KLF15 Is a Transcriptional Regulator of the Human 17β-Hydroxysteroid Dehydrogenase Type 5 Gene. A Potential Link between Regulation of Testosterone Production and Fat Stores in Women

Context: Kruppel-like factor 15 (KLF15) is a newly discovered transcription factor that plays an important role in glucose homeostasis and lipid accumulation in cells. We present evidence for KLF15 as a transcriptional regulator of the human 17 beta-hydroxysteroid dehydrogenase type 5 gene (HSD17B5) and its potential role in the pathogenesis of hyperandrogenism. Objective: The aim was to investigate the molecular mechanism of HSD17B5 regulation. Methods: Diverse molecular biology techniques were used. Design and Results: We identified a KLF15 binding site in the HSD17B5 promoter by using luciferase promoter constructs, EMSA, and chromatin immunoprecipitation assays. Overexpression of KLF15 increased HSD17B5 promoter activity and testosterone formation at least 3-fold in cultured H295R cells. Insulin increased KLF15 mRNA expression according to real-time RT-PCR and increased HSD17B5 promoter activity according to luciferase assays. KLF15 overexpression in combination with insulin, glucocorticoid, and cAMP stimulated adipogenesis in H295R cells. In silico and RT-PCR analyses showed that the KLF15 gene promoter undergoes alternative splicing in a tissue-specific manner. Comparison of the HSD17B5 promoter in seven different species revealed that the KLF15 binding site has no human homolog in species other than orangutans. Conclusions: KLF15 is potentially a novel link between the regulation of testosterone production and fat stores by insulin in humans. (J Clin Endocrinol Metab 94: 2594-2601, 2009)