCBI
  78. Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, et al. PPARγ signaling and metabolism: the good, the bad and the future. Nat Med 2013;19(5):557-566 View Article PubMed/NCBI
  79. Bajaj M, Suraamornkul S, Piper P, Hardies LJ, Glass L, Cersosimo E, et al. Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone-treated type 2 diabetic patients. J Clin Endocrinol Metab 2004;89(1):200-206 View Article PubMed/NCBI
  80. Lin JH, Walter P, Yen TS. Endoplasmic reticulum stress in disease pathogenesis. Annu Rev Pathol 2008;3:399-425 View Article PubMed/NCBI
  81. Moslehi A, Nabavizadeh F, Zekri A, Amiri F. Naltrexone changes the expression of lipid metabolism-related proteins in the endoplasmic reticulum stress induced hepatic steatosis in mice. Clin Exp Pharmacol Physiol 2017;44(2):207-212 View Article PubMed/NCBI
  82. Moslehi A, Komeili-movahed T, Moslehi M. Antioxidant effects of amygdalin on tunicamycin-induced endoplasmic reticulum stress in the mice liver: Cross talk between endoplasmic reticulum stress and oxidative stress. J Rep Pharm Sci 2019;8(2):298-302 View Article PubMed/NCBI
  83. Ozcan L, Tabas I. Role of endoplasmic reticulum stress in metabolic disease and other disorders. Annu Rev Med 2012;63:317-328 View Article PubMed/NCBI
  84. Xu L, Zhang X, Tian Y, Fan Z, Li W, Liu M, et al. The critical role of PPARα in the binary switch between life and death induced by endoplasmic reticulum stress. Cell Death Dis 2020;11(8):691 View Article PubMed/NCBI
  85. van der Krieken SE, Popeijus HE, Mensink RP, Plat J. Link Between ER-Stress, PPAR-Alpha Activation, and BET Inhibition in Relation to Apolipoprotein A-I Transcription in HepG2 Cells. J Cell Biochem 2017;118(8):2161-2167 View Article PubMed/NCBI
  86. Zarei M, Barroso E, Palomer X, Dai J, Rada P, Quesada-López T, et al. Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease. Mol Metab 2018;8:117-131 View Article PubMed/NCBI
  87. Jeong JW, Lee B, Kim DH, Jeong HO, Moon KM, Kim MJ, et al. Mechanism of Action of Magnesium Lithospermate B against Aging and Obesity-Induced ER Stress, Insulin Resistance, and Inflammsome Formation in the Liver. Molecules 2018;23(9):2098 View Article PubMed/NCBI
  88. Lee AH, Glimcher LH. Intersection of the unfolded protein response and hepatic lipid metabolism. Cell Mol Life Sci 2009;66(17):2835-2850 View Article PubMed/NCBI
  89. Ma J, Zeng P, Liu L, Zhu M, Zheng J, Wang C, et al. Peroxisome Proliferator-Activated Receptor-Gamma Reduces ER Stress and Inflammation via Targeting NGBR Expression. Front Pharmacol 2021;12:817784 View Article PubMed/NCBI
  90. Ge J, Miao JJ, Sun XY, Yu JY. Huangkui capsule, an extract from Abelmoschus manihot (L.) medic, improves diabetic nephropathy via activating peroxisome proliferator-activated receptor (PPAR)-α/γ and attenuating endoplasmic reticulum stress in rats. J Ethnopharmacol 2016;189:238-249 View Article PubMed/NCBI
  91. Park MH, Kim DH, Kim MJ, Lee EK, An HJ, Jeong JW, et al. Effects of MHY908, a New Synthetic PPARα/γ Dual Agonist, on Inflammatory Responses and Insulin Resistance in Aged Rats. J Gerontol A Biol Sci Med Sci 2016;71(3):300-309 View Article PubMed/NCBI
  92. Odenwald MA, Paul S. Viral hepatitis: Past, present, and future. World J Gastroenterol 2022;28(14):1405-1429 View Article PubMed/NCBI
