Modulation of bile acid and cholesterol metabolism in health and disease

University dissertation from Stockholm : Karolinska Institutet, Department of Medicine at Huddinge University Hospital

Abstract: 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.

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