Biomaterial Database

The role of cholesterol esterification in ovarian steroidogenesis: studies in cultured swine granulosa cells using a novel inhibitor of acyl coenzyme A: cholesterol acyltransferase. 1985

J D Veldhuis, and J F Strauss, and S L Silavin, and L A Kolp

We have used a novel competitive inhibitor of acyl coenzyme A:cholesterol acyltransferase (ACAT), Sandoz compound 58-035 [3-(decyldimethyl-silyl)N-[2-(4-methyl-phenyl)1-phenylethyl propanamide], to assess the importance of the cholesterol esterification reaction in ovarian steroidogenesis. Compound 58-035 markedly (greater than or equal to 96%) inhibited ACAT activity of swine ovarian microsomes in a dose-dependent (0.1-3.5 micrograms/ml) fashion. In addition, treatment of cultured granulosa cells with this fatty acylamide effectively (greater than or equal to 98%) suppressed hormonally stimulated cholesterol esterification, as assessed by the incorporation of [3H]oleic acid into cholesteryl ester. Accordingly, we used this inhibitor to test the role of cholesterol esterification in ovarian cells. In cultures with limited or no serum supplementation, long term (2- to 6-day) treatment of granulosa cells with compound 58-035 significantly increased basal progesterone production and amplified by 2- to 10-fold the stimulatory actions of trophic hormones, such as estradiol, FSH, estradiol combined with FSH, or insulin. The amplifying effect of ACAT inhibition on hormone-stimulated progesterone production could be mimicked by providing exogenous cholesterol substrate in the form of low density lipoprotein (LDL). Cotreatment with compound 58-035 and LDL resulted in no further augmentation of steroidogenesis. In contrast to the facilitative effects of compound 58-035 in longer term cultures, this ACAT inhibitor did not alter progesterone biosynthesis acutely (2-20 h) in swine or hamster ovarian cells. These observations suggest that there is an obligatory partitioning of some sterol into the ester pool in granulosa cells. In times of diminished availability of cholesterol, inhibition of the esterification pathway can make additional cholesterol available for use in steroid hormone biosynthesis. Thus, in the intact Graafian follicle, where LDL cholesterol delivery to granulosa cells and intracellular cholesteryl ester stores are limited, regulation of the ACAT reaction may significantly modulate rates of progesterone biosynthesis. The present results indicate that the use of a selective inhibitor of cholesterol esterification can permit one to probe the functional significance of the esterification reaction in steroidogenic cells.

