Endocrine Abstracts

Over the 5 years, the field of bile acid (BA) research has undergone a considerable evolution. Besides their well-established roles in dietary lipid absorption and cholesterol homeostasis, it has recently become clear that BAs are also biological signaling molecules. For instance, BAs were shown to be natural ligands that activate FXR, which controls both the synthesis and enterohepatic recycling of BAs. We have shown that the FXR-mediated SHP induction attenuates the capacity of LXR and LRH-1 to induce the expression of SREBP-1c, explaining the inhibition of hepatic fatty acid and triglyceride biosynthesis and VLDL production by BA administration.

BAs may also signal in peripheral tissues through a newly-identified pathway involving the binding and activation of GPCR, TGR5. The subsequent activation of type 2 iodothyronine deiodinase (D2), the enzyme that converts inactive thyroxine into active 3,5,3′-triiodothyronine and hence determines thyroid hormone receptor saturation in cells, and of PGC-1 then stimulates energy expenditure in brown adipose tissue (BAT) and skeletal muscle. Thus, activation of this pathway explains how administration of BAs to mouse models of ‘diabesity’ induces weight loss and insulin sensitization. These observations build a strong case that BAs have effects beyond the strict control of BA homeostasis and function as general metabolic integrators.

Bile acid-binding resins (BABRs) are effective drugs for lowering LDL-cholesterol and the primary prevention of coronary heart disease. BABRs absorb BAs in the intestine thereby preventing their uptake in the ileum and interrupting their enterohepatic cycling. We characterize in detail the molecular and functional impact of BABR on metabolic homeostasis in mouse and hamster models and human subjects with the metabolic syndrome. Interestingly, BABR are not only shown to reduce cholesterol levels but also to decrease body weight and to improve glucose tolerance, qualifying them as ideal agents to treat the metabolic syndrome.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details are unavailable.