Bile Acids Lower Triglyceride Levels via a Pathway Involving FXR, SHP, and SREBP-1c

J Clin Invest. 2004 May;113(10):1408-18. doi: 10.1172/JCI21025.

Abstract

We explored the effects of bile acids on triglyceride (TG) homeostasis using a combination of molecular, cellular, and animal models. Cholic acid (CA) prevents hepatic TG accumulation, VLDL secretion, and elevated serum TG in mouse models of hypertriglyceridemia. At the molecular level, CA decreases hepatic expression of SREBP-1c and its lipogenic target genes. Through the use of mouse mutants for the short heterodimer partner (SHP) and liver X receptor (LXR) alpha and beta, we demonstrate the critical dependence of the reduction of SREBP-1c expression by either natural or synthetic farnesoid X receptor (FXR) agonists on both SHP and LXR alpha and LXR beta. These results suggest that strategies aimed at increasing FXR activity and the repressive effects of SHP should be explored to correct hypertriglyceridemia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Cell Line
  • Cholic Acid / pharmacology*
  • DNA / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression / drug effects
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mice, Obese
  • Promoter Regions, Genetic
  • Rats
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Triglycerides / blood*

Substances

  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Srebf1 protein, mouse
  • Srebf1 protein, rat
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors
  • Triglycerides
  • nuclear receptor subfamily 0, group B, member 2
  • farnesoid X-activated receptor
  • DNA
  • Cholic Acid