ALTERED LIPID-METABOLISM IN APOLIPOPROTEIN E-DEFICIENT MICE DOES NOT AFFECT CHOLESTEROL BALANCE ACROSS THE LIVER

Adaptation of cholesterol and bile acid synthesis and of biliary chole sterol secretion represent key metabolic responses to maintain cholest erol homeostasis and have been suggested to be influenced by apolipopr otein E (apoE) phenotype in humans, We have investigated hepatic metab olism and secretion of cholesterol into bile in homozygous apoE-defici ent (apoE -/-) mice fed normal lab chow, Plasma cholesterol levels wer e 10 times higher in apoE (-/-) mice than in controls (+/+); triacylgl ycerol levels were only minimally affected Hepatic cholesterol (+56%) and triacylglycerol (+232%) contents were significantly increased in a poE (-/-) mice, whereas those of cholesteryl ester and of phospholipid s were similar in both groups, Lipid accumulated predominantly in peri portal areas of apoE (-/-) livers, Hepatic 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMG CoA reductase) messenger RNA (mRNA) level an d activity were reduced by 45% and 50%, respectively, in apoE (-/-) mi ce, In contrast, plasma lathosterol/cholesterol ratios, indicative for whole-body cholesterol synthesis, were fourfold increased in these mi ce, Acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity was si milar in livers of both groups, Despite the marked changes in hepatic cholesterol metabolism, neither hepatic bile acid synthesis, bile acid pool size and composition, nor hepatic cholesterol 7 alpha-hydroxylas e and sterol 27-hydroxylase mRNA levels differed between apoE (-/-) an d (+/+) mice. In addition, biliary cholesterol secretion was unaffecte d in the knock-out mice, Our results show that lack of apoE leads to m arked changes in hepatic cholesterol metabolism without altering chole sterol balance across the liver, The data are compatible with increase d peripheral cholesterol biosynthesis in apoE-deficient mice.