Branched-Chain Amino Acid Negatively Regulates KLF15 Expression Via PI3K-AKT Pathway

Overview

Journal Front Physiol

Date 2017 Nov 10

PMID 29118722

Citations 14

Authors

Yunxia Liu

Weibing Dong

Jing Shao

Yibin Wang

Meiyi Zhou

Haipeng Sun

Affiliations

Soon will be listed here.

Abstract

Recent studies have linked branched-chain amino acid (BCAA) with numerous metabolic diseases. However, the molecular basis of BCAA's roles in metabolic regulation remains to be established. KLF15 (Krüppel-like factor 15) is a transcription factor and master regulator of glycemic, lipid, and amino acids metabolism. In the present study, we found high concentrations of BCAA suppressed KLF15 expression while BCAA starvation induced KLF15 expression, suggesting KLF15 expression is negatively controlled by BCAA.Interestingly, BCAA starvation induced PI3K-AKT signaling. KLF15 induction by BCAA starvation was blocked by PI3K and AKT inhibitors, indicating the activation of PI3K-AKT signaling pathway mediated the KLF15 induction. BCAA regulated KLF15 expression at transcriptional level but not post-transcriptional level. However, BCAA starvation failed to increase the KLF15-promoter-driven luciferase expression, suggesting KLF15 promoter activity was not directly controlled by BCAA. Finally, fasting reduced BCAA abundance in mice and KLF15 expression was dramatically induced in muscle and white adipose tissue, but not in liver. Together, these data demonstrated BCAA negatively regulated KLF15 expression, suggesting a novel molecular mechanism underlying BCAA's multiple functions in metabolic regulation.

Citing Articles

Primary Roles of Branched Chain Amino Acids (BCAAs) and Their Metabolism in Physiology and Metabolic Disorders.

Bo T, Fujii J Molecules. 2025; 30(1.

PMID: 39795113 PMC: 11721030. DOI: 10.3390/molecules30010056.

Branched-chain amino acids alleviate NAFLD via inhibiting de novo lipogenesis and activating fatty acid β-oxidation in laying hens.

Jian H, Li R, Huang X, Li J, Li Y, Ma J Redox Biol. 2024; 77:103385.

PMID: 39426289 PMC: 11536022. DOI: 10.1016/j.redox.2024.103385.

Krüppel-like Factor 15 Suppresses Ferroptosis by Activating an NRF2/GPX4 Signal to Protect against Folic Acid-Induced Acute Kidney Injury.

Yang X, Dong S, Fan Y, Xia Y, Yang F, Chen Z Int J Mol Sci. 2023; 24(19).

PMID: 37833977 PMC: 10572468. DOI: 10.3390/ijms241914530.

Astragalus improves intestinal barrier function and immunity by acting on intestinal microbiota to treat T2DM: a research review.

Su M, Tang T, Tang W, Long Y, Wang L, Liu M Front Immunol. 2023; 14:1243834.

PMID: 37638043 PMC: 10450032. DOI: 10.3389/fimmu.2023.1243834.

Branched-Chain Amino Acids Metabolism and Their Roles in Retinopathy: From Relevance to Mechanism.

Zhang X, Xia M, Wu Y, Zhang F Nutrients. 2023; 15(9).

PMID: 37432261 PMC: 10180926. DOI: 10.3390/nu15092161.

References

Mori T, Sakaue H, Iguchi H, Gomi H, Okada Y, Takashima Y . Role of Krüppel-like factor 15 (KLF15) in transcriptional regulation of adipogenesis. J Biol Chem. 2005; 280(13):12867-75. DOI: 10.1074/jbc.M410515200. View

Shimizu N, Yoshikawa N, Ito N, Maruyama T, Suzuki Y, Takeda S . Crosstalk between glucocorticoid receptor and nutritional sensor mTOR in skeletal muscle. Cell Metab. 2011; 13(2):170-82. DOI: 10.1016/j.cmet.2011.01.001. View

Saxton R, Knockenhauer K, Wolfson R, Chantranupong L, Pacold M, Wang T . Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science. 2015; 351(6268):53-8. PMC: 4698039. DOI: 10.1126/science.aad2087. View

