Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c
Mitsuhiro Watanabe, Sander M. Houten, Li Wang, Antonio Moschetta, David J. Mangelsdorf, Richard A. Heyman, David D. Moore, Johan Auwerx
Mitsuhiro Watanabe, Sander M. Houten, Li Wang, Antonio Moschetta, David J. Mangelsdorf, Richard A. Heyman, David D. Moore, Johan Auwerx
View: Text | PDF
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

×

Figure 1

Options: View larger image (or click on image) Download as PowerPoint
CA lowers serum TGs in KK-Ay mice. (A) Food intake of KK-Ay mice during ...
CA lowers serum TGs in KK-Ay mice. (A) Food intake of KK-Ay mice during 1 week on the diets as described in the figure. Serum levels of TGs, total cholesterol (Chol), and FFA in KK-Ay mice after 1 week on the different diets (age 7 weeks, n = 5). Kcal, kilocalories; BW, body weight. (B) TG and cholesterol lipoprotein profiles after size-exclusion chromatography of serum pools from five animals. The quantification of the VLDL TGs is shown in an inset. (C) Serum TGs in KK-Ay (top, age 12 weeks, n = 4) and ob/ob (bottom, age 12 weeks, n = 4) mice after 0, 1, 3, and 7 days of treatment with the synthetic FXR agonist GW4064. *P < 0.05; **P < 0.01 throughout the figures.