Studies on the hormonal regulation of bile acid synthesis

Abstract

The maintenance of a normal turnover of cholesterol is of vital importance, and disturbances of cholesterol metabolism may result in several important disease conditions. The major route for the elimination of cholesterol from the body is by hepatic secretion of cholesterol and bile acids (BAs) into the bile for subsequent fecal excretion. A better understanding of how hepatic cholesterol metabolism and BA synthesis are regulated is therefore of fundamental clinical importance, particularly for the prevention and treatment of cardiovascular disease.

In the current thesis, the roles of known and newly recognized hormones in the regulation of BA synthesis were studied with the aim to broaden our understanding of how extrahepatic structures regulate BA synthesis in the liver. In normal humans, circulating levels of the intestinal fibroblast growth factor 19 (FGF19) were related to the amount of BAs absorbed from the intestine. The results support the concept that intestinal release of FGF19 signals to the liver suppressing BA synthesis. Thus, in addition to the liver - which harbors the full machinery for regulation of BA synthesis - the transintestinal flux of BAs is one important factor in this regulation.

In mice, abrogation of the BA enterohepatic circulation by targeted deletion or pharmacological inhibition of the intestinal BA transporter ASBT reduces triglycerides in plasma and in the liver, concomitantly with a reduced hepatic triglyceride synthesis, Sucrose feeding results in an increased intestinal expression of the mouse orthologue of FGF19, FGF15, which can at least partly account for the reduced BA synthesis observed when this diet is fed. The powerful hepatic metabolic regulator FGF21 is induced in ASBT deficient mice, and is strongly upregulated by dietary sucrose. Specific inhibition of ASBT in leptin-deficient ob/ob mice reduces plasma triglyceride and glucose levels concomitantly with increased hepatic FGF21 expression. The ob/ob mice display reduced levels of hepatic LDL and HDL receptors, as well as of the rate-limiting enzyme of BA synthesis, Cyp7a1. These findings may in part explain the elevated plasma (particularly HDL) cholesterol levels in these animals. The Cyp7a1 response to dietary cholesterol is attenuated in ob/ob mice, and - in contrast to wt animals - the plasma cholesterol levels are increased. The HDL receptor SR-BI is positively regulated by leptin treatment of ob/ob mice, whereas Cyp7a1 is not.

Selective stimulation of hepatic thyroid hormone receptor â with the drug GC-1 decreases plasma cholesterol and triglycerides dosedependently, and stimulates hepatic SR-BI and Cyp7a1 in normal mice. GC-1 also reduces elevated levels of plasma cholesterol in animals challenged with cholesterol and BAs. This indicates an important role for TRâ in reverse cholesterol transport, which might be useful in the treatment and prevention of atherosclerosis.

It is concluded that hepatic BA synthesis in man is in part controlled from the intestine via FGF19, a novel pleiotropic metabolic regulator. Plasma glucose and triglycerides can be reduced by specific stimulation of BA synthesis. Thus, modulation of BA synthesis is a promising approach for the metabolic control of lipid and glucose metabolism which may be important in our attempts to treat and prevent cardiovascular disease.