Nuclear receptors as drug targets in cholestatic liver diseases

Abstract

Cholestatic liver diseases encompass a wide spectrum of disorders with different causes, resulting in impaired bile flow and accumulation of bile acids and other potentially hepatotoxic cholephils. The understanding of the molecular mechanisms of bile formation and cholestasis has recently improved significantly through new insights into nuclear receptor (patho)biology. Nuclear receptors are ligand-activated transcription factors, which act as central players in the regulation of genes responsible for elimination and detoxification of biliary constituents accumulating in cholestasis. They also control other pathophysiologic processes such as inflammation, fibrogenesis, and carcinogenesis involved in the pathogenesis and disease progression of cholestasis liver diseases.

Fig. 1

Role of nuclear receptors in maintaining hepatobiliary homeostasis. Activation of nuclear receptors (NRs) in hepatocytes ensures the balance between BA synthesis and detoxification, uptake, and excretion via regulation of expression of key hepatobiliary transporters. A network of negative feed-back and positive feed-forward mechanisms controls the intracellular load of biliary constituents, which may be hepatotoxic when they accumulate. BA-activated FXR is a central player in this network and represses (via GR in humans) hepatic BA uptake (NTCP) and (via SHP) BA synthesis (CYP7A1), promotes bile secretion via induction of canalicular transporters (BSEP, MRP2, ABCG5/8, MDR3), and induces BA elimination via alternative export systems at the hepatocellular basolateral (sinusoidal) membrane (OSTα/β). Several NR pathways converge at the level of CYP7A1 as a rate-limiting enzyme in BA synthesis. CAR and PXR facilitate adaptation to increased intracellular BA concentrations by upregulation of alternative hepatic export routes (MRP3 and MRP4) and induction of detoxification enzymes. PPARα regulates phospholipid secretion (via MDR3), but is also involved in detoxification pathways. Stimulation of AE2 expression by GR stimulates biliary bicarbonate secretion, thus reducing bile toxicity. Apart from regulating BA homeostasis, NRs have additional anti-inflammatory and anti-fibrotic effects. Their activation may result in induction of defensive mechanisms in bile duct epithelial cells. Green arrows indicate stimulatory effects and red lines indicate suppressive effects on target genes. AE, anion exchanger; BAs, bile acids; Bili-glu, bilirubin glucuronide; BSEP, bile salt export pump; CAR, constitutive androstane receptor; CYP7A1, cholesterol-7α-hydroxylase, CYPs, cytochrome P450 enzymes; FGF, fibroblast growth factor; FXR, farnesoid X receptor; GR, glucocorticoid receptor; MDR3, multidrug resistance protein 3, phospholipid flippase; MRP2, multidrug resistance-associated protein 2; MRP3, multidrug resistance-associated protein 3; MRP4, multidrug resistance-associated protein 4; NTCP, sodium taurocholate cotransporting polypeptide; OSTα/β, organic solute transporter α and β; PC, phosphatidylcholine; PXR, pregnane X receptor; PPARα, peroxisome proliferator-activated receptor α; PPARγ, peroxisome proliferator-activated receptor γ; SHP, small heterodimer partner; SULTs, sulfatation enzymes; UGTs, glucuronidation enzymes; VDR, vitamin D receptor.