Peroxisome proliferator-activated receptor delta and liver diseases

Abstract

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in transcriptional regulation and play an important role in many physiological and metabolic processes. Unlike PPAR-alpha and PPAR-gamma, PPAR-delta is ubiquitously expressed, and its activity is key to maintaining proper metabolic homeostasis within the liver. PPAR-delta not only regulates physiologic processes of lipid, glucose, and bile acid metabolism but also attenuates pathologic responses to alcohol metabolism, inflammation, fibrosis, and carcinogenesis, and is considered an important therapeutic target in liver diseases. Promising results have been reported in clinical trials for PPAR-delta agonists in liver disease, and the selective agonist seladelpar was recently conditionally approved in the United States as a new treatment option for primary biliary cholangitis. This review provides an overview of PPAR-delta's function and biology in the liver, examines its kinetics and therapeutic potential across different liver diseases, and discusses the current status of clinical trials involving its agonists.

FIGURE 1

Major functions of PPARD in the liver. (A) PPARD regulates various metabolic pathways by modulating its downstream genes in the liver. It is also thought to have diverse functions, including anti-inflammatory, antifibrotic, and inhibiting cholestasis. (B) PPARD is ubiquitously expressed not only in the liver. In mouse liver, PPARD is highly expressed in cholangiocytes, HSCs, and LSECs compared with hepatocytes. On the other hand, PPARD is expressed at low levels in all human hepatic cells. Gender differences and diurnal variation in PPARD expression in the liver have been reported. Abbreviations: PPAR, peroxisome proliferator–activated receptor; PPRE, PPAR response element; RXR, retinoid X receptor.

FIGURE 2

Role of PPARD for the pathogenesis of liver diseases. (A) MASLD/MASH. Activation of PPARD improves energy consumption and insulin sensitivity, leading to weight loss and liver fat reduction. Autophagy is involved in this process. PPARD activation modulates circadian rhythms of hepatic metabolism and may represent a novel therapeutic approach for MASLD/MASH. Anti-inflammatory effects via reduction of inflammatory cytokines such as TNF and IL-1β and antifibrotic effects via reduction of TGF-β1 are also expected benefits. (B) PBC. Activation of PPARD inhibits bile acid synthesis and ameliorates cholestasis, which is a hallmark in patients with PBC. This inhibitory pathway depends on the induction of FGF21. In PBC, PDC-E2 released from apoptotic cholangiocytes is presented to immune cells, resulting in the production of anti-mitochondrial antibodies. PPARD is involved in promoting differentiation into anti-inflammatory macrophages, including KCs, and in suppressing polarization of type 1 and type 17 helper T cells. The detailed mechanism of improvement in pruritus and its direct effect on cholangiocytes is not yet known. (C) Alcohol-associated liver disease. PPARD regulates cytochrome P450 enzymes that play an important role in alcohol metabolism in the liver, reducing toxic acetaldehyde. In addition, amelioration of alcohol-induced insulin resistance and amelioration of steatosis through autophagy are potential therapeutic roles of PPARD in ALD. PPARD also contributes to decreased liver and serum bile acids, and improved intestinal barrier function in ALD. (D) HCC. The function of PPARD in HCC is still under discussion, with both tumor-promoting and tumor-suppressing effects reported. Abbreviations: AE2, anion exchanger 2; Cyp2e1, cytochrome P450 Family 2 Subfamily E Member 1; Cyp2b10, cytochrome P450 Family 2 Subfamily B Member 10; DLGAP4, DLG associated protein 4; FAO, fatty acid oxidation; GSK3β, glycogen synthase kinase-3β; IGF, insulin-like growth factor; IL, interleukin; PDC-E2, E2 components of pyruvate dehydrogenase complexes; PDK1, pyruvate dehydrogenase kinase 1; PPAR, peroxisome proliferator–activated receptor; SGK1, serum/glucocorticoid regulated kinase 1.