7 research outputs found
Modulation of bile acid and cholesterol metabolism in health and disease
An increased level of plasma cholesterol is associated with premature
development of atherosclerosis. It is therefore important to understand
the regulation of plasma cholesterol. Stimulation of hepatic bile acid
synthesis is a strategy to reduce plasma cholesterol. This partly occurs
due to an induction of hepatic LDL receptors. Thus, it is important to
estimate the bile acid synthesis. A method was developed to monitor
7alpha-hydroxy-4-cholesten-3-one (C4) in plasma, a bile acid intermediate
that reflects the activity of the hepatic rate limiting enzyme in bile
acid synthesis, cholesterol 7alphahydroxylase. Effects of ACTH treatment
and ASBT inhibition on cholesterol metabolism were also studied.
Pharmacological inhibition of the intestinal bile acid transporter ASBT
strongly reduced plasma cholesterol and induced cholesterol
7alpha-hydroxylase. Combined treatment with a statin improved the
lipid-lowering effect. These results were obtained in a mouse model
deficient in both the LDL receptor and its ligand Apo E. The reduction of
plasma cholesterol could not be explained by induction of other known
hepatic lipoprotein receptors. This suggests that ASBT is a promising
target in order to reduce plasma lipids.
C4 was found to be a reliable marker for hepatic cholesterol
7alpha-hydroxylase activity in the rat, both at steady state conditions
and during the diurnal changes in bile acid synthesis that occur in this
species. It was established that also humans have a diurnal rhythm in
bile acid synthesis. However, the pattern in humans was completely
different from that in rats. Thus, in humans the synthesis of bile acids
occurs predominantly at daytime. The diurnal changes in serum C4 were not
simply a consequence of food intake, since they remained during fasting.
Furthermore, they were not dependent of the presence of a gallbladder. It
was concluded that the major part of C4 enters the circulation directly
form the liver and not after intestinal uptake as do bile acids.
The distribution of C4 in 276 healthy individuals was skewed. The level
of C4 did not change with age, whereas females had 15% lower serum C4 as
compared to males. There was a correlation between serum C4 and total
triglycerides. Statin treatment did not alter plasma C4 in patients with
familial hypercholesterolemia whereas cholestyramine treatment resulted
in a pronounced increase. Gemfibrozil treatment reduced plasma C4.
Plasma C4 levels were increased in women with gallstone disease, whereas
Mapuche Indian women - a population known to have a high incidence of
cholesterol gallstones, had increased C4 levels regardless of gallstones
were present or not. This suggests that the synthesis of bile acids is
induced in gallstone disease and that this condition precedes gallstone
formation. This induction presumably occur as a response to an increased
intestinal loss of bile acids, suggesting that gallstone disease may be
due an intestinal defect.
Treatment of rats with ACTH reduced hepatic levels of SR-BI and LDL
receptors. Simultaneously, cholesterol in plasma LDL and HDL was
increased. None of these effects could be reproduced using
glucocorticoids instead of ACTH, and they were abolished in
adrenalectomized rats