Involvement of Hepatic IL-1 in the Strain-Dependent Sex Differences in Serum Total Cholesterol Levels in Rats

Abstract

The strain and sex differences in serum total cholesterol (TC) levels were examined in F344 and Sprague-Dawley (SD) rats. A sex difference (male<female) was observed in F344 rats but not in SD rats. The strain-dependent sex difference (male<female) was also observed in the constitutive gene expression level of hepatic 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), a rate-limiting enzyme for cholesterol biosynthesis, but not in the expression of hepatic cholesterol 7α-hydroxylase, a rate-limiting enzyme for cholesterol catabolism (bile acid biosynthesis from cholesterol). The strain-dependent sex difference in hepatic HMGR gene expression was closely correlated with the levels of hepatic interleukins (ILs), especially of IL-1α, which acts as a positive regulator for the hepatic HMGR gene. Hepatic IL-1α protein expression was higher in female F344 rats than in male F344 rats and compared with male and female SD rats. Similar to hepatic IL-1α protein expression, serum TC levels were highest in female F344 rats than in the other groups of rats. Serum TC and hepatic IL-1α levels in male F344 rats were similar to those in male and female SD rats. The present findings demonstrate for the first time that strain-dependent sex difference in serum TC level between F344 and SD rats is, at least in part, related to difference in the IL-1α-mediated HMGR gene expression level in the liver.