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Hepatic TANK (TRAF family member associated NFκB activator)-binding kinase 1 (TBK1) activity is increased during obesity, and administration of a TBK1 inhibitor reduces fatty liver. Surprisingly, liver-specific TBK1 knockout in mice produces fatty liver by reducing fatty acid oxidation. TBK1 functions as a scaffolding protein to localize acyl-CoA synthetase long-chain family member 1 (ACSL1) to mitochondria, which generates acyl-CoAs that are channeled for β-oxidation. TBK1 is induced during fasting and maintained in the unphosphorylated, inactive state, enabling its high affinity binding to ACSL1 in mitochondria. In TBK1-deficient liver, ACSL1 is shifted to the endoplasmic reticulum to promote fatty acid re-esterification in lieu of oxidation in response to fasting, which accelerates hepatic lipid accumulation. The impaired fatty acid oxidation in TBK1-deficient hepatocytes is rescued by the expression of kinase-dead TBK1. Thus, TBK1 operates as a rheostat to direct the fate of fatty acids in hepatocytes, supporting oxidation when inactive during fasting and promoting re-esterification when activated during obesity.

Competing Interests: Declaration of Interests A.R.S. is a founder of Elgia Therapeutics and named inventor on several patent applications that include amlexanox. The other authors declare that they have no competing interests.

Titel:	TANK-Binding Kinase 1 Regulates the Localization of Acyl-CoA Synthetase ACSL1 to Control Hepatic Fatty Acid Oxidation.
Autor/in / Beteiligte Person:	Huh, JY ; Reilly, SM ; Abu-Odeh, M ; Murphy, AN ; Mahata, SK ; Zhang, J ; Cho, Y ; Seo, JB ; Hung, CW ; Green, CR ; Metallo, CM ; Saltiel, AR
Zeitschrift:	Cell metabolism, Jg. 32 (2020-12-01), Heft 6, S. 1012
Veröffentlichung:	Cambridge, Mass. : Cell Press, c2005-, 2020
Medientyp:	academicJournal
ISSN:	1932-7420 (electronic)
DOI:	10.1016/j.cmet.2020.10.010
Schlagwort:	Animals HEK293 Cells Humans Male Mice Mice, Inbred C57BL Mice, Knockout Oxidation-Reduction Coenzyme A Ligases metabolism Fatty Acids metabolism Non-alcoholic Fatty Liver Disease metabolism Obesity metabolism Protein Serine-Threonine Kinases metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Language: English [Cell Metab] 2020 Dec 01; Vol. 32 (6), pp. 1012-1027.e7. <i>Date of Electronic Publication: </i>2020 Nov 04. MeSH Terms: Coenzyme A Ligases / metabolism ; Fatty Acids / metabolism ; Non-alcoholic Fatty Liver Disease / metabolism ; Obesity / metabolism ; Protein Serine-Threonine Kinases / *metabolism ; Animals ; HEK293 Cells ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Oxidation-Reduction References: Eur J Biochem. 1997 Feb 15;244(1):1-14. (PMID: 9063439) ; J Clin Invest. 2005 Apr;115(4):1030-8. (PMID: 15761499) ; PLoS One. 2011;6(9):e23971. (PMID: 21931631) ; J Clin Invest. 2007 Jan;117(1):175-84. (PMID: 17200717) ; Am J Physiol Endocrinol Metab. 2000 Aug;279(2):E425-32. (PMID: 10913044) ; Diabetes. 