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, whereas other, more advanced cases often remain unresponsive. For PSC, UDCA
therapy does not improve survival, and recommendations for its use remain 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 (NRs) are critically involved in the regulation of these hepatic transporters and are natural targets for
therapy of cholestatic
liver diseases. One of these NRs 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,
uridine 5'-diphospho-glucuronosyltransferase 1A1, 1A3, 1A4, 1A6,
hydroxysteroid sulfotransferase enzyme 2A1,
multidrug resistance protein 3, and apical
sodium-dependent
bile salt transporter. 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, such as
fenofibrate, in various cholestatic liver disorders.