Cholesterol synthesis inhibition elicits an integrated molecular response in human livers including decreased ACAT2.

Abstract

OBJECTIVE:

The purpose of this study was to identify how different degrees of cholesterol synthesis inhibition affect human hepatic cholesterol metabolism.

METHODS AND RESULTS:

Thirty-seven normocholesterolemic gallstone patients randomized to treatment with placebo, 20 mg/d fluvastatin, or 80 mg/d atorvastatin for 4 weeks were studied. Based on serum lathosterol determinations, cholesterol synthesis was reduced by 42% and 70% in the 2 groups receiving statins. VLDL cholesterol was reduced by 20% and 55%. During gallstone surgery, a liver biopsy was obtained and hepatic protein and mRNA expression of rate-limiting steps in cholesterol metabolism were assayed and related to serum lipoproteins. A marked induction of LDL receptors and 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase was positively related to the degree of cholesterol synthesis inhibition (ChSI). The activity, protein, and mRNA for ACAT2 were all reduced during ChSI, as was apoE mRNA. The lowering of HDL cholesterol in response to high ChSI could not be explained by altered expression of the HDL receptor CLA-1, ABCA1, or apoA-I.

CONCLUSIONS:

Statin treatment reduces ACAT2 activity in human liver and this effect, in combination with a reduced Apo E expression, may contribute to the favorable lowering of VLDL cholesterol seen in addition to the LDL lowering during statin treatment.

• Authors: Paolo Parini, Ulf Gustafsson, Matt A Davis, Lilian Larsson, Curt Einarsson, Martha Wilson, Mats Rudling, Hiroshi Tomoda, Satoshi Omura, Staffan Sahlin, Bo Angelin, Lawrence L Rudel, Mats Eriksson
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 28 Issue 6 Pg. 1200-6 (Jun 2008) ISSN: 1524-4636 [Electronic] United States
• PMID: 18340009 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• Cholesterol, VLDL
• Fatty Acids, Monounsaturated
• Heptanoic Acids
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Indoles
• Pyrroles
• RNA, Messenger
• Receptors, LDL
• Fluvastatin
• lathosterol
• Cholesterol
• Atorvastatin
• Hydroxymethylglutaryl CoA Reductases
• Sterol O-Acyltransferase

Topics

• Apolipoproteins E (metabolism)
• Atorvastatin
• Biopsy
• Cholesterol (blood, metabolism)
• Cholesterol, VLDL (metabolism)
• Fatty Acids, Monounsaturated (pharmacology)
• Female
• Fluvastatin
• Heptanoic Acids (pharmacology)
• Humans
• Hydroxymethylglutaryl CoA Reductases (metabolism)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Indoles (pharmacology)
• Liver (drug effects, metabolism, pathology)
• Male
• Middle Aged
• Pyrroles (pharmacology)
• RNA, Messenger (metabolism)
• Receptors, LDL (metabolism)
• Sterol O-Acyltransferase (drug effects, metabolism)
• Sterol O-Acyltransferase 2