KLF15

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Krüppel-like factor 15 is a protein that in humans is encoded by the KLF15 gene[1] in the Krüppel-like factor family. Its former designation KKLF stands for kidney-enriched Krüppel-like factor.[2]

Expression

Activated glucocorticoid receptor upregulates the expression of KLF15.[3]

KLF15 is increased by fasting and decreased by feeding and insulin via PI3K signalling. KLF15 was increased by glucocorticoid signalling and was also increased by inhibition of PI3K. Insulin and its counteracting hormones regulate the hepatic expression of KLF15. Forced expression of KLF15 in cultured hepatocytes increased both the expression and the promoter activity of the gene for phosphoenolpyruvate carboxykinase (PEPCK).[4]

KLF15 levels in both humans and mice increase two to three times in response to exercise and control the ability of muscle tissue to burn fat and generate force. Deficiency of the KLF15 gene in mice was shown to prevent the efficient burning of fat and prevented mice from sustaining aerobic exercise.[5]

KLF15 in adipose tissue is down-regulated in obese mice. aP2-KLF15 Tg mice which overexpress KLF15 manifest insulin resistance and are resistant to the development of obesity induced by maintenance on a high fat diet. However, they also exhibit improved glucose tolerance as a result of enhanced insulin secretion. The enhancement of insulin secretion resulted from down-regulation of stearoyl-CoA desaturase-1 (SCD1) in white adipose tissue and a consequent reduced level of oxidative stress. This is supported by the findings that restoration of SCD1 expression in WAT of aP2-KLF15 Tg mice exhibited increased oxidative stress in WAT, reduced insulin secretion with hyperglycemia. The data indicates an example of cross talk between white adipose tissue and pancreatic β cells mediated through modulation of oxidative stress.[6]

Using deletion and mutation analysis, EMSA and ChIP, demonstrated that USF1 and Spl can bind to E-box in-80 to-45 and GC-box in-189 to-155 in the KLF15 promoter respectively, thus regulating the transcription of KLF15 gene.[7]

Gene regulation

KLF15 binding site in the HSD17B5 promoter leading to the upregulation of testosterone production. In addition 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 [8]

KLF15 is a strong and direct activator of BMPER expression which is inhibited by SP1. BMPER is inhibited by endothelin-1, which may be mediated by endothelin inhibition of KLF15.[9]

The LRP5 promoter has a KLF15 binding site.[10]

KLF15 specifically interacts with MEF2A and synergistically activates the GLUT4 promoter via an intact KLF15-binding site proximal to the MEF2A site. Cardiac and skeletal muscle expressed miR-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiomyocytes.[11][12]

Transforming growth factor-beta1 (TGFbeta1) strongly reduces KLF15 expression. Adenoviral overexpression of KLF15 inhibits basal and TGFbeta1-induced CTGF expression in neonatal rat ventricular fibroblasts. Hearts from KLF15-/- mice subjected to aortic banding exhibited increased CTGF levels and fibrosis. KLF15 inhibits basal and TGFbeta1-mediated induction of the CTGF promoter. KLF15 inhibits recruitment of the co-activator P/CAF to the CTGF promoter with no significant effect on Smad3-DNA binding. KLF15 is implicated as a novel negative regulator of CTGF expression and cardiac fibrosis.[13]

KLF15 inhibits myocardin. TGFbeta mediated activation of p38 MAPK decreases KLF15 permitting the upreg of myocardin and stimulate the expression of serum response factor target genes, such as atrial natriuretic factor eventually leading to left ventricular hypertrophy which often progresses to heart failure.[14]

The combination of KLF15 and Sp1 resulted in a synergistic activation of the acetyl-CoA synthetase 2 (AceCS2) promoter. AceCS2 produces acetyl-CoA for oxidation through the citric acid cycle in the mitochondrial matrix. Fasting upregulated KLF15 which upregulated AceCS2.[15]

Progesterone receptor-mediated induction of Krüppel-like factor 15 (KLF15), which can bind to GC-rich DNA within the E2F1 promoter, is required for maximal induction of E2F1 expression by progestins.[16]

KLF15 may function as an inhibitor of cardiac hypertrophycan by the inhibition of GATA4 and MEF2.[17]

REDD1 and KLF15 are direct target genes of the glucocorticoid receptor (GR) in skeletal muscle. KLF15 inhibits mTOR activity via a distinct mechanism involving BCAT2 gene activation. KLF15 upregulates the expression of the E3 ubiquitin ligases atrogin-1 and SMuRF1 genes and negatively modulates myofiber size.[18]

