title: A Dietary Medium-Chain Fatty Acid, Decanoic Acid, Inhibits Recruitment of Nur77 to the HSD3B2 Promoter In Vitro and Reverses Endocrine and Metabolic Abnormalities in a Rat Model of Polycystic Ovary Syndrome.
abstract: Hyperandrogenism is the central feature of polycystic ovary syndrome (PCOS). Due to the intricate relationship between hyperandrogenism and insulin resistance in PCOS, 50%-70% of these patients also present with hyperinsulinemia. Metformin, an insulin sensitizer, has been used to reduce insulin resistance and improve fertility in women with PCOS. In previous work, we have noted that a dietary medium-chain fatty acid, decanoic acid (DA), improves glucose tolerance and lipid profile in a mouse model of diabetes. Here, we report for the first time that DA, like metformin, inhibits androgen biosynthesis in NCI-H295R steroidogenic cells by regulating the enzyme 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase type 2 (HSD3B2). The inhibitory effect on HSD3B2 and androgen production required cAMP stimulation, suggesting a mechanistic action via the cAMP-stimulated pathway. Specifically, both DA and metformin reduced cAMP-enhanced recruitment of the orphan nuclear receptor Nur77 to the HSD3B2 promoter, coupled with decreased transcription and protein expression of HSD3B2. In a letrozole-induced PCOS rat model, treatment with DA or metformin reduced serum-free testosterone, lowered fasting insulin, and restored estrous cyclicity. In addition, DA treatment lowered serum total testosterone and decreased HSD3B2 protein expression in the adrenals and ovaries. We conclude that DA inhibits androgen biosynthesis via mechanisms resulting in the suppression of HSD3B2 expression, an effect consistently observed both in vitro and in vivo. The efficacy of DA in reversing the endocrine and metabolic abnormalities of the letrozole-induced PCOS rat model are promising, raising the possibility that diets including DA could be beneficial for the management of both hyperandrogenism and insulin resistance in PCOS.
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
authors.forename: Bao Hui
authors.initials: BH
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
authors.forename: Inthrani Raja
authors.initials: IR
authors.lastname: Indran
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
authors.forename: Huey Min
authors.initials: HM
authors.lastname: Tan
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
authors.forename: Eu-Leong
authors.initials: EL
authors.lastname: Yong
mesh_terms: D000302:Adrenal Cortex / Q000201:enzymology / Q000378:metabolism; D000311:Adrenal Glands / Q000201:enzymology / Q000378:metabolism; D000728:Androgens / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D003652:Decanoic Acids / Q000378:metabolism / Q000627:therapeutic use*; D004041:Dietary Fats / Q000378:metabolism / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004794:Enzyme Repression; D005260:Female; D006801:Humans; D017588:Hyperandrogenism / Q000209:etiology / Q000517:prevention & control; D007333:Insulin Resistance; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010053:Ovary / Q000201:enzymology / Q000378:metabolism; D011085:Polycystic Ovary Syndrome / Q000178:diet therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011375:Progesterone Reductase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011897:Random Allocation; D017208:Rats, Wistar
chemical_list: D000728:Androgens; D003652:Decanoic Acids; D004041:Dietary Fats; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; C031071:decanoic acid; D000242:Cyclic AMP; C533068:3 beta-hydroxysteroid dehydrogenase type II; D011375:Progesterone Reductase