UI	MeSH Term	Description	Entries
D007328	Insulin	A 51-amino acid pancreatic hormone that plays a major role in the regulation of glucose metabolism, directly by suppressing endogenous glucose production (GLYCOGENOLYSIS; GLUCONEOGENESIS) and indirectly by suppressing GLUCAGON secretion and LIPOLYSIS. Native insulin is a globular protein comprised of a zinc-coordinated hexamer. Each insulin monomer containing two chains, A (21 residues) and B (30 residues), linked by two disulfide bonds. Insulin is used as a drug to control insulin-dependent diabetes mellitus (DIABETES MELLITUS, TYPE 1).	Iletin,Insulin A Chain,Insulin B Chain,Insulin, Regular,Novolin,Sodium Insulin,Soluble Insulin,Chain, Insulin B,Insulin, Sodium,Insulin, Soluble,Regular Insulin
D007700	Kinetics	The rate dynamics in chemical or physical systems.
D007986	Luteinizing Hormone	A major gonadotropin secreted by the adenohypophysis (PITUITARY GLAND, ANTERIOR). Luteinizing hormone regulates steroid production by the interstitial cells of the TESTIS and the OVARY. The preovulatory LUTEINIZING HORMONE surge in females induces OVULATION, and subsequent LUTEINIZATION of the follicle. LUTEINIZING HORMONE consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH and FSH), but the beta subunit is unique and confers its biological specificity.	ICSH (Interstitial Cell Stimulating Hormone),Interstitial Cell-Stimulating Hormone,LH (Luteinizing Hormone),Lutropin,Luteoziman,Luteozyman,Hormone, Interstitial Cell-Stimulating,Hormone, Luteinizing,Interstitial Cell Stimulating Hormone
D008077	Lipoproteins, LDL	A class of lipoproteins of small size (18-25 nm) and light (1.019-1.063 g/ml) particles with a core composed mainly of CHOLESTEROL ESTERS and smaller amounts of TRIGLYCERIDES. The surface monolayer consists mostly of PHOSPHOLIPIDS, a single copy of APOLIPOPROTEIN B-100, and free cholesterol molecules. The main LDL function is to transport cholesterol and cholesterol esters to extrahepatic tissues.	Low-Density Lipoprotein,Low-Density Lipoproteins,beta-Lipoprotein,beta-Lipoproteins,LDL(1),LDL(2),LDL-1,LDL-2,LDL1,LDL2,Low-Density Lipoprotein 1,Low-Density Lipoprotein 2,LDL Lipoproteins,Lipoprotein, Low-Density,Lipoproteins, Low-Density,Low Density Lipoprotein,Low Density Lipoprotein 1,Low Density Lipoprotein 2,Low Density Lipoproteins,beta Lipoprotein,beta Lipoproteins
D009829	Oleic Acids	A group of fatty acids that contain 18 carbon atoms and a double bond at the omega 9 carbon.	Octadecenoic Acids,Acids, Octadecenoic,Acids, Oleic
D011374	Progesterone	The major progestational steroid that is secreted primarily by the CORPUS LUTEUM and the PLACENTA. Progesterone acts on the UTERUS, the MAMMARY GLANDS and the BRAIN. It is required in EMBRYO IMPLANTATION; PREGNANCY maintenance, and the development of mammary tissue for MILK production. Progesterone, converted from PREGNENOLONE, also serves as an intermediate in the biosynthesis of GONADAL STEROID HORMONES and adrenal CORTICOSTEROIDS.	Pregnenedione,Progesterone, (13 alpha,17 alpha)-(+-)-Isomer,Progesterone, (17 alpha)-Isomer,Progesterone, (9 beta,10 alpha)-Isomer
D002478	Cells, Cultured	Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.	Cultured Cells,Cell, Cultured,Cultured Cell
D002785	Sterol O-Acyltransferase	An enzyme that catalyzes the formation of cholesterol esters by the direct transfer of the fatty acid group from a fatty acyl CoA derivative. This enzyme has been found in the adrenal gland, gonads, liver, intestinal mucosa, and aorta of many mammalian species. EC 2.3.1.26.	Acyl-CoA-Cholesterol Acyltransferase,Cholesterol Acyltransferase,Cholesterol Esterifying Enzyme,Acyl CoA Cholesterol Acyltransferase,Acyltransferase, Acyl-CoA-Cholesterol,Acyltransferase, Cholesterol,Enzyme, Cholesterol Esterifying,Esterifying Enzyme, Cholesterol,O-Acyltransferase, Sterol,Sterol O Acyltransferase
D002788	Cholesterol Esters	Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis.	Cholesterol Ester,Cholesteryl Ester,Cholesteryl Esters,Ester, Cholesterol,Ester, Cholesteryl,Esters, Cholesterol,Esters, Cholesteryl
D004958	Estradiol	The 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids.	17 beta-Estradiol,Estradiol-17 beta,Oestradiol,17 beta-Oestradiol,Aerodiol,Delestrogen,Estrace,Estraderm TTS,Estradiol Anhydrous,Estradiol Hemihydrate,Estradiol Hemihydrate, (17 alpha)-Isomer,Estradiol Monohydrate,Estradiol Valerate,Estradiol Valeriante,Estradiol, (+-)-Isomer,Estradiol, (-)-Isomer,Estradiol, (16 alpha,17 alpha)-Isomer,Estradiol, (16 alpha,17 beta)-Isomer,Estradiol, (17-alpha)-Isomer,Estradiol, (8 alpha,17 beta)-(+-)-Isomer,Estradiol, (8 alpha,17 beta)-Isomer,Estradiol, (9 beta,17 alpha)-Isomer,Estradiol, (9 beta,17 beta)-Isomer,Estradiol, Monosodium Salt,Estradiol, Sodium Salt,Estradiol-17 alpha,Estradiol-17beta,Ovocyclin,Progynon-Depot,Progynova,Vivelle,17 beta Estradiol,17 beta Oestradiol,Estradiol 17 alpha,Estradiol 17 beta,Estradiol 17beta,Progynon Depot