Two kidney-specific CLC chloride channels, CLC-K1 and CLC-K2, are transcriptionally regulated on a tissue-specific basis. KLF15 (KKLF) is abundantly expressed in the liver, kidney, heart, and skeletal muscle. In the kidney, KKLF protein was localized in interstitial cells, mesangial cells, and nephron segments where CLC-K1 and CLC-K2 were not expressed. KKLF and MAZ proteins exhibited sequence-specific binding to the CLC-K1 GA element. MAZ had a strong activating effect on CLC-K1 gene transcription but KKLF coexpression with MAZ appeared to block the activating effect of MAZ.[19]

Clinical significance

KLF15 plays an important role in regulation of the expression of genes for gluconeogenic and amino acid-degrading enzymes and that the inhibitory effect of metformin on gluconeogenesis is mediated at least in part by downregulation of KLF15 and consequent attenuation of the expression of such genes.[20]

Klf15 concentrations are markedly reduced in failing human hearts and in human aortic aneurysm tissues. Mice deficient in Klf15 develop heart failure and aortic aneurysms in a p53-dependent and p300 acetyltransferase-dependent fashion. KLF15 activation inhibits p300-mediated acetylation of p53. Conversely, Klf15 deficiency leads to hyperacetylation of p53 in the heart and aorta, a finding that is recapitulated in human tissues. Finally, Klf15-deficient mice are rescued by p53 deletion or p300 inhibition. These findings highlight a molecular perturbation common to the pathobiology of heart failure and aortic aneurysm formation and suggest that manipulation of KLF15 function may be a productive approach to treat these morbid diseases.[21]

The expression of the KLF15 gene is markedly up-regulated during the differentiation of 3T3-L1 preadipocytes into adipocytes. Ectopic expression of KLF15 in NIH 3T3 or C2C12 cells triggered both lipid accumulation and the expression of PPAR-γ in the presence of inducers of adipocyte differentiation. Ectopic expression of C/EBPbeta, C/EBPdelta, or C/EBPalpha in 3T3 cells also elicited the expression of KLF15 in the presence of inducers of adipocyte differentiation. KLF15 and C/EBPalpha act synergistically to increase the activity of the PPARgamma2 gene promoter in 3T3-L1 adipocytes demonstrating that KLF15 plays an essential role in adipogenesis in 3T3-L1 cells through its regulation of PPAR gamma expression.[22]

The minimal transactivation domain of erythroid Krüppel-like factor EKLFTAD) has two functional subdomains EKLFTAD1 and EKLFTAD2 of which EKLFTAD2 is conserved in KLF15. EKLFTAD2 binds the amino-terminal PH domain of the Tfb1/p62 subunit of TFIIH (Tfb1PH/p62PH) and four domains of CREB-binding protein/p300.[23]

KLF15 is a novel transcriptional activator for hepatitis B virus core and surface promoters. It is possible that KLF15 may serve as a potential therapeutic target to reduce HBV gene expression and viral replication.[24]

Circadian control of KLF15 expression controls the expression of kChIP2 which affects how potassium flows out of heart cells. Too much or too little of KLF15 or kChIP2 may result in arrhythmias.[25]

In rodents KLF15 appears to control the actions of estradiol and progesterone in the endometrium by inhibiting the production of MCM2, a protein involved in DNA synthesis raising the possibility of preventing or treating endometrial and breast cancer and other diseases related to estrogen by promoting the action of KLF15.[26]

