PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases

Abstract

Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs’ critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.

Lipid Metabolism Regulation Based on Nanotechnology for Enhancement of Tumor Immunity

“…Lipid-derived metabolites serve as the natural ligands of PPARs. The tissue distribution of PPAR subtypes and their endogenous ligands and target genes are summarized in a review by Monroy-Ramirez, et al ( Monroy-Ramirez et al, 2021 ). PPARα is a regulator of fatty acid metabolism and involved in substrate transport, substrate oxidation, and oxidative phosphorylation (OXPHOS); PPARδ plays a vital role in fatty acid oxidation and blood glucose regulation; PPARγ can facilitate energy storage by promoting adipogenesis and lipid synthesis in different cell and play a major role in adipocyte differentiation ( Christofides et al, 2021 ).…”

Therapeutic developments in metabolic dysfunction-associated fatty liver disease

“…Different isoforms of PPARs (PPARα, PPARβ/δ, and PPARγ) have different tissue distribution, affinity, and specificity for agonists. All isoforms participate in lipid homeostasis and glucose regulation [88] . Fibroblast growth factors (FGFs) are a large family involved in a myriad of biological functions, among which FGF19 and FGF21 participate in inter-organ endocrine signaling axes including bile acid, glucose, and lipid metabolism.…”

“…All isoforms participate in lipid homeostasis and glucose regulation. [88] Fibroblast growth factors (FGFs) are a large family involved in a myriad of biological functions, among which FGF19 and FGF21 participate in inter-organ endocrine signaling axes including bile acid, glucose, and lipid metabolism. Endocrine FGFs may serve as risk factors, biomarkers, or even treatment targets for MAFLD.…”

Fibrates for the Treatment of Primary Biliary Cholangitis Unresponsive to Ursodeoxycholic Acid: An Exploratory Study

“…PPARs are a family of ligand-dependent transcription factors composed of three subtypes PPARα, PPARβ/δ, and PPARγ with different functions, distributions, affinities, and specificities for their ligands. Each of them has distinct pleiotropic roles in the modulation of energy, lipid, cholesterol, and bile acid homeostasis ( Ghonem et al, 2015 ; Tanaka et al, 2017 ; Monroy–Ramirez et al, 2021 ). In this regard, it has been demonstrated that PPARα activation is capable of modulating bile acid metabolism due to activation of genes involved in bile acid synthesis and transportation.…”