title: SF-1 deficiency causes lipid accumulation in Leydig cells via suppression of STAR and CYP11A1.
abstract: Genetic mutations of steroidogenic factor 1 (also known as Ad4BP or Nr5a1) have increasingly been reported in patients with 46,XY disorders of sex development (46,XY disorders of sex development). However, because the phenotype of 46,XY disorders of sex development with a steroidogenic factor 1 mutation is wide-ranging, its precise diagnosis remains a clinical problem. We previously reported the frequent occurrence of lipid accumulation in Leydig cells among patients with 46,XY disorders of sex development with a steroidogenic factor 1 mutation, an observation also reported by other authors. To address the mechanism of lipid accumulation in this disease, we examined the effects of steroidogenic factor 1 deficiency on downstream targets of steroidogenic factor 1 in in vitro and in vivo. We found that lipid accumulation in Leydig cells was enhanced after puberty in heterozygous steroidogenic factor 1 knockout mice compared with wild-type mice, and was accompanied by a significant decrease in steroidogenic acute regulatory protein and CYP11A1 expression. In mouse Leydig cell lines, steroidogenic factor 1 knockdown induced a remarkable accumulation of neutral lipids and cholesterol with reduced androgen levels. Steroidogenic factor 1 knockdown reduced the expression of steroidogenic acute regulatory protein and CYP11A1, both of which are transcriptional targets of steroidogenic factor 1 and key molecules for steroidogenesis from cholesterol in the mitochondria. Knockdown of either steroidogenic acute regulatory protein or CYP11A1 also induced lipid accumulation, and knockdown of both had an additive effect. Our data suggested that lipid accumulation in the Leydig cells of the 46,XY disorders of sex development phenotype with a steroidogenic factor 1 mutation is due, at least in part, to the suppression of steroidogenic acute regulatory protein and CYP11A1, and a resulting increase in unmetabolized cholesterol.
authors.affiliation: Department of Molecular Medical Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.|Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.|Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Hatano
authors.affiliation: Department of Molecular Medical Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan. toshiro.migita@gmail.com.|Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. toshiro.migita@gmail.com.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Migita
authors.affiliation: Department of Molecular Medical Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.|Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.|Institute of Microbial Chemistry (BIKAKEN), Numazu, Shizuoka, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Ohishi
authors.affiliation: Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shima
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Ken-Ichirou
authors.initials: KI
authors.lastname: Morohashi
authors.affiliation: Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Department of Molecular Medical Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Shibasaki
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism*; D007985:Leydig Cells / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000378:metabolism*; D054339:Steroidogenic Factor 1 / Q000235:genetics* / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D010750:Phosphoproteins; D054339:Steroidogenic Factor 1; D000098682:Steroidogenic Acute Regulatory Protein; C515058:steroidogenic factor 1, mouse; D002784:Cholesterol; D002786:Cholesterol Side-Chain Cleavage Enzyme
keywords: Leydig; Lipid; SF-1