Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity

Abstract

Background & aims: Bile acids (BAs) are major regulators of hepatic BA and lipid metabolism but their mechanisms of action in non-alcoholic fatty liver disease (NAFLD) are still poorly understood. Here we aimed to explore the molecular and biochemical mechanisms of ursodeoxycholic acid (UDCA) in modulating the cross-talk between liver and visceral white adipose tissue (vWAT) regarding BA and cholesterol metabolism and fatty acid/lipid partitioning in morbidly obese NAFLD patients.

Methods: In this randomized controlled pharmacodynamic study, we analyzed serum, liver and vWAT samples from 40 well-matched morbidly obese patients receiving UDCA (20 mg/kg/day) or no treatment three weeks prior to bariatric surgery.

Results: Short term UDCA administration stimulated BA synthesis by reducing circulating fibroblast growth factor 19 and farnesoid X receptor (FXR) activation, resulting in cholesterol 7α-hydroxylase induction mirrored by elevated C4 and 7α-hydroxycholesterol. Enhanced BA formation depleted hepatic and LDL-cholesterol with subsequent activation of the key enzyme of cholesterol synthesis 3-hydroxy-3-methylglutaryl-CoA reductase. Blunted FXR anti-lipogenic effects induced lipogenic stearoyl-CoA desaturase (SCD) in the liver, thereby increasing hepatic triglyceride content. In addition, induced SCD activity in vWAT shifted vWAT lipid metabolism towards generation of less toxic and more lipogenic monounsaturated fatty acids such as oleic acid.

Conclusion: These data demonstrate that by exerting FXR-antagonistic effects, UDCA treatment in NAFLD patients strongly impacts on cholesterol and BA synthesis and induces neutral lipid accumulation in both liver and vWAT.

Keywords: 3-hydroxy-3-methylglutaryl-CoA reductase; FGF19; Lipogenesis; Non-alcoholic fatty liver disease; Stearoyl-CoA desaturase.

Graphical abstract

Fig. 1

UDCA alters key determinants of hepatic bile acid and cholesterol homeostasis. (A) mRNA analysis of bile acid biosynthesis markers. Controls: n = 18; UDCA: n = 19. (B) Representative Western blots of CYP7A1, FXR and densitometry (all samples) of protein levels relative to β-actin. Controls: n = 7; UDCA: n = 6. (C) ABCD-assay indicating FXR activity. Controls: n = 7; UDCA: n = 6. (D) mRNA analysis of cholesterol biosynthesis markers. Controls: n = 18; UDCA: n = 19. (E) Representative Western blots of HMGCR, phosphorylation status of HMGCR (HMGCRp), LDLR and densitometry (all samples). Controls: n = 7; UDCA: n = 6. Mean values ± SD are expressed for all data. ^∗p ⩽0.05, ^∗∗p ⩽0.01 vs. control group.

Fig. 2

UDCA increases hepatic triglyceride formation and modulates hepatic SCD expression. (A) Hepatic cholesterol and (B) triglyceride concentrations. (C) Hepatic mRNA expression analysis of markers of lipid metabolism in morbidly obese NAFLD patients. Control: n = 18; UDCA: n = 19. (D) Representative Western blot and densitometry (all samples) of hepatic SCD relative to β-actin. Control: n = 7; UDCA: n = 6. (E) mRNA expression of APOB and MTTP in NAFLD patients. Control: n = 18; UDCA: n = 19. Mean values ± SD are expressed for all data. ^∗p ⩽0.05, ^∗∗p ⩽0.01 vs. control group.

Fig. 3

UDCA induces triglyceride formation and lipogenic gene expression in visceral white adipose tissue (vWAT). (A) Measurement of cholesterol and (B) triglyceride content in vWAT. (C) Relative mRNA expression of markers of de novo lipogenesis and fatty acid (FA) transport in vWAT. (D) SCD activity calculated according to C16:1/C16:0 and C18:1/C18:0 concentrations in total and free FA obtained from lipid profiling. Control: n = 16; UDCA: n = 14. Mean values ± SD are expressed for all data. ^∗p ⩽0.05, ^∗∗p ⩽0.01, ^∗∗∗p ⩽0.001 vs. control group.

Fig. 4

Overview of UDCA mediated effects in morbid obesity. UDCA decreases intestinal FXR activation. Reduced circulating FGF19 levels induce CYP7A1 activity and BA formation. Compensation of stimulated cholesterol conversion into BAs is regulated via LDL-C import and cholesterol de novo biosynthesis. Elevated UDCA concentrations repress hepatic FXR activity, thereby decreasing FXR mediated anti-lipogenic effects resulting in induced SCD expression and TG accumulation. Hepatic TG-overload is secreted into the circulation and stored in vWAT. Delivered free FAs (FFA) are converted into OA in the total fatty acid (TFA) pool and TG formation occurs due to elevated SCD activity in vWAT. (This figure appears in colour on the web.)