References

  1. ↑ "Entrez Gene: Kruppel-like factor 15".
  2. ↑ Uchida S, Tanaka Y, Ito H, Saitoh-Ohara F, Inazawa J, Yokoyama KK, Sasaki S, Marumo F (October 2000). "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. 20 (19): 7319–31. doi:10.1128/mcb.20.19.7319-7331.2000. PMC 86286. PMID 10982849.
  3. ↑ Asada M, Rauch A, Shimizu H, Maruyama H, Miyaki S, Shibamori M, Kawasome H, Ishiyama H, Tuckermann J, Asahara H (February 2011). "DNA binding-dependent glucocorticoid receptor activity promotes adipogenesis via Krüppel-like factor 15 gene expression". Lab. Invest. 91 (2): 203–15. doi:10.1038/labinvest.2010.170. PMC 3025047. PMID 20956975.
  4. ↑ Teshigawara K, Ogawa W, Mori T, Matsuki Y, Watanabe E, Hiramatsu R, Inoue H, Miyake K, Sakaue H, Kasuga M (February 2005). "Role of Krüppel-like factor 15 in PEPCK gene expression in the liver". Biochem. Biophys. Res. Commun. 327 (3): 920–6. doi:10.1016/j.bbrc.2004.12.096. PMID 15649433.
  5. ↑ Saptarsi M. Haldar, Darwin Jeyaraj, Priti Anand, Han Zhu, Yuan Lu, Domenick A. Prosdocimo, Betty Eapen, Daiji Kawanami, Mitsuharu Okutsu, Leticia Brotto, Hisashi Fujioka, Janos Kerner, Mariana G. Rosca, Owen P. McGuinness, Rod J. Snow, Aaron P. Russell, Anthony N. Gerber, Xiaodong Bai, Zhen Yan, Thomas M. Nosek, Marco Brotto, Charles L. Hoppel, and Mukesh K. Jain. Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation. Proceedings of the National Academy of Sciences, April 9, 2012 doi:10.1073/pnas.1121060109
  6. ↑ Nagare T, Sakaue H, Matsumoto M, Cao Y, Inagaki K, Sakai M, Takashima Y, Nakamura K, Mori T, Okada Y, Matsuki Y, Watanabe E, Ikeda K, Taguchi R, Kamimura N, Ohta S, Hiramatsu R, Kasuga M (August 2011). "Overexpression of KLF15 in adipocytes of mice results in down-regulation of SCD1 expression in adipocytes and consequent enhancement of glucose-induced insulin secretion". J Biol Chem. 286 (43): 37458–69. doi:10.1074/jbc.M111.242651. PMC 3199492. PMID 21862590.
  7. ↑ http://www.technology-articles.org/Genetics/Study-of-Transcription-Regulation-of-Human-LRP5-Gene-and-KLF15-Gene.html
  8. ↑ Du X, Rosenfield RL, Qin K (July 2009). "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". J. Clin. Endocrinol. Metab. 94 (7): 2594–601. doi:10.1210/jc.2009-0139. PMC 2708951. PMID 19366843.
  9. ↑ Helbing T, Volkmar F, Goebel U, Heinke J, Diehl P, Pahl HL, Bode C, Patterson C, Moser M (February 2010). "Krüppel-like factor 15 regulates BMPER in endothelial cells". Cardiovasc. Res. 85 (3): 551–9. doi:10.1093/cvr/cvp314. PMC 4110462. PMID 19767294.
  10. ↑ Li J, Yang Y, Jiang B, et al. (2010). "Sp1 and KLF15 regulate basal transcription of the human LRP5 gene". BMC Genet. 11: 12. doi:10.1186/1471-2156-11-12. PMC 2831824. PMID 20141633.
  11. ↑ Horie T, Ono K, Nishi H, Iwanaga Y, Nagao K, Kinoshita M, Kuwabara Y, Takanabe R, Hasegawa K, Kita T, Kimura T (November 2009). "MicroRNA-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiac myocytes". Biochem. Biophys. Res. Commun. 389 (2): 315–20. doi:10.1016/j.bbrc.2009.08.136. PMID 19720047.
  12. ↑ Gray S, Feinberg MW, Hull S, Kuo CT, Watanabe M, Sen-Banerjee S, DePina A, Haspel R, Jain MK (September 2002). "The Krüppel-like factor KLF15 regulates the insulin-sensitive glucose transporter GLUT4". J. Biol. Chem. 277 (37): 34322–8. doi:10.1074/jbc.M201304200. PMID 12097321.
  13. ↑ Wang B, Haldar SM, Lu Y, Ibrahim OA, Fisch S, Gray S, Leask A, Jain MK (August 2008). "The Kruppel-like factor KLF15 inhibits connective tissue growth factor (CTGF) expression in cardiac fibroblasts". J. Mol. Cell. Cardiol. 45 (2): 193–7. doi:10.1016/j.yjmcc.2008.05.005. PMC 2566509. PMID 18586263.
  14. ↑ Leenders JJ, Wijnen WJ, Hiller M, van der Made I, Lentink V, van Leeuwen RE, Herias V, Pokharel S, Heymans S, de Windt LJ, Høydal MA, Pinto YM, Creemers EE (August 2010). "Regulation of cardiac gene expression by KLF15, a repressor of myocardin activity". J. Biol. Chem. 285 (35): 27449–56. doi:10.1074/jbc.M110.107292. PMC 2930743. PMID 20566642.
