title: Ovarian granulosa cells utilize scavenger receptor SR-BI to evade cellular cholesterol homeostatic control for steroid synthesis.
abstract: Cellular cholesterol is known to be under homeostatic control in nonsteroidogenic cells, and this intrigued us to understand how such control works in steroidogenic cells that additionally use cholesterol for steroid hormone synthesis. We employed primary culture of rat ovarian granulosa cells to study how steroidogenic cells adapt to acquire sufficient cholesterol to meet the demand of active steroidogenesis under the stimulation of gonadotropin follicle-stimulating hormone (FSH) and cytokine transforming growth factor (TGF)β1. We found that TGFβ1 potentiated FSH to upregulate scavenger receptor class B member I (SR-BI) and LDL receptor (LDLR), both functional in uptaking cholesterol as hHDL(3) and hLDL supplementation enhanced progesterone production, and the effect of each lipoprotein was completely or partially blocked by SR-BI selective inhibitor BLT-1. Uptaken cholesterol could also be stored in lipid droplets. Importantly, LDLR and SR-BI responded to sterol with different sensitivity. Giving cells lipoproteins or 25-hydroxycholesterol downregulated Ldlr but not Scarb1; Scarb1 was ultimately downregulated by excessive sterol accumulation under 25-hydroxycholesterol and aminoglutethimide (inhibitor of steroidogenesis) cotreatment. Furthermore, transcription factors sterol regulatory element-binding protein (SREBP)-2 and liver receptor homolog (LRH)-1 crucially mediated Ldlr and Scarb1 differential response to sterol challenge. This study reveals that ovarian granulosa cells retain the cholesterol homeostatic control machinery like nonsteroidogenic cells, although during active steroidogenesis, they utilize SR-BI to evade such feedback control.
authors.affiliation: Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Wei-An
authors.initials: WA
authors.lastname: Lai
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Yeh
authors.forename: Ming-Ting
authors.initials: MT
authors.lastname: Lee
authors.forename: Leang-Shin
authors.initials: LS
authors.lastname: Wu
authors.forename: Ferng-Chun
authors.initials: FC
authors.lastname: Ke
authors.forename: Jiuan-Jiuan
authors.initials: JJ
authors.lastname: Hwang
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006107:Granulosa Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D013256:Steroids / Q000096:biosynthesis*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D018955:CD36 Antigens; C417002:NR5A2 protein, rat; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D013256:Steroids; D051782:Sterol Regulatory Element Binding Protein 2; D053773:Transforming Growth Factor beta1; D005640:Follicle Stimulating Hormone; D002784:Cholesterol