Estrogen increases hepatic lipase levels in inbred strains of mice: A possible mechanism for estrogen-dependent lowering of high density lipoprotein

We have shown mouse to be an useful animal model for studies on the estroge n-mediated synthesis and secretion of lipoproteins since, unlike in rats, l ow density lipoprotein receptors are not upregulated in mice [3]. This resu lts into the elevation of plasma levels of apolipoprotein (apo) B and apoE, and lowering of apoA-I-containing particles. The mechanisms of apoB and ap oE elevation by estrogen have been elucidated [6], but the mechanism of low ering of plasma levels of HDL is still not known. Among other factors, apoA -I, cholesterol ester transfer protein (CETP), scavenger receptor B1 (SR-B1 ), and hepatic lipase are potential candidates that modulate plasma levels of HDL. Since estrogen treatment increased hepatic apoA-I mRNA and apoA-I s ynthesis, and mouse express undetectable levels of CETP, we tested the hypo thesis that estradiol-mediated lowering of HDL in mice may occur through mo dulation of hepatic lipase (HL). Four mouse strains (C57L, C57BL, BALB, C3H ) were administered supraphysiological doses of estradiol, and plasma level s of HDL as well as HL mRNA were quantitated. In all 4 strains estradiol de creased plasma levels of HDL by 30%, and increased HL mRNA 2-3 fold. In a s eparate experiment groups of male C57BL mouse were castrated or sham-operat ed, and low and high doses of estradiol administered. We found 1.4-2.5 fold elevation of HL mRNA with concomitant lowering of HDL levels. Ten other mo use strains examined also showed estradiol-induced elevation of HL mRNA, bu t the extent of elevation was found to be strain-specific. Based on these s tudies, we conclude that hepatic lipase is an important determinant of plas ma levels of HDL and that HL mRNA is modulated by estrogen which in turn ma y participate in the lowering of plasma levels of HDL.