2015 Jan;64(1):23-35. (PMID: 25071025) ; Diabetes. 2017 Apr;66(4):835-847. (PMID: 28082459) ; J Leukoc Biol. 2010 Dec;88(6):1171-80. (PMID: 20651301) ; Nat Med. 2018 Jul;24(7):908-922. (PMID: 29967350) ; Nat Immunol. 2003 May;4(5):491-6. (PMID: 12692549) ; Diabetes. 2010 Apr;59(4):916-25. (PMID: 20103702) ; J Clin Invest. 2017 Jan 3;127(1):1-4. (PMID: 28045402) ; Nat Commun. 2015 Jan 12;6:6047. (PMID: 25581158) ; Nat Med. 2009 Aug;15(8):930-9. (PMID: 19633656) ; Nat Med. 2013 Mar;19(3):313-21. (PMID: 23396211) ; Diabetes. 2017 Nov;66(11):2888-2902. (PMID: 28566273) ; Cell Tissue Res. 2016 Mar;363(3):693-712. (PMID: 26572539) ; Obesity (Silver Spring). 2006 Oct;14(10):1747-54. (PMID: 17062804) ; Clin Mol Hepatol. 2013 Sep;19(3):210-5. (PMID: 24133660) ; Structure. 2013 Jul 2;21(7):1137-48. (PMID: 23746807) ; J Clin Invest. 2008 Sep;118(9):2992-3002. (PMID: 18769626) ; Nat Rev Gastroenterol Hepatol. 2018 Jun;15(6):349-364. (PMID: 29740166) ; FEBS Lett. 2013 Mar 18;587(6):542-8. (PMID: 23395611) ; J Lipid Res. 2003 May;44(5):878-83. (PMID: 12639976) ; Curr Protoc Mouse Biol. 2017 Mar 2;7(1):47-54. (PMID: 28252199) ; J Hepatol. 2016 Dec;65(6):1245-1257. (PMID: 27486010) ; J Hepatol. 2015 Apr;62(1 Suppl):S47-64. (PMID: 25920090) ; Methods Mol Biol. 2016;1376:43-53. (PMID: 26552674) ; J Lipid Res. 2016 Mar;57(3):433-42. (PMID: 26711138) ; Cell. 2009 Sep 4;138(5):961-75. (PMID: 19737522) ; Life Sci. 2019 Dec 15;239:117010. (PMID: 31672578) ; Annu Rev Physiol. 2010;72:219-46. (PMID: 20148674) ; Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):233-8. (PMID: 14679297) ; Mol Cells. 2014 May;37(5):365-71. (PMID: 24781408) ; Diabetes. 2008 Dec;57(12):3239-46. (PMID: 18829989) ; J Biol Chem. 2002 Apr 19;277(16):13840-7. (PMID: 11839743) ; J Lipid Res. 2019 Mar;60(3):490-497. (PMID: 30683668) ; Methods Enzymol. 1978;52:83-9. (PMID: 672658) ; Nat Rev Gastroenterol Hepatol. 2013 Jun;10(6):330-44. (PMID: 23507799) ; J Biol Chem. 2009 Oct 9;284(41):27816-26. (PMID: 19648649) ; Cell. 2018 Feb 8;172(4):731-743.e12. (PMID: 29425491) ; Elife. 2013 Dec 24;2:e01119. (PMID: 24368730) ; Hepatology. 2018 Jan;67(1):123-133. (PMID: 28802062) ; PLoS One. 2011;6(7):e21746. (PMID: 21799747) ; Nat Med. 2009 Aug;15(8):921-9. (PMID: 19633657) ; Diabetes. 2002 Apr;51(4):1131-7. (PMID: 11916936) ; J Biol Methods. 2017 Jan 20;4(1):e62. (PMID: 31453222) ; Methods Enzymol. 2014;542:391-405. (PMID: 24862277) ; J Lipid Res. 2006 Sep;47(9):2004-10. (PMID: 16772660) ; Annu Rev Nutr. 2000;20:77-103. (PMID: 10940327) ; Lancet Diabetes Endocrinol. 2014 Nov;2(11):901-10. (PMID: 24731669) ; Cell Rep. 2016 Jun 28;16(1):201-212. (PMID: 27320917) ; Nat Med. 2016 Oct;22(10):1108-1119. (PMID: 27643638) ; Cell Metab. 2017 Jul 5;26(1):157-170.e7. (PMID: 28683283) ; J Clin Invest. 2005 May;115(5):1343-51. (PMID: 15864352) ; Oncol Lett. 2018 Aug;16(2):1390-1396. (PMID: 30008815) ; J Lipid Res. 2005 Sep;46(9):2023-8. (PMID: 15995182) Grant Information: R01 DK076906 United States DK NIDDK NIH HHS; R01 DK125820 United States DