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The Roles of Circulating High-Density Lipoproteins and Trophic Hormones in the Phenotype of Knockout Mice Lacking the Steroidogenic Acute Regulatory Protein

Department of Internal Medicine (T.I., T.H., L.Z., G.M., K.L.P.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-8857; Institute of Molecular Biology (C.-I.P., B.-C.C.) , Academia Sinica, Nankang, Taipei, Taiwan 115, Republic of China; and Department of Biological Chemistry (N.Y.-O., R.T., J.O.), The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel

Address all correspondence and requests for reprints to: Dr. Keith L. Parker, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8857. E-mail: kparke{at}mednet.swmed.edu.

The steroidogenic acute regulatory protein (StAR) is essential for the regulated production of steroid hormones, mediating the translocation of intracellular cholesterol to the inner mitochondrial membrane where steroidogenesis begins. Steroidogenic cells lacking StAR have impaired steroidogenesis and progressively accumulate lipid, ultimately causing cytopathic changes and deterioration of steroidogenic capacity. Developmental studies of StAR knockout (KO) mice have correlated gonadal lipid deposits with puberty, suggesting that trophic hormones contribute to this lipid accumulation. To delineate the role of gonadotropins in this process, we examined double mutant mice deficient in both StAR and gonadotropins [StAR KO/hpg (hypogonadal)]. Lipid accumulation was ameliorated considerably in StAR KO/hpg mice but was restored by treatment with exogenous gonadotropins, directly linking trophic hormones with gonadal lipid accumulation. To define the relative roles of exogenous vs. endogenous cholesterol in the lipid accumulation, we also examined mice lacking both StAR and apolipoprotein A-I (StAR KO/Apo A-I KO). Steroidogenic tissues of StAR KO/Apo A-I KO mice had markedly decreased lipid deposits, supporting the predominant role of high-density lipoprotein-derived cholesterol in the lipid accumulation caused by StAR deficiency. Finally, we used electron microscopy to compare mitochondrial ultrastructure in StAR KO and cholesterol side-chain cleavage enzyme (Cyp11a1) KO mice; despite comparable lipid accumulation within adrenocortical cells, the effects of StAR deficiency and Cyp11a1 deficiency on mitochondrial ultrastructure were markedly different. These findings extend our understanding of steroidogenic cell dysfunction in StAR KO mice and highlight key roles of trophic hormones and high-density lipoprotein-derived cholesterol in lipid deposits within StAR-deficient steroidogenic cells.

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