  93. Castaneda D, Gonzalez AJ, Alomari M, Tandon K, Zervos XB. From hepatitis A to E: A critical review of viral hepatitis. World J Gastroenterol 2021;27(16):1691-1715 View Article PubMed/NCBI
  94. Wakui Y, Inoue J, Ueno Y, Fukushima K, Kondo Y, Kakazu E, et al. Inhibitory effect on hepatitis B virus in vitro by a peroxisome proliferator-activated receptor-gamma ligand, rosiglitazone. Biochem Biophys Res Commun 2010;396(2):508-514 View Article PubMed/NCBI
  95. Du L, Ma Y, Liu M, Yan L, Tang H. Peroxisome Proliferators Activated Receptor (PPAR) agonists activate hepatitis B virus replication in vivo. Virol J 2017;14(1):96 View Article PubMed/NCBI
  96. Wu YL, Peng XE, Zhu YB, Yan XL, Chen WN, Lin X. Hepatitis B Virus X Protein Induces Hepatic Steatosis by Enhancing the Expression of Liver Fatty Acid Binding Protein. J Virol 2016;90(4):1729-1740 View Article PubMed/NCBI
  97. Paumelle R, Haas JT, Hennuyer N, Baugé E, Deleye Y, Mesotten D, et al. Hepatic PPARα is critical in the metabolic adaptation to sepsis. J Hepatol 2019;70(5):963-973 View Article PubMed/NCBI
  98. Huen SC, Wang A, Feola K, Desrouleaux R, Luan HH, Hogg R, et al. Hepatic FGF21 preserves thermoregulation and cardiovascular function during bacterial inflammation. J Exp Med 2021;218(10):e20202151 View Article PubMed/NCBI
  99. Wang A, Huen SC, Luan HH, Yu S, Zhang C, Gallezot JD, et al. Opposing Effects of Fasting Metabolism on Tissue Tolerance in Bacterial and Viral Inflammation. Cell 2016;166(6):1512-1525.e12 View Article PubMed/NCBI
  100. Eslam M, Khattab MA, Harrison SA. Peroxisome proliferator-activated receptors and hepatitis C virus. Therap Adv Gastroenterol 2011;4(6):419-431 View Article PubMed/NCBI
  101. Shores NJ, Mendes-Corrêa MC, Maida I, Turner J, High KP, Babudieri S, et al. Hepatic peroxisome proliferator-activated receptor γ and α-mRNA expression in HCV-infected adults is decreased by HIV co-infection and is also affected by ethnicity. Clinics (Sao Paulo) 2015;70(12):790-796 View Article PubMed/NCBI
  102. Dharancy S, Lemoine M, Mathurin P, Serfaty L, Dubuquoy L. Peroxisome proliferator-activated receptors in HCV-related infection. PPAR Res 2009;2009:357204 View Article PubMed/NCBI
  103. Akbari R, Behdarvand T, Afarin R, Yaghooti H, Jalali MT, Mohammadtaghvaei N. Saroglitazar improved hepatic steatosis and fibrosis by modulating inflammatory cytokines and adiponectin in an animal model of non-alcoholic steatohepatitis. BMC Pharmacol Toxicol 2021;22(1):53 View Article PubMed/NCBI
  104. Pazienza V, Vinciguerra M, Andriulli A, Mangia A. Hepatitis C virus core protein genotype 3a increases SOCS-7 expression through PPAR-{gamma} in Huh-7 cells. J Gen Virol 2010;91(Pt 7):1678-1686 View Article PubMed/NCBI
  105. Sumanasekera WK, Tien ES, Turpey R, Vanden Heuvel JP, Perdew GH. Evidence that peroxisome proliferator-activated receptor alpha is complexed with the 90-kDa heat shock protein and the hepatitis virus B X-associated protein 2. J Biol Chem 2003;278(7):4467-4473 View Article PubMed/NCBI
  106. Xi Y, Zhang Y, Zhu S, Luo Y, Xu P, Huang Z. PPAR-Mediated Toxicology and Applied Pharmacology. Cells 2020;9(2):352 View Article PubMed/NCBI
  107. Jiao M, Ren F, Zhou L, Zhang X, Zhang L, Wen T, et al. Peroxisome proliferator-activated receptor α activation attenuates the inflammatory response to protect the liver from acute failure by promoting the autophagy pathway. Cell Death Dis 2014;5(8):e1397 View Article PubMed/NCBI