Melnik B . Leucine signaling in the pathogenesis of type 2 diabetes and obesity. World J Diabetes. 2012; 3(3):38-53. PMC: 3310004. DOI: 10.4239/wjd.v3.i3.38. View

Meijer A, Dubbelhuis P . Amino acid signalling and the integration of metabolism. Biochem Biophys Res Commun. 2003; 313(2):397-403. DOI: 10.1016/j.bbrc.2003.07.012. View

Newgard C, An J, Bain J, Muehlbauer M, Stevens R, Lien L . A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 2009; 9(4):311-26. PMC: 3640280. DOI: 10.1016/j.cmet.2009.02.002. View

Lynch C, Adams S . Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol. 2014; 10(12):723-36. PMC: 4424797. DOI: 10.1038/nrendo.2014.171. View

Novarino G, El-Fishawy P, Kayserili H, Meguid N, Scott E, Schroth J . Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science. 2012; 338(6105):394-7. PMC: 3704165. DOI: 10.1126/science.1224631. View

Ribeiro C, Sgaravatti A, Rosa R, Schuck P, Grando V, Schmidt A . Inhibition of brain energy metabolism by the branched-chain amino acids accumulating in maple syrup urine disease. Neurochem Res. 2007; 33(1):114-24. DOI: 10.1007/s11064-007-9423-9. View

10.

Tarlungeanu D, Deliu E, Dotter C, Kara M, Janiesch P, Scalise M . Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder. Cell. 2016; 167(6):1481-1494.e18. PMC: 5554935. DOI: 10.1016/j.cell.2016.11.013. View

11.

Wolfson R, Chantranupong L, Saxton R, Shen K, Scaria S, Cantor J . Sestrin2 is a leucine sensor for the mTORC1 pathway. Science. 2015; 351(6268):43-8. PMC: 4698017. DOI: 10.1126/science.aab2674. View

12.

Funchal C, Latini A, Jacques-Silva M, Santos A, Buzin L, Gottfried C . Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. Neurochem Int. 2006; 49(7):640-50. DOI: 10.1016/j.neuint.2006.05.007. View

13.

Nair K, Short K . Hormonal and signaling role of branched-chain amino acids. J Nutr. 2005; 135(6 Suppl):1547S-52S. DOI: 10.1093/jn/135.6.1547S. View

14.

Takeuchi Y, Yahagi N, Aita Y, Murayama Y, Sawada Y, Piao X . KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting. Cell Rep. 2016; 16(9):2373-86. PMC: 5031553. DOI: 10.1016/j.celrep.2016.07.069. View

15.

Jeyaraj D, Scheer F, Ripperger J, Haldar S, Lu Y, Prosdocimo D . Klf15 orchestrates circadian nitrogen homeostasis. Cell Metab. 2012; 15(3):311-23. PMC: 3299986. DOI: 10.1016/j.cmet.2012.01.020. View

16.

Jang C, Oh S, Wada S, Rowe G, Liu L, Chan M . A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat Med. 2016; 22(4):421-6. PMC: 4949205. DOI: 10.1038/nm.4057. View

17.

Gray S, Feinberg M, Hull S, Kuo C, Watanabe M, Sen-Banerjee S . The Krüppel-like factor KLF15 regulates the insulin-sensitive glucose transporter GLUT4. J Biol Chem. 2002; 277(37):34322-8. DOI: 10.1074/jbc.M201304200. View

18.

Chaveroux C, Lambert-Langlais S, Cherasse Y, Averous J, Parry L, Carraro V . Molecular mechanisms involved in the adaptation to amino acid limitation in mammals. Biochimie. 2010; 92(7):736-45. DOI: 10.1016/j.biochi.2010.02.020. View

19.

Han S, Han S, Zhang R, Jain R, Shi H, Zhang L . Circadian control of bile acid synthesis by a KLF15-Fgf15 axis. Nat Commun. 2015; 6:7231. PMC: 4457302. DOI: 10.1038/ncomms8231. View

20.

Haldar S, Jeyaraj D, Anand P, Zhu H, Lu Y, Prosdocimo D . Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation. Proc Natl Acad Sci U S A. 2012; 109(17):6739-44. PMC: 3340075. DOI: 10.1073/pnas.1121060109. View