Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c
Mitsuhiro Watanabe, … , David D. Moore, Johan Auwerx
Mitsuhiro Watanabe, … , David D. Moore, Johan Auwerx
Published May 15, 2004
Citation Information: J Clin Invest. 2004;113(10):1408-1418. https://doi.org/10.1172/JCI21025.
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Article Metabolism

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

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) α and β, 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 LXRα and LXRβ. These results suggest that strategies aimed at increasing FXR activity and the repressive effects of SHP should be explored to correct hypertriglyceridemia.

Authors

Mitsuhiro Watanabe, Sander M. Houten, Li Wang, Antonio Moschetta, David J. Mangelsdorf, Richard A. Heyman, David D. Moore, Johan Auwerx

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Figure 5

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SHP is essential for bile acid_mediated downregulation of lipogenesis. (...
SHP is essential for bile acid_mediated downregulation of lipogenesis. (A) SHP_/_ and SHP+/+ mice were fed a diet containing 0.5% CA or received GW4064 by oral gavage, and serum TG levels were measured after 0, 3, and 7 days (age 9 weeks, n = 5). (B) In two separate experiments, mice received CA or GW4064 as just described and were sacrificed after 1 day. Hepatic expression levels of SREBP-1c, CYP7A1, ME, and ANGPTL3 were determined using quantitative RT-PCR (age 9 weeks, n = 5).