  108. Mehendale HM. PPAR-alpha: a key to the mechanism of hepatoprotection by clofibrate. Toxicol Sci 2000;57(2):187-190 View Article PubMed/NCBI
  109. Chen C, Hennig GE, Whiteley HE, Corton JC, Manautou JE. Peroxisome proliferator-activated receptor alpha-null mice lack resistance to acetaminophen hepatotoxicity following clofibrate exposure. Toxicol Sci 2000;57(2):338-344 View Article PubMed/NCBI
  110. Li D, Du Y, Yuan X, Han X, Dong Z, Chen X, et al. Hepatic hypoxia-inducible factors inhibit PPARα expression to exacerbate acetaminophen induced oxidative stress and hepatotoxicity. Free Radic Biol Med 2017;110:102-116 View Article PubMed/NCBI
  111. Peraza MA, Burdick AD, Marin HE, Gonzalez FJ, Peters JM. The toxicology of ligands for peroxisome proliferator-activated receptors (PPAR). Toxicol Sci 2006;90(2):269-295 View Article PubMed/NCBI
  112. Ernst MC, Sinal CJ, Pollak PT. Influence of peroxisome proliferator-activated receptor-alpha (PPARα) activity on adverse effects associated with amiodarone exposure in mice. Pharmacol Res 2010;62(5):408-415 View Article PubMed/NCBI
  113. Sun J, Bian Y, Ma Y, Ali W, Wang T, Yuan Y, et al. Melatonin alleviates cadmium-induced nonalcoholic fatty liver disease in ducks by alleviating autophagic flow arrest via PPAR-α and reducing oxidative stress. Poult Sci 2023;102(8):102835 View Article PubMed/NCBI
  114. Lloyd S, Hayden MJ, Sakai Y, Fackett A, Silber PM, Hewitt NJ, et al. Differential in vitro hepatotoxicity of troglitazone and rosiglitazone among cryopreserved human hepatocytes from 37 donors. Chem Biol Interact 2002;142(1-2):57-71 View Article PubMed/NCBI
  115. Hellemans K, Michalik L, Dittie A, Knorr A, Rombouts K, De Jong J, et al. Peroxisome proliferator-activated receptor-beta signaling contributes to enhanced proliferation of hepatic stellate cells. Gastroenterology 2003;124(1):184-201 View Article PubMed/NCBI
  116. Xu M, Li Y, Wang X, Zhang Q, Wang L, Zhang X, et al. Role of Hepatocyte- and Macrophage-Specific PPARγ in Hepatotoxicity Induced by Diethylhexyl Phthalate in Mice. Environ Health Perspect 2022;130(1):17005 View Article PubMed/NCBI
  117. Wang Y, Nakajima T, Gonzalez FJ, Tanaka N. PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice. Int J Mol Sci 2020;21(6):2061 View Article PubMed/NCBI
  118. de Souza Basso B, Haute GV, Ortega-Ribera M, Luft C, Antunes GL, Bastos MS, et al. Methoxyeugenol deactivates hepatic stellate cells and attenuates liver fibrosis and inflammation through a PPAR-ɣ and NF-kB mechanism. J Ethnopharmacol 2021;280:114433 View Article PubMed/NCBI
  119. Sanderson LM, Boekschoten MV, Desvergne B, Müller M, Kersten S. Transcriptional profiling reveals divergent roles of PPARalpha and PPARbeta/delta in regulation of gene expression in mouse liver. Physiol Genomics 2010;41(1):42-52 View Article PubMed/NCBI
  120. Chidambaranathan-Reghupaty S, Fisher PB, Sarkar D. Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification. Adv Cancer Res 2021;149:1-61 View Article PubMed/NCBI
  121. Park JH, Kim JH. Pathologic differential diagnosis of metastatic carcinoma in the liver. Clin Mol Hepatol 2019;25(1):12-20 View Article PubMed/NCBI
