Studies on the Hormonal Regulation of Bile Acid Synthesis
Year: 2007
Type: dissertation
Abstract: The maintenance of a normal turnover of cholesterol is of vital\nimportance, and disturbances of cholesterol metabolism may result in\nseveral important disease conditions. The major route for the elimination\nof cholesterol from the body is by hepatic secretion of cholesterol and\nbile acids (BAs) into the bile for subsequent fecal excretion. A better\nunderstanding of how hepatic cholesterol metabolism and BA synthesis are\nregulated is therefore of fundamental clinical importance, particularly\nfor the prevention and treatment of cardiovascular disease.\n\nIn the current thesis, the roles of known and newly recognized hormones\nin the regulation of BA synthesis were studied with the aim to broaden\nour understanding of how extrahepatic structures regulate BA synthesis in\nthe liver. In normal humans, circulating levels of the intestinal\nfibroblast growth factor 19 (FGF19) were related to the amount of BAs\nabsorbed from the intestine. The results support the concept that\nintestinal release of FGF19 signals to the liver suppressing BA\nsynthesis. Thus, in addition to the liver - which harbors the full\nmachinery for regulation of BA synthesis - the transintestinal flux of\nBAs is one important factor in this regulation.\n\nIn mice, abrogation of the BA enterohepatic circulation by targeted\ndeletion or pharmacological inhibition of the intestinal BA transporter\nASBT reduces triglycerides in plasma and in the liver, concomitantly with\na reduced hepatic triglyceride synthesis, Sucrose feeding results in an\nincreased intestinal expression of the mouse orthologue of FGF19, FGF15,\nwhich can at least partly account for the reduced BA synthesis observed\nwhen this diet is fed. The powerful hepatic metabolic regulator FGF21 is\ninduced in ASBT deficient mice, and is strongly upregulated by dietary\nsucrose. Specific inhibition of ASBT in leptin-deficient ob/ob mice\nreduces plasma triglyceride and glucose levels concomitantly with\nincreased hepatic FGF21 expression. The ob/ob mice display reduced levels\nof hepatic LDL and HDL receptors, as well as of the rate-limiting enzyme\nof BA synthesis, Cyp7a1. These findings may in part explain the elevated\nplasma (particularly HDL) cholesterol levels in these animals. The Cyp7a1\nresponse to dietary cholesterol is attenuated in ob/ob mice, and - in\ncontrast to wt animals - the plasma cholesterol levels are increased. The\nHDL receptor SR-BI is positively regulated by leptin treatment of ob/ob\nmice, whereas Cyp7a1 is not.\n\nSelective stimulation of hepatic thyroid hormone receptor â with the drug\nGC-1 decreases plasma cholesterol and triglycerides dosedependently, and\nstimulates hepatic SR-BI and Cyp7a1 in normal mice. GC-1 also reduces\nelevated levels of plasma cholesterol in animals challenged with\ncholesterol and BAs. This indicates an important role for TRâ in reverse\ncholesterol transport, which might be useful in the treatment and\nprevention of atherosclerosis.\n\nIt is concluded that hepatic BA synthesis in man is in part controlled\nfrom the intestine via FGF19, a novel pleiotropic metabolic regulator.\nPlasma glucose and triglycerides can be reduced by specific stimulation\nof BA synthesis. Thus, modulation of BA synthesis is a promising approach\nfor the metabolic control of lipid and glucose metabolism which may be\nimportant in our attempts to treat and prevent cardiovascular disease.
Source: Figshare
Author: Thomas Lundåsen
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1714996478