Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c.
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.
Watanabe
Mitsuhiro
M
Institut de Génétique et Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Illkirch, France.
Houten
Sander M
SM
Wang
Li
L
Moschetta
Antonio
A
Mangelsdorf
David J
DJ
Heyman
Richard A
RA
Moore
David D
DD
Auwerx
Johan
J
D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D019826:Cholic Acid / Q000494:pharmacology*; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D011401:Promoter Regions, Genetic; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood*; D000099150:Receptor, Farnesoid X-Activated
D022762:CCAAT-Enhancer-Binding Proteins; D019826:Cholic Acid; D004247:DNA; D004268:DNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C497388:Srebf1 protein, mouse; C497389:Srebf1 protein, rat; C099713:nuclear receptor subfamily 0, group B, member 2