Regulation of ovarian cholesterol metabolism: control of 3-hydroxy-3-methylglutaryl coenzyme A reductase and acyl coenzyme A:cholesterol acyltransferase.
Activities of enzymes involved in cholesterol metabolism were measured in ovaries of PMS-hCG-primed immature rats. Microsomal 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme in sterol synthesis, was low during the period of maximal steroid production and cholesteryl ester storage. Acyl CoA:cholesterol acyltransferase (ACAT), the microsomal enzyme catalyzing sterol esterification and cytosolic cholesteryl ester hydrolase and mitochondrial cholesterol side chain cleavage activities, paralleled storage of sterol esters and levels of plasma progesterone, being highest on day 7 post hCG. Further experiments demonstrated that HMG-CoA reductase and ACAT are regulated by different mechanisms than the sterol esterase and cholesterol side chain cleavage system. When blood sterol levels were lowered by 4-aminopyrazolo (3,4-d)pyrimidine, plasma progestin concentrations fell and ovaries failed to accumulate sterol esters. HMG-CoA reductase increased more than 10-fold as a result of this treatment, while ACAT was 15% of that measured in controls. In contrast, cholesteryl esterase and the cholesterol side chain cleavage system were not affected. Intravenous infusion of human lipoproteins reversed the effects of 4-aminopyrazolo (3,4-d)pyrimidine. Raising blood levels up to 6-fold with either cholesterol-supplemented diets or intravenous injections of rat lipoproteins had no effect upon ovarian sterol metabolism, suggesting that the process by which blood cholesterol is utilized is saturated at normal blood sterol levels. Intravenous injection of LH on day 7 post hCG increased HMG-CoA reductase and decreased ACAT activity in addition to depleting cholesteryl esters. Prior treatment of rats with aminoglutethimide prevented the effects of LH on both HMG-CoA reductase and ACAT, indicating that changes in these enzymes were a consequence of the steroidogenic stimulus imposed by LH. Treatment with aminoglutethimide alone on day 7 post hCG did not further depress the already low HMG-CoA reductase activity, but ACAT and cholesterol ester storage were stimulated while sterol esterase activity was not altered. Aminoglutethimide also produced elevated ACAT activity and sterol ester storage in animals treated on day 2 post hCG, a time when there is normally little sterol ester accumulation. We conclude that HMG-CoA reductase and ACAT are regulated, in a reciprocal fashion, by ovarian cholesterol balance. When sufficient cholesterol is available, HMG-CoA reductase is suppressed and ACAT increases to facilitate esterification of sterol in excess of cell needs. When exogenous sterol supplies cannot meet ovarian demands, HMG-CoA reductase rises, and there is a concomitant decline in ACAT. Thus, gonadotropic control over these enzymes may be exerted, in part, through modulation of the supply of cholesterol to the ovary and/or through regulation of the rate of sterol utilization for hormone synthesis.
D000217:Acyltransferases / Q000378:metabolism*; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000616:Aminoglutethimide / Q000494:pharmacology; D000818:Animals; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D005260:Female; D006064:Gonadotropins, Equine / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D006937:Hypercholesterolemia / Q000097:blood; D007700:Kinetics; D007986:Luteinizing Hormone / Q000494:pharmacology; D008861:Microsomes / Q000201:enzymology; D010053:Ovary / Q000187:drug effects / Q000201:enzymology*; D011374:Progesterone / Q000097:blood; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000378:metabolism*
D006063:Chorionic Gonadotropin; D006064:Gonadotropins, Equine; D000616:Aminoglutethimide; C004420:4-aminopyrazolo(3,4-d)pyrimidine; D011374:Progesterone; D007986:Luteinizing Hormone; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D000217:Acyltransferases; D002785:Sterol O-Acyltransferase; D000225:Adenine