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

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Hypertriglyceridemia is a metabolic disorder characterized by elevated triglyceride levels.
• Bile acids play a role in lipid metabolism, but their precise effects on triglyceride homeostasis are not fully understood.

Purpose of the Study:

• To investigate the impact of bile acids, specifically cholic acid (CA), on triglyceride homeostasis.
• To elucidate the molecular mechanisms by which CA influences hepatic triglyceride accumulation and VLDL secretion.

Main Methods:

• Utilized a combination of molecular, cellular, and animal models, including mouse models of hypertriglyceridemia.
• Examined the effects of CA on hepatic expression of sterol regulatory element-binding protein 1c (SREBP-1c) and its downstream lipogenic genes.
• Employed mouse mutants deficient in short heterodimer partner (SHP) and liver X receptor (LXR) alpha and beta to assess the roles of these proteins in CA-mediated effects.

Main Results:

• Cholic acid (CA) administration prevented hepatic triglyceride accumulation, reduced VLDL secretion, and lowered serum triglyceride levels in hypertriglyceridemic mice.
• CA decreased the hepatic expression of SREBP-1c and its lipogenic target genes.
• The reduction in SREBP-1c expression by farnesoid X receptor (FXR) agonists was critically dependent on the presence of both SHP and LXR alpha/beta.

Conclusions:

• Bile acids, particularly CA, can effectively improve triglyceride homeostasis.
• The mechanism involves the downregulation of hepatic lipogenesis via the FXR-SHP-LXR pathway.
• Strategies enhancing FXR activity and SHP repression offer potential therapeutic avenues for hypertriglyceridemia.