Benefit of farnesoid X receptor inhibition in obstructive cholestasis

Abstract

The nuclear hormone receptors farnesoid X receptor (FXR) and pregnane X receptor have been implicated in regulating bile acid, lipid, carbohydrate, and xenobiotic metabolism. Bile duct ligation was used to increase endogenous bile acids and evaluate the roles of these receptors in modulating cholestatic liver injury. FXR knockout (KO) mice were found to be protected from obstructive cholestasis. Concurrent deletion of FXR also could ameliorate an increase in liver injury that is seen usually in pregnane X receptor KO mice with cholestasis. Mechanisms proposed for this protection include the lowering of bile acid concentrations and altered expression of the hepatic transporters Mdr1, Mdr2, BSEP, and Mrp4. FXR KO mice also exhibit a biphasic lipid profile after bile duct ligation, with an increase in high-density lipoprotein cholesterol and triglycerides by day 6. The expression of apolipoprotein AV was reduced in these mice, implicating FXR in triglyceride regulation. We show that FXR modulates cholestasis by controlling bile acids within the hepatocyte and is involved in bile acid synthesis, bile excretion via BSEP, and serum export via Mrp4. This study strongly suggests a potential clinical role for FXR antagonists in the treatment of obstructive cholestatic liver disorders.bile acids ͉ Mrp4 ͉ pregnane X receptor ͉ apolipoprotein AV ͉ triglycerides C holestatic liver disorders include a spectrum of hepatobiliary diseases of diverse etiologies that are characterized by impaired hepatocellular secretion of bile, resulting in accumulation of bile acids, bilirubin, and cholesterol. Pharmacological therapy for cholestasis is limited, and ursodeoxycholic acid (UDCA) is the only disease-modifying therapy with evidence of efficacy, so new therapeutic approaches are essential.Farnesoid X receptor (FXR) (NR1H4) and pregnane X receptor (PXR) (NR1I2) are nuclear hormone receptors that function as ligand-activated transcription factors. FXR is known to regulate genes involved in lipid and lipoprotein metabolism, including apolipoprotein (apo) AI, apoCII, very low-density lipoprotein (VLDL) receptor, PPAR␣, and the phospholipid transfer protein (1, 2), but the role of FXR in lipid homeostasis remains to be clarified. Other FXR targets include genes involved in bile acid synthesis such as cytochrome P450 7A1 (CYP7A1) and CYP8B1, and bile acid transporters including bile salt export pump (BSEP; ABCB11), sodium-taurocholate cotransporting polypeptide (NTCP; SLC10A1), and intestinal bile acid-binding protein (1, 3). PXR also regulates genes involved in bile acid synthesis, metabolism, and transport, including CYP7A1, CYP3A, sulfotransferase, and Na ϩ -dependent organic anion transporter 2 (Oatp2; Slc21a6) (4, 5).Bile acids are the end products of hepatic cholesterol metabolism, which also act as signaling molecules that regulate their own synthesis and metabolism and other metabolic pathways, via nuclear receptors (1). Bile acids are ligands for both PXR and FXR, with affinities differing for individual bile acids (6, 7). It has...

Loss of orphan receptor small heterodimer partner sensitizes mice to liver injury from obstructive cholestasis

“…At 2 days after surgery, mortality of the WT mice (16%) was comparable to that of previous reports (for example, Stedman et al 14 ), whereas that of the Shp Ϫ/Ϫ mice was approximately 2-fold higher (33%) ( Table 2). Histologic examination of the livers of Shp Ϫ/Ϫ mice showed extensive areas of bile infarcts, indicating severe liver injury, which were not observed in WT livers ( Fig.…”

“…12 To further investigate the role of SHP in bile acid homeostasis, we examined the response of C57BL/6 and congenic C57BL/6 Shp Ϫ/Ϫ mice to acute cholestasis induced by ligation of the common bile duct. In contrast to recent results demonstrating relative resistance of Fxr Ϫ/Ϫ mice to bile duct ligation (BDL), 13,14 the Shp Ϫ/Ϫ mice showed increased sensitivity, which was associated with increased bile acid levels and acute liver damage at very early times after BDL.…”

“…The increased sensitivity of the Shp Ϫ/Ϫ mice to BDL provides a dramatic contrast with the decreased sensitivity of Fxr Ϫ/Ϫ mice, 13,14 which seems paradoxical on the basis of the coordinate function of the two receptors in negative regulation of bile acid production. At later times after BDL, the decreased sensitivity of the Fxr Ϫ/Ϫ mice has been linked to increased detoxification of bile acids within hepatocytes and also increased transport into the blood and clearance by the kidneys.…”

“…30 This decreased pressure can neatly account for the reduction in bile infarcts and liver damage in the Fxr Ϫ/Ϫ mice. 14,30 More generally, we note that both the predicted and observed effects of loss of the transactivator FXR or the repressor SHP are similar for negative targets but opposite for positive targets. Thus, Cyp7A1 expression increases in basal circumstances in both cases, as expected.…”

Resveratrol effectively attenuates α-naphthyl-isothiocyanate-induced acute cholestasis and liver injury through choleretic and anti-inflammatory mechanisms

“…These compensatory processes provide a suitable window for the treatment of cholestasis. A number of alternative drugs are currently being tested in pre-clinical studies as potential treatments for cholestatic disease, including selective modulators of nuclear receptors and signaling pathways that are thought to mediate cholestasis [8,9] . Resveratrol (3,5,4'-trans-trihydroxystilbene), a polyphenol phytoalexin abundantly found in grape skins and wine, possesses diverse biochemical and physiological actions.…”