  122. Pinter M, Trauner M, Peck-Radosavljevic M, Sieghart W. Cancer and liver cirrhosis: implications on prognosis and management. ESMO Open 2016;1(2):e000042 View Article PubMed/NCBI
  123. Kimura O, Kondo Y, Shimosegawa T. PPAR Could Contribute to the Pathogenesis of Hepatocellular Carcinoma. PPAR Res 2012;2012:574180 View Article PubMed/NCBI
  124. Xiao YB, Cai SH, Liu LL, Yang X, Yun JP. Decreased expression of peroxisome proliferator-activated receptor alpha indicates unfavorable outcomes in hepatocellular carcinoma. Cancer Manag Res 2018;10:1781-1789 View Article PubMed/NCBI
  125. Reddy JK, Rao S, Moody DE. Hepatocellular carcinomas in acatalasemic mice treated with nafenopin, a hypolipidemic peroxisome proliferator. Cancer Res 1976;36(4):1211-1217 View Article PubMed/NCBI
  126. Tanaka N, Moriya K, Kiyosawa K, Koike K, Gonzalez FJ, Aoyama T. PPARalpha activation is essential for HCV core protein-induced hepatic steatosis and hepatocellular carcinoma in mice. J Clin Invest 2008;118(2):683-694 View Article PubMed/NCBI
  127. Vacca M, D’Amore S, Graziano G, D’Orazio A, Cariello M, Massafra V, et al. Clustering nuclear receptors in liver regeneration identifies candidate modulators of hepatocyte proliferation and hepatocarcinoma. PLoS One 2014;9(8):e104449 View Article PubMed/NCBI
  128. Kim MJ, Choi YK, Park SY, Jang SY, Lee JY, Ham HJ, et al. PPARδ Reprograms Glutamine Metabolism in Sorafenib-Resistant HCC. Mol Cancer Res 2017;15(9):1230-1242 View Article PubMed/NCBI
  129. Yu J, Shen B, Chu ES, Teoh N, Cheung KF, Wu CW, et al. Inhibitory role of peroxisome proliferator-activated receptor gamma in hepatocarcinogenesis in mice and in vitro. Hepatology 2010;51(6):2008-2019 View Article PubMed/NCBI
  130. Zuo Q, He J, Zhang S, Wang H, Jin G, Jin H, et al. PPARγ Coactivator-1α Suppresses Metastasis of Hepatocellular Carcinoma by Inhibiting Warburg Effect by PPARγ-Dependent WNT/β-Catenin/Pyruvate Dehydrogenase Kinase Isozyme 1 Axis. Hepatology 2021;73(2):644-660 View Article PubMed/NCBI
  131. Zhou X, Chi Y, Dong Z, Tao T, Zhang X, Pan W, et al. A nomogram combining PPARγ expression profiles and clinical factors predicts survival in patients with hepatocellular carcinoma. Oncol Lett 2021;21(4):319 View Article PubMed/NCBI
  132. Xiong Z, Chan SL, Zhou J, Vong JSL, Kwong TT, Zeng X, et al. Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma. Gut 2023;72(9):1758-1773 View Article PubMed/NCBI
  133. Feng J, Dai W, Mao Y, Wu L, Li J, Chen K, et al. Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis. J Exp Clin Cancer Res 2020;39(1):24 View Article PubMed/NCBI
  134. Saber S, Khodir AE, Soliman WE, Salama MM, Abdo WS, Elsaeed B, et al. Telmisartan attenuates N-nitrosodiethylamine-induced hepatocellular carcinoma in mice by modulating the NF-κB-TAK1-ERK1/2 axis in the context of PPARγ agonistic activity. Naunyn Schmiedebergs Arch Pharmacol 2019;392(12):1591-1604 View Article PubMed/NCBI
  135. Abd-Elbaset M, Mansour AM, Ahmed OM, Abo-Youssef AM. The potential chemotherapeutic effect of β-ionone and/or sorafenib against hepatocellular carcinoma via its antioxidant effect, PPAR-γ, FOXO-1, Ki-67, Bax, and Bcl-2 signaling pathways. Naunyn Schmiedebergs Arch Pharmacol 2020;393(9):1611-1624 View Article PubMed/NCBI
  136. Ye X, Zhang T, Han H. PPARα: A potential therapeutic target of cholestasis. Front Pharmacol 2022;13:916866 View Article PubMed/NCBI
