SF-1 deficiency causes lipid accumulation in Leydig cells via suppression of STAR and CYP11A1 View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2016-11

AUTHORS

Megumi Hatano, Toshiro Migita, Tomokazu Ohishi, Yuichi Shima, Yoshihiro Ogawa, Ken-Ichirou Morohashi, Yukihiro Hasegawa, Futoshi Shibasaki

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. More... »

PAGES

484-496

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s12020-016-1043-1

DOI

http://dx.doi.org/10.1007/s12020-016-1043-1

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1041054793

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/27455990


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