CHOLESTEROL 7-ALPHA-HYDROXYLASE INFLUENCES THE EXPRESSION OF HEPATIC APOA-I IN 2 INBRED MOUSE STRAINS DISPLAYING DIFFERENT SUSCEPTIBILITIESTO ATHEROSCLEROSIS AND IN HEPATOMA-CELLS

C57BL/6 mice are susceptible to diet-induced atherosclerosis, whereas BALB/c mice are resistant. The susceptibility of C57BL/6 mice has been linked to decreased plasma HDL cholesterol in response to a diet cont aining fat, cholesterol, and cholic acid. Feeding C57BL/6 mice a diet consisting of fat and cholesterol, but no cholic acid, increased plasm a high density lipoprotein (HDL) cholesterol. The increase in HDL was associated with increases in both plasma apolipoprotein (apo)A-I and h epatic apoA-I mRNA. Supplementation of the cholesterol-rich diet with cholic acid inhibited the stimulatory effect of cholesterol on hepatic apoA-I mRNA expression, resulting in similar hepatic apoA-I mRNA leve ls compared to cho iv-fed mice. Atherosclerosis-resistant BALB/c mice were also resistant to diet-induced changes in plasma HDL, apoA-I, and hepatic apoA-I mRNA levels. Previous studies showed that the diets ch anged both the activity and mRNA encoding the liver specific enzyme 7 alpha-hydroxylase (1993. J. Lipid Res. 34: 923-931). In both strains o f mice, hepatic expression of apoA-I and 7 alpha-hydroxylase mRNA vari ed in parallel. Whereas susceptible C57BL/6 mice also showed a signifi cant correlation between HDL cholesterol and expression of 7 alpha-hyd roxylase, no such correlation was observed in BALB/c mice, suggesting that genetic differences in HDL metabolism, not hepatic apoA-I synthes is, are responsible for the strain specific differences in plasma HDL levels. The finding that lecithin:cholesterol acyltransferase (LCAT) a ctivity was significantly decreased in C57BL/6 mice, but not in BALB/c mice fed the atherogenic diet, further supports this conclusion. Addi tional studies show that McArdle hepatoma cells stably expressing plas mid-derived rat 7 alpha-hydroxylase recapitulated the parallel linear relationship between 7 alpha-hydroxylase and apoA-I mRNA expression ob served in both strains of mice. These data link hepatic apoA-I mRNA ex pression to hepatic cholesterol/bile acid metabolism.