  137. Yu L, Liu Y, Wang S, Zhang Q, Zhao J, Zhang H, et al. Cholestasis: exploring the triangular relationship of gut microbiota-bile acid-cholestasis and the potential probiotic strategies. Gut Microbes 2023;15(1):2181930 View Article PubMed/NCBI
  138. Li F, Patterson AD, Krausz KW, Tanaka N, Gonzalez FJ. Metabolomics reveals an essential role for peroxisome proliferator-activated receptor α in bile acid homeostasis. J Lipid Res 2012;53(8):1625-1635 View Article PubMed/NCBI
  139. Zhao Q, Yang R, Wang J, Hu DD, Li F. PPARα activation protects against cholestatic liver injury. Sci Rep 2017;7(1):9967 View Article PubMed/NCBI
  140. Dai M, Yang J, Xie M, Lin J, Luo M, Hua H, et al. Inhibition of JNK signalling mediates PPARα-dependent protection against intrahepatic cholestasis by fenofibrate. Br J Pharmacol 2017;174(18):3000-3017 View Article PubMed/NCBI
  141. Yang S, Wei L, Xia R, Liu L, Chen Y, Zhang W, et al. Formononetin ameliorates cholestasis by regulating hepatic SIRT1 and PPARα. Biochem Biophys Res Commun 2019;512(4):770-778 View Article PubMed/NCBI
  142. Sun N, Shen C, Zhang L, Wu X, Yu Y, Yang X, et al. Hepatic Krüppel-like factor 16 (KLF16) targets PPARα to improve steatohepatitis and insulin resistance. Gut 2021;70(11):2183-2195 View Article PubMed/NCBI
  143. Xiang J, Yang G, Ma C, Wei L, Wu H, Zhang W, et al. Tectorigenin alleviates intrahepatic cholestasis by inhibiting hepatic inflammation and bile accumulation via activation of PPARγ. Br J Pharmacol 2021;178(12):2443-2460 View Article PubMed/NCBI
  144. Ma C, Xia R, Yang S, Liu L, Zhang J, Feng K, et al. Formononetin attenuates atherosclerosis via regulating interaction between KLF4 and SRA in apoE(-/-) mice. Theranostics 2020;10(3):1090-1106 View Article PubMed/NCBI
  145. Zhang Y, Huang X, Zhou J, Yin Y, Zhang T, Chen D. PPARγ provides anti-inflammatory and protective effects in intrahepatic cholestasis of pregnancy through NF-κB pathway. Biochem Biophys Res Commun 2018;504(4):834-842 View Article PubMed/NCBI
  146. Cursio R, Colosetti P, Gugenheim J. Autophagy and liver ischemia-reperfusion injury. Biomed Res Int 2015;2015:417590 View Article PubMed/NCBI
  147. Wang W, Wu L, Li J, Ji J, Chen K, Yu Q, et al. Alleviation of Hepatic Ischemia Reperfusion Injury by Oleanolic Acid Pretreating via Reducing HMGB1 Release and Inhibiting Apoptosis and Autophagy. Mediators Inflamm 2019;2019:3240713 View Article PubMed/NCBI
  148. Perry BC, Soltys D, Toledo AH, Toledo-Pereyra LH. Tumor necrosis factor-α in liver ischemia/reperfusion injury. J Invest Surg 2011;24(4):178-188 View Article PubMed/NCBI
  149. Wang C, Li Z, Zhao B, Wu Y, Fu Y, Kang K, et al. PGC-1α Protects against Hepatic Ischemia Reperfusion Injury by Activating PPARα and PPARγ and Regulating ROS Production. Oxid Med Cell Longev 2021;2021:6677955 View Article PubMed/NCBI
  150. Demir EA, Tutuk O, Dogan-Gocmen H, Ozyilmaz DS, Karagul MI, Kara M, et al. CREB1 and PPAR-α/γ Pathways in Hepatic Ischemia/Reperfusion: Route for Curcumin to Hepatoprotection. Iran J Pharm Res 2022;21(1):e133779 View Article PubMed/NCBI
  151. Hong F, Pan S, Guo Y, Xu P, Zhai Y. PPARs as Nuclear Receptors for Nutrient and Energy Metabolism. Molecules 2019;24(14):2545 View Article PubMed/NCBI
