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.Key words cholesterol; interleukin-1α; rat; 3-hydroxy-3-methyl-glutaryl-CoA reductase; strain difference; sex difference Cholesterol is not only an essential component of biological membranes but also a precursor for all steroid hormones. Serum cholesterol homeostasis is tightly controlled by the coordinated regulation of biosynthesis, uptake, and metabolism of cholesterol.1,2) The gene expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), a rate-limiting enzyme involved in cholesterol biosynthesis, is controlled through feedback regulation by oxysterols, including cholesterol.1) The gene expression of cholesterol 7α-hydroxylase (CYP7A1), a rate-limiting enzyme for bile acid biosynthesis from cholesterol, is controlled by feedforward regulation by oxysterols and feedback regulation by bile acids.2,3) Despite these overall patterns of regulation, the serum total cholesterol (TC) level in animals, including humans, shows marked sex differences. In most mice strains and in humans, the serum TC level is much higher in the male sex than in the female sex, 4-7) whereas the opposite is found in rats and pigs. 8,9) To date, however, the causes of these sex and species differences remain unclear.It was reported that inflammatory cytokines, including interleukin-1 (IL-1), alter the gene expression levels of HMGR and CYP7A1.10,11) More recently, Kojima et al. 7) demonstrated that the constitutive serum TC levels were higher in IL-1α/β-knockout (IL-1-KO) BALB/c mice than in sex-matched wildtype mice, and that hepatic IL-1 levels were significantly higher in female than in male wild-type BALB/c mice, while opposite results were found for the...