Cholestasis, including primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), results from an impairment or disruption of bile production and causes intracellular retention of toxic bile constituents, including bile salts. If left untreated, cholestasis leads to liver fibrosis and cirrhosis, which eventually results in liver failure and the need for liver transplantation. Currently, the only therapeutic option available for these patients is ursodeoxycholic acid (UDCA), which slows the progression of PBC, particularly in stage I and II of the disease. However some patients have an incomplete response to UDCA therapy, while other more advanced cases often remain unresponsive. For PSC, UDCA therapy does not improve survival, and recommendations for its use remains controversial. These considerations emphasize the need for alternative therapies. Hepatic transporters, located along basolateral (sinusoidal) and apical (canalicular) membranes of hepatocytes, are integral determinants of bile formation and secretion. Nuclear receptors are critically involved in the regulation of these hepatic transporters and are natural targets for therapy of cholestatic liver diseases. One of these nuclear receptors is peroxisome proliferator-activated receptor alpha (PPARα) which plays a central role in maintaining cholesterol, lipid and bile acid homeostasis by regulating genes responsible for bile acid synthesis, and transport in humans, including Cytochrome P450 (CYP) isoform 7A1 (CYP7A1), CYP27A1, CYP8B1, UGT1A1, 1A3, 1A4, 1A6, SULT2A1, MDR3, and ASBT. The expression of many of these genes is altered in cholestatic liver diseases but few have been extensively studied or had the mechanism of PPARα effect identified. In this review we examine what is known about these mechanisms and consider the rationale for the use of PPARα ligand therapy in various cholestatic liver disorders.

Multidrug resistance transporter 3/ATP-binding cassette protein subfamily B4 (MDR3/ABCB4) is a critical determinant of biliary phosphatidylcholine (PC) secretion. Clinically, mutations and partial deficiencies in MDR3 result in cholestatic liver injury. Thus, MDR3 is a potential therapeutic target for cholestatic liver disease. Fenofibrate is a peroxisome proliferator-activated receptor (PPAR) α ligand that has antiinflammatory actions and regulates bile acid detoxification. Here we examined the mechanism by which fenofibrate regulates MDR3 gene expression. Fenofibrate significantly up-regulated MDR3 messenger RNA (mRNA) and protein expression in primary cultured human hepatocytes, and stimulated MDR3 promoter activity in HepG2 cells. In silico analysis of 5′-upstream region of human MDR3 gene revealed a number of PPARα response elements (PPRE). Electrophoretic mobility shift (EMSA) and chromatin immunoprecipitation (ChIP) assays demonstrated specific binding of PPARα to the human MDR3 promoter. Targeted mutagenesis of three novel PPREs reduced inducibility of the MDR3 promoter by fenofibrate. In collagen sandwich cultured rat hepatocytes, treatment with fenofibrate increased secretion of fluorescent PC into bile canaliculi. Conclusion Fenofibrate transactivates MDR3 gene transcription by way of the binding of PPARα to three novel and functionally critical PPREs in the MDR3 promoter. Fenofibrate treatment further stimulates biliary phosphatidylcholine secretion in rat hepatocytes, thereby providing a functional correlate. We have established a molecular mechanism that may contribute to the beneficial use of fenofibrate therapy in human cholestatic liver disease.

Cholestatic liver diseases result in the hepatic retention of bile acids, causing subsequent liver toxicity. Peroxisome proliferator-activated receptor alpha (PPARα) regulates bile acid metabolism. In this retrospective observational study, we assessed the effects of fenofibrate (a PPARα agonist) therapy on bile acid metabolism when given to patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) who have had an incomplete response to Ursodiol monotherapy. When fenofibrate was added to Ursodiol therapy there was a significant reduction and in some cases normalization of serum alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase abnormalities, as well as pro-inflammatory cytokines. Combination fenofibrate treatment also reduced 7α-hydroxy-4cholesten-3-one (C4), the bile acid precursor, as well as total, primary, and conjugated bile acids. In addition, principal components analysis and heatmap analysis show that bile acid metabolites trended closer to that of healthy control subjects. These favorable effects of fenofibrate on bile acid metabolism may contribute to its beneficial clinical effects in patients with PBC and PSC experiencing a subtherapeutic response to Ursodiol monotherapy. Hepatic bile acid secretion and bile formation are essential functions of the mammalian liver. 1 Cholestatic liver diseases (i.e., primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC)), result from an impairment or disruption of bile flow that causes an intracellular accumulation of toxic bile constituents, notably bile acids. Although critical for intestinal absorption of dietary cholesterol, bile acids are inherently cytotoxic, and, when accumulating in the liver, lead to inflammation, fibrosis, cirrhosis, and

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