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

Overview

Journal J Clin Endocrinol Metab

Publisher Oxford University Press

Specialty Endocrinology

Date 2009 Apr 16

PMID 19366843

Citations 32

Authors

Xiaofei Du

Robert L Rosenfield

Kenan Qin

Affiliations

Soon will be listed here.

Abstract

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 17beta-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.

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References

Deng X, Yellaturu C, Cagen L, Wilcox H, Park E, Raghow R . Expression of the rat sterol regulatory element-binding protein-1c gene in response to insulin is mediated by increased transactivating capacity of specificity protein 1 (Sp1). J Biol Chem. 2007; 282(24):17517-29. DOI: 10.1074/jbc.M702228200. View

Uchida S, Tanaka Y, Ito H, Inazawa J, Yokoyama K, Sasaki S . Transcriptional regulation of the CLC-K1 promoter by myc-associated zinc finger protein and kidney-enriched Krüppel-like factor, a novel zinc finger repressor. Mol Cell Biol. 2000; 20(19):7319-31. PMC: 86286. DOI: 10.1128/MCB.20.19.7319-7331.2000. View

Kaczynski J, Cook T, Urrutia R . Sp1- and Krüppel-like transcription factors. Genome Biol. 2003; 4(2):206. PMC: 151296. DOI: 10.1186/gb-2003-4-2-206. View

Steckelbroeck S, Watzka M, Stoffel-Wagner B, Hans V, Redel L, Clusmann H . Expression of the 17beta-hydroxysteroid dehydrogenase type 5 mRNA in the human brain. Mol Cell Endocrinol. 2001; 171(1-2):165-8. DOI: 10.1016/s0303-7207(00)00432-9. View

Fung K, Samara E, Wong C, Metwalli A, Krlin R, Bane B . Increased expression of type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma. Endocr Relat Cancer. 2006; 13(1):169-80. DOI: 10.1677/erc.1.01048. View

Quinkler M, Sinha B, Tomlinson J, Bujalska I, Stewart P, Arlt W . Androgen generation in adipose tissue in women with simple obesity--a site-specific role for 17beta-hydroxysteroid dehydrogenase type 5. J Endocrinol. 2004; 183(2):331-42. DOI: 10.1677/joe.1.05762. View

Rosenfield R . Clinical practice. Hirsutism. N Engl J Med. 2005; 353(24):2578-88. DOI: 10.1056/NEJMcp033496. View

Fukuda H, Iritani N, Noguchi T . Transcriptional regulatory regions for expression of the rat fatty acid synthase. FEBS Lett. 1997; 406(3):243-8. DOI: 10.1016/s0014-5793(97)00219-6. View

Rosenfield R . Relationship of sebaceous cell stage to growth in culture. J Invest Dermatol. 1989; 92(5):751-4. DOI: 10.1111/1523-1747.ep12722448. View

10.

Li T, Chen Y, Liu T, Jia J, Hampson S, Shan Y . Using DNA microarray to identify Sp1 as a transcriptional regulatory element of insulin-like growth factor 1 in cardiac muscle cells. Circ Res. 2003; 93(12):1202-9. DOI: 10.1161/01.RES.0000104085.76261.02. View

11.

Ehrmann D . Polycystic ovary syndrome. N Engl J Med. 2005; 352(12):1223-36. DOI: 10.1056/NEJMra041536. View

12.

Qin K, Ehrmann D, Cox N, Refetoff S, Rosenfield R . Identification of a functional polymorphism of the human type 5 17beta-hydroxysteroid dehydrogenase gene associated with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005; 91(1):270-6. PMC: 1522092. DOI: 10.1210/jc.2005-2012. View

13.

Majumdar G, Harrington A, Hungerford J, Martinez-Hernandez A, Gerling I, Raghow R . Insulin dynamically regulates calmodulin gene expression by sequential o-glycosylation and phosphorylation of sp1 and its subcellular compartmentalization in liver cells. J Biol Chem. 2005; 281(6):3642-50. DOI: 10.1074/jbc.M511223200. View

14.

Luu-The V, Dufort I, Pelletier G, Labrie F . Type 5 17beta-hydroxysteroid dehydrogenase: its role in the formation of androgens in women. Mol Cell Endocrinol. 2001; 171(1-2):77-82. DOI: 10.1016/s0303-7207(00)00425-1. View

15.

Yamamoto J, Ikeda Y, Iguchi H, Fujino T, Tanaka T, Asaba H . A Kruppel-like factor KLF15 contributes fasting-induced transcriptional activation of mitochondrial acetyl-CoA synthetase gene AceCS2. J Biol Chem. 2004; 279(17):16954-62. DOI: 10.1074/jbc.M312079200. View

16.

Goodarzi M, Jones M, Antoine H, Pall M, Chen Y, Azziz R . Nonreplication of the type 5 17beta-hydroxysteroid dehydrogenase gene association with polycystic ovary syndrome. J Clin Endocrinol Metab. 2007; 93(1):300-3. PMC: 2190745. DOI: 10.1210/jc.2007-1712. View

17.

Fisch S, Gray S, Heymans S, Haldar S, Wang B, Pfister O . Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A. 2007; 104(17):7074-9. PMC: 1855421. DOI: 10.1073/pnas.0701981104. View

18.

Khanna M, Qin K, Klisak I, Belkin S, Sparkes R, Cheng K . Localization of multiple human dihydrodiol dehydrogenase (DDH1 and DDH2) and chlordecone reductase (CHDR) genes in chromosome 10 by the polymerase chain reaction and fluorescence in situ hybridization. Genomics. 1995; 25(2):588-90. DOI: 10.1016/0888-7543(95)80066-u. View

19.

Pelletier G, Luu-The V, Li S, Labrie F . Localization of type 5 17beta-hydroxysteroid dehydrogenase mRNA in mouse tissues as studied by in situ hybridization. Cell Tissue Res. 2005; 320(3):393-8. DOI: 10.1007/s00441-005-1105-9. View

20.

Qin K, New M, Cheng K . Molecular cloning of multiple cDNAs encoding human enzymes structurally related to 3 alpha-hydroxysteroid dehydrogenase. J Steroid Biochem Mol Biol. 1993; 46(6):673-9. DOI: 10.1016/0960-0760(93)90308-j. View