Bile acid metabolism in humans : regulation of synthesis and circadian rhythms

Abstract

Interfering with bile acids (BAs) signaling within the enterohepatic circulation (EHC) has recently emerged as an important way of controlling human metabolic homeostasis. This is highly relevant to a number of frequent disease entities such as dyslipidemia, fatty liver disease, insulin resistance, obesity, type 2 diabetes, gallstone disease and BA-induced diarrhea. The studies presented in this thesis focus on exploring how changes in the fluxes of BAs in the EHC may influence the synthesis and turnover of BAs and cholesterol, the metabolic signaling by endocrine fibroblast growth factors (FGFs) 19 and 21, and the modulation of lipid and carbohydrate metabolism.

Paper I presents a series of experiments characterizing the normal diurnal rhythms of BA EHC in 8 healthy males, and how they relate to BA and cholesterol synthesis. Responses to interruption of the EHC following treatment with cholestyramine, with and without adding statin, were examined in the same individuals. We identified an important difference between the diurnal rhythms of conjugated and unconjugated BAs, and could show that the transintestinal flux of conjugated BAs is responsible for changes in FGF19 secretion and regulation of BA production. We established that there is a previously unrecognized nocturnal influx of unconjugated BAs, which does not influence FGF19 or BA synthesis.

Paper II describes the relative contribution of hepatic vs intestinal FXR signaling in the regulation of BA synthesis in 57 healthy males, treated with 7 ascending doses of the potent non-steroidal FXR agonist Px-102 or placebo. Px-102 increased the level of circulating FGF19 in a dose dependent manner, while BA synthesis was almost completely suppressed already at the lowest dose, without increasing FGF19. Suppression of BA synthesis occurred before FGF19 levels were increased, indicating that activation of hepatic FXR is a major pathway for downregulation of BA synthesis in humans.

Paper III reports the effects of 55 hours of sleep deprivation or 66 hours of starvation on BA and lipid metabolism in 12 healthy volunteers. Deprivation of food, but not of sleep, markedly suppressed BA synthesis, despite lower/unchanged serum FGF19. Sleep deprivation progressively reduced FGF19, despite unchanged BA levels, indicating the presence of an independent (central) regulation of FGF19. Paper IV explores how modulation of BA metabolism may influence circulating levels of the metabolic regulator FGF21, utilizing samples from Papers I and II. Data established the presence of a circadian rhythm with a nocturnal peak in the basal state. Both treatment with cholestyramine and Px-102 reduced serum FGF21 levels, indicating that the intracellular concentration of BAs may influence its secretion.

In conclusion, our experiments provide an ample characterization of the normal diurnal variation of the EHC of BAs, and of how its manipulation may influence human metabolism. This information is not only of significance for understanding normal physiology, but should also provide a foundation for later development of diagnostic and therapeutic principles to be applied on highly prevalent disease entities, including dyslipidemia, diabetes, fatty liver and cardiovascular disease.