Studies on the hormonal regulation of bile acid synthesis
Author: Lundåsen, Thomas
Date: 2007-01-26
Location: Föreläsningssalen M63, Huddinge Universitetssjukhus
Time: 09.00
Department: Institutionen för medicin, Huddinge Sjukhus / Department of Medicine at Huddinge University Hospital
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thesis.pdf (549.7Kb)
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.
List of papers:
I. Lundasen T, Liao W, Angelin B, Rudling M. (2003). "Leptin induces the hepatic high density lipoprotein receptor scavenger receptor B type I (SR-BI) but not cholesterol 7alpha-hydroxylase (Cyp7a1) in leptin-deficient (ob/ob) mice." J Biol Chem 278(44): 43224-8
Pubmed
II. Johansson L, Rudling M, Scanlan TS, Lundasen T, Webb P, Baxter J, Angelin B, Parini P. (2005). "Selective thyroid receptor modulation by GC-1 reduces serum lipids and stimulates steps of reverse cholesterol transport in euthyroid mice." Proc Natl Acad Sci U S A 102(29): 10297-302
Pubmed
III. Lundasen T, Galman C, Angelin B, Rudling M. (2006). "Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man." J Intern Med 260(6): 530-6
Pubmed
IV. Lundåsen T, Andersson E-M, Snaith M, Lindmark H, Schreyer S, Östlund-Lindqvist A-M, Angelin B, Rudling M (2006). "Interruption of bile acid circulation improves triglyceride metabolism and normalizes elevated plasma levels." (Submitted)
I. Lundasen T, Liao W, Angelin B, Rudling M. (2003). "Leptin induces the hepatic high density lipoprotein receptor scavenger receptor B type I (SR-BI) but not cholesterol 7alpha-hydroxylase (Cyp7a1) in leptin-deficient (ob/ob) mice." J Biol Chem 278(44): 43224-8
Pubmed
II. Johansson L, Rudling M, Scanlan TS, Lundasen T, Webb P, Baxter J, Angelin B, Parini P. (2005). "Selective thyroid receptor modulation by GC-1 reduces serum lipids and stimulates steps of reverse cholesterol transport in euthyroid mice." Proc Natl Acad Sci U S A 102(29): 10297-302
Pubmed
III. Lundasen T, Galman C, Angelin B, Rudling M. (2006). "Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man." J Intern Med 260(6): 530-6
Pubmed
IV. Lundåsen T, Andersson E-M, Snaith M, Lindmark H, Schreyer S, Östlund-Lindqvist A-M, Angelin B, Rudling M (2006). "Interruption of bile acid circulation improves triglyceride metabolism and normalizes elevated plasma levels." (Submitted)
Issue date: 2007-01-05
Rights:
Publication year: 2007
ISBN: 978-91-7357-053-4
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