PPARα: A potential therapeutic target of cholestasis

Abstract

The accumulation of bile acids in the liver leads to the development of cholestasis and hepatocyte injury. Nuclear receptors control the synthesis and transport of bile acids in the liver. Among them, the farnesoid X receptor (FXR) is the most common receptor studied in treating cholestasis. The activation of this receptor can reduce the amount of bile acid synthesis and decrease the bile acid content in the liver, alleviating cholestasis. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) have a FXR excitatory effect, but the unresponsiveness of some patients and the side effect of pruritus seriously affect the results of UDCA or OCA treatment. The activator of peroxisome proliferator-activated receptor alpha (PPARα) has emerged as a new target for controlling the synthesis and transport of bile acids during cholestasis. Moreover, the anti-inflammatory effect of PPARα can effectively reduce cholestatic liver injury, thereby improving patients’ physiological status. Here, we will focus on the function of PPARα and its involvement in the regulation of bile acid transport and metabolism. In addition, the anti-inflammatory effects of PPARα will be discussed in some detail. Finally, we will discuss the application of PPARα agonists for cholestatic liver disorders.

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

“…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.…”

“…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 .…”

“…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.…”

The role of peroxisome proliferator‐activated receptors in the regulation of bile acid metabolism

“…PPARα agonists have an important role in the regulation of bile acid homeostasis by affecting hepatic bile acid synthesis and excretion as well as the expression of genes related to bile acid metabolism in the intestine. 25 Statins and fibrates have emerged as major lipid-lowering drugs in clinical practice since the 1960s, and their molecular mechanism involves activating PPARα and modulating the expression of downstream proteins involved in lipid metabolism. [26][27][28] However, PPARα not only regulates lipid metabolism but also exerts a direct regulatory effect on genes involved in bile acid metabolism, such as Cyp7a1, Cyp8b1 and Asbt.…”

New IMB16-4 Hot-Melt Extrusion Preparation Improved Oral Bioavailability and Enhanced Anti-Cholestatic Effect on Rats

“…Activated PPARα inhibits the expression of CYP7A1, which is a crucial enzyme for the biosynthesis of bile acid. [12][13][14][15] As the typical drugs of PPARα agonists, Fibrates were commonly recommended for the treatment of cholestasis in clinic. [16][17][18] N-(3,4,5-trichlorophenyl)-2 (3-nitrobenzenesulfonamido) benzamide, also known as IMB16-4, was the sister compound of IMB17-15.…”