  15. ↑ Yamamoto J, Ikeda Y, Iguchi H, Fujino T, Tanaka T, Asaba H, Iwasaki S, Ioka RX, Kaneko IW, Magoori K, Takahashi S, Mori T, Sakaue H, Kodama T, Yanagisawa M, Yamamoto TT, Ito S, Sakai J (April 2004). "A Kruppel-like factor KLF15 contributes fasting-induced transcriptional activation of mitochondrial acetyl-CoA synthetase gene AceCS2". J. Biol. Chem. 279 (17): 16954–62. doi:10.1074/jbc.M312079200. PMID 14960588.
  16. ↑ Wade HE, Kobayashi S, Eaton ML, Jansen MS, Lobenhofer EK, Lupien M, Geistlinger TR, Zhu W, Nevins JR, Brown M, Otteson DC, McDonnell DP (April 2010). "Multimodal regulation of E2F1 gene expression by progestins". Mol. Cell. Biol. 30 (8): 1866–77. doi:10.1128/MCB.01060-09. PMC 2849472. PMID 20123965.
  17. ↑ Fisch S, Gray S, Heymans S, Haldar SM, Wang B, Pfister O, Cui L, Kumar A, Lin Z, Sen-Banerjee S, Das H, Petersen CA, Mende U, Burleigh BA, Zhu Y, Pinto YM, Pinto Y, Liao R, Jain MK (April 2007). "Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy". Proc. Natl. Acad. Sci. U.S.A. 104 (17): 7074–9. doi:10.1073/pnas.0701981104. PMC 1855421. PMID 17438289.
  18. ↑ Shimizu N, Yoshikawa N, Ito N, Maruyama T, Suzuki Y, Takeda S, Nakae J, Tagata Y, Nishitani S, Takehana K, Sano M, Fukuda K, Suematsu M, Morimoto C, Tanaka H (February 2011). "Crosstalk between glucocorticoid receptor and nutritional sensor mTOR in skeletal muscle". Cell Metab. 13 (2): 170–82. doi:10.1016/j.cmet.2011.01.001. PMID 21284984.
  19. ↑ *Uchida S, Sasaki S, Marumo F (2001). "Isolation of a novel zinc finger repressor that regulates the kidney-specific CLC-K1 promoter". Kidney Int. 60 (2): 416–21. doi:10.1046/j.1523-1755.2001.060002416.x. PMID 11473619.
  20. ↑ Takashima M, Ogawa W, Hayashi K, Inoue H, Kinoshita S, Okamoto Y, Sakaue H, Wataoka Y, Emi A, Senga Y, Matsuki Y, Watanabe E, Hiramatsu R, Kasuga M (July 2010). "Role of KLF15 in regulation of hepatic gluconeogenesis and metformin action". Diabetes. 59 (7): 1608–15. doi:10.2337/db09-1679. PMC 2889759. PMID 20393151.
  21. ↑ Haldar SM, Lu Y, Jeyaraj D, Kawanami D, Cui Y, Eapen SJ, Hao C, Li Y, Doughman YQ, Watanabe M, Shimizu K, Kuivaniemi H, Sadoshima J, Margulies KB, Cappola TP, Jain MK (April 2010). "Klf15 deficiency is a molecular link between heart failure and aortic aneurysm formation". Sci Transl Med. 2 (26): 26ra26. doi:10.1126/scitranslmed.3000502. PMC 3003709. PMID 20375365.
  22. ↑ Mori T, Sakaue H, Iguchi H, Gomi H, Okada Y, Takashima Y, Nakamura K, Nakamura T, Yamauchi T, Kubota N, Kadowaki T, Matsuki Y, Ogawa W, Hiramatsu R, Kasuga M (April 2005). "Role of Krüppel-like factor 15 (KLF15) in transcriptional regulation of adipogenesis". J. Biol. Chem. 280 (13): 12867–75. doi:10.1074/jbc.M410515200. PMID 15664998.
  23. ↑ Mas C, Lussier-Price M, Soni S, Morse T, Arseneault G, Di Lello P, Lafrance-Vanasse J, Bieker JJ, Omichinski JG (June 2011). "Structural and functional characterization of an atypical activation domain in erythroid Kruppel-like factor (EKLF)". Proc. Natl. Acad. Sci. U.S.A. 108 (26): 10484–9. doi:10.1073/pnas.1017029108. PMC 3127900. PMID 21670263.
  24. ↑ Zhou J, Tan T, Tian Y, Zheng B, Ou JH, Huang EJ, Yen TS (July 2011). "Krüppel-like factor 15 activates hepatitis B virus gene expression and replication". Hepatology. 54 (1): 109–21. doi:10.1002/hep.24362. PMC 3125411. PMID 21503941.
  25. ↑ Jeyaraj D, Haldar SM, Wan X, McCauley MD, Ripperger JA, Hu K, Lu Y, Eapen BL, Sharma N, Ficker E, Cutler MJ, Gulick J, Sanbe A, Robbins J, Demolombe S, Kondratov RV, Shea SA, Albrecht U, Wehrens XH, Rosenbaum DS, Jain Mukesh K (2012). "Circadian rhythms govern cardiac repolarization and arrhythmogenesis". Nature. 483: 96–99. doi:10.1038/nature10852. PMC 3297978. PMID 22367544.
  26. ↑ http://www.eurekalert.org/pub_releases/2012-05/aeco-mft050912.php

Further reading

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