Phenotypic characterization of Lith genes that determine susceptibility tocholesterol cholelithiasis in inbred mice: integrated activities of hepatic lipid regulatory enzymes

There is no consensus whether hepatic lipid regulatory enzymes play primary or secondary roles in cholesterol cholelithiasis. We have used inbred mice with Liht genes that determine cholesterol gallstone susceptibility to eva luate the question. We studied activities of regulatory enzymes in choleste rol biosynthesis (HMG-CoA reductase), cholesterol esterification (acyl-CoA: cholesterol acyltransferase) and the "neutral" (cholesterol 7 alpha-hydroxy lase) and "acidic" (sterol 27-hydroxylase) pathways of bile salt synthesis in strains C57L/J and SWR/J as web as recombinant inbred (AKXL-29) mice, al l of which have susceptible Lith alleles, and compared them to AKR/J mice w ith resistant Lith alleles, We determined hepatic enzyme activities of male mice before and at frequent intervals during feeding a lithogenic diet (15 % dairy fat, 1% cholesterol, 0.5% cholic acid) for 12 weeks. Basal activiti es on chow show significant genetic variations for HMG-CoA reductase, stero l 27-hydroxylase, and acyl-CoA: cholesterol acyltranferase, but not for cho lesterol 7 alpha-hydroxylase, In response to the lithogenic diet, activitie s of the regulatory enzymes in the two bile salt synthetic pathways are coo rdinately down-regulated and correlate inversely with prevalence rates of c holesterol crystals and gallstones, Compared with gallstone-resistant mice, significantly higher HMG-CoA reductase activities together with lower acti vities of both bile salt synthetic enzymes are hallmarks of the enzymatic p henotype in mice with susceptible Lith alleles, The most parsimonious expla nation for the multiple enzymatic alterations is that the primary Lith phen otype induces secondary events to increase availability of cholesterol to s upply the sterol to the hepatocyte canalicular membrane for hypersecretion into bile.