  152. Gao Z, Li YH. Antioxidant Stress and Anti-Inflammation of PPARα on Warm Hepatic Ischemia-Reperfusion Injury. PPAR Res 2012;2012:738785 View Article PubMed/NCBI
  153. Massip-Salcedo M, Zaouali MA, Padrissa-Altés S, Casillas-Ramirez A, Rodés J, Roselló-Catafau J, et al. Activation of peroxisome proliferator-activated receptor-alpha inhibits the injurious effects of adiponectin in rat steatotic liver undergoing ischemia-reperfusion. Hepatology 2008;47(2):461-472 View Article PubMed/NCBI
  154. Zúñiga J, Cancino M, Medina F, Varela P, Vargas R, Tapia G, et al. N-3 PUFA supplementation triggers PPAR-α activation and PPAR-α/NF-κB interaction: anti-inflammatory implications in liver ischemia-reperfusion injury. PLoS One 2011;6(12):e28502 View Article PubMed/NCBI
  155. Liu X, Zhang P, Song X, Cui H, Shen W. PPARγ Mediates Protective Effect against Hepatic Ischemia/Reperfusion Injury via NF-κB Pathway. J Invest Surg 2022;35(8):1648-1659 View Article PubMed/NCBI
  156. Huang R, Zhang C, Wang X, Hu H. PPARγ in Ischemia-Reperfusion Injury: Overview of the Biology and Therapy. Front Pharmacol 2021;12:600618 View Article PubMed/NCBI
  157. Wu L, Yu Q, Cheng P, Guo C. PPARγ Plays an Important Role in Acute Hepatic Ischemia-Reperfusion Injury via AMPK/mTOR Pathway. PPAR Res 2021;2021:6626295 View Article PubMed/NCBI
  158. Linares I, Farrokhi K, Echeverri J, Kaths JM, Kollmann D, Hamar M, et al. PPAR-gamma activation is associated with reduced liver ischemia-reperfusion injury and altered tissue-resident macrophages polarization in a mouse model. PLoS One 2018;13(4):e0195212 View Article PubMed/NCBI
  159. Nakajima A, Eguchi Y, Yoneda M, Imajo K, Tamaki N, Suganami H, et al. Randomised clinical trial: Pemafibrate, a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), versus placebo in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2021;54(10):1263-1277 View Article PubMed/NCBI
  160. Yamashita S, Rizzo M, Su TC, Masuda D. Novel Selective PPARα Modulator Pemafibrate for Dyslipidemia, Nonalcoholic Fatty Liver Disease (NAFLD), and Atherosclerosis. Metabolites 2023;13(5):626 View Article PubMed/NCBI
  161. Yamashita S, Masuda D, Matsuzawa Y. Pemafibrate, a New Selective PPARα Modulator: Drug Concept and Its Clinical Applications for Dyslipidemia and Metabolic Diseases. Curr Atheroscler Rep 2020;22(1):5 View Article PubMed/NCBI
  162. Yamashita S, Masuda D, Matsuzawa Y. Clinical Applications of a Novel Selective PPARα Modulator, Pemafibrate, in Dyslipidemia and Metabolic Diseases. J Atheroscler Thromb 2019;26(5):389-402 View Article PubMed/NCBI
  163. Jun M, Foote C, Lv J, Neal B, Patel A, Nicholls SJ, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010;375(9729):1875-1884 View Article PubMed/NCBI
  164. Reyes-Soffer G, Rondon-Clavo C, Ginsberg HN. Combination therapy with statin and fibrate in patients with dyslipidemia associated with insulin resistance, metabolic syndrome and type 2 diabetes mellitus. Expert Opin Pharmacother 2011;12(9):1429-1438 View Article PubMed/NCBI
  165. Saha SA, Arora RR. Hyperlipidaemia and cardiovascular disease: do fibrates have a role?. Curr Opin Lipidol 2011;22(4):270-276 View Article PubMed/NCBI
  166. Fernández-Miranda C, Pérez-Carreras M, Colina F, López-Alonso G, Vargas C, Solís-Herruzo JA. A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease. Dig Liver Dis 2008;40(3):200-205 View Article PubMed/NCBI
