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PMID: 15146238 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c.

The Journal of clinical investigation ·Vol. 113 ·No. 10 ·2004-05-00 ·Pages 1408-18

Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA, Moore DD, Auwerx J

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.

MeSH Terms
Animals Base Sequence CCAAT-Enhancer-Binding Proteins/genetics,metabolism Cell Line Cholic Acid/pharmacology DNA/genetics DNA-Binding Proteins/genetics,metabolism Gene Expression/drug effects Liver/drug effects,metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Mutant Strains Mice, Obese Promoter Regions, Genetic Rats Receptors, Cytoplasmic and Nuclear/genetics,metabolism Sterol Regulatory Element Binding Protein 1 Transcription Factors/genetics,metabolism Triglycerides/blood
Chemicals
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
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Watanabe Mitsuhiro
Institut de Génétique et Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Illkirch, France.
Houten Sander M
Wang Li
Moschetta Antonio
Mangelsdorf David J
Heyman Richard A
Moore David D
Auwerx Johan
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI21025
Published
2004-05-00
Pages
1408-18
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC406532
Subset
IM
Grants
NIDDK NIH HHS · P01 DK059820 · United States
NIDDK NIH HHS · 1P01 DK59820-01 · United States
External Links
PubMed source DOI: 10.1172/JCI21025 PMC Full Text View journal details
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