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

J Hepatol. 2015 Jun;62(6):1398-404. doi: 10.1016/j.jhep.2014.12.034. Epub 2015 Jan 21.


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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bile Acids and Salts / biosynthesis
  • Bile Acids and Salts / metabolism*
  • Humans
  • Intra-Abdominal Fat / drug effects
  • Intra-Abdominal Fat / metabolism
  • Lipid Metabolism / drug effects*
  • Liver / drug effects
  • Liver / metabolism
  • Non-alcoholic Fatty Liver Disease / drug therapy
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Obesity, Morbid / drug therapy*
  • Obesity, Morbid / metabolism*
  • Oleic Acid / metabolism
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Stearoyl-CoA Desaturase / biosynthesis
  • Ursodeoxycholic Acid / administration & dosage
  • Ursodeoxycholic Acid / pharmacology*


  • Bile Acids and Salts
  • Receptors, Cytoplasmic and Nuclear
  • farnesoid X-activated receptor
  • Oleic Acid
  • Ursodeoxycholic Acid
  • SCD1 protein, human
  • Stearoyl-CoA Desaturase