  167. Bays HE, Schwartz S, Littlejohn T, Kerzner B, Krauss RM, Karpf DB, et al. MBX-8025, a novel peroxisome proliferator receptor-delta agonist: lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin. J Clin Endocrinol Metab 2011;96(9):2889-2897 View Article PubMed/NCBI
  168. Aguilar-Recarte D, Palomer X, Wahli W, Vázquez-Carrera M. The PPARβ/δ-AMPK Connection in the Treatment of Insulin Resistance. Int J Mol Sci 2021;22(16):8555 View Article PubMed/NCBI
  169. Lee WH, Kim SG. AMPK-Dependent Metabolic Regulation by PPAR Agonists. PPAR Res 2010;2010:549101 View Article PubMed/NCBI
  170. Chiarelli F, Di Marzio D. Peroxisome proliferator-activated receptor-gamma agonists and diabetes: current evidence and future perspectives. Vasc Health Risk Manag 2008;4(2):297-304 View Article PubMed/NCBI
  171. Chang E, Park CY, Park SW. Role of thiazolidinediones, insulin sensitizers, in non-alcoholic fatty liver disease. J Diabetes Investig 2013;4(6):517-524 View Article PubMed/NCBI
  172. Arnold SV, Inzucchi SE, Echouffo-Tcheugui JB, Tang F, Lam CSP, Sperling LS, et al. Understanding Contemporary Use of Thiazolidinediones. Circ Heart Fail 2019;12(6):e005855 View Article PubMed/NCBI
  173. Neuschwander-Tetri BA, Isley WL, Oki JC, Ramrakhiani S, Quiason SG, Phillips NJ, et al. Troglitazone-induced hepatic failure leading to liver transplantation. A case report. Ann Intern Med 1998;129(1):38-41 View Article PubMed/NCBI
  174. Li H, Heller DS, Leevy CB, Zierer KG, Klein KM. Troglitazone-induced fulminant hepatitis: report of a case with autopsy findings. J Diabetes Complications 2000;14(3):175-177 View Article PubMed/NCBI
  175. Cheng-Lai A, Levine A. Rosiglitazone: an agent from the thiazolidinedione class for the treatment of type 2 diabetes. Heart Dis 2000;2(4):326-333 View Article PubMed/NCBI
  176. Liao X, Wang Y, Wong CW. Troglitazone induces cytotoxicity in part by promoting the degradation of peroxisome proliferator-activated receptor γ co-activator-1α protein. Br J Pharmacol 2010;161(4):771-781 View Article PubMed/NCBI
  177. Graham DJ, Green L, Senior JR, Nourjah P. Troglitazone-induced liver failure: a case study. Am J Med 2003;114(4):299-306 View Article PubMed/NCBI
  178. Ndakotsu A, Vivekanandan G. The Role of Thiazolidinediones in the Amelioration of Nonalcoholic Fatty Liver Disease: A Systematic Review. Cureus 2022;14(5):e25380 View Article PubMed/NCBI
  179. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 1995;270(22):12953-12956 View Article PubMed/NCBI
  180. Lebovitz HE, Kreider M, Freed MI. Evaluation of liver function in type 2 diabetic patients during clinical trials: evidence that rosiglitazone does not cause hepatic dysfunction. Diabetes Care 2002;25(5):815-821 View Article PubMed/NCBI
  181. Kaupang Å, Paulsen SM, Steindal CC, Ravna AW, Sylte I, Halvorsen TG, et al. Synthesis, biological evaluation and molecular modeling studies of the PPARβ/δ antagonist CC618. Eur J Med Chem 2015;94:229-236 View Article PubMed/NCBI

Copyright © 2022 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819

Download PDF

Metrics

Article accesses:
1909

Citation

Order Reprints
  • Copyright © 2022 JCTH. All Rights Reserved.
  • Published by Xia & He Publishing Inc.
  • Address: 14090 Southwest Freeway, Suite 300, Sugar Land, Texas 77478, USA
  • Email: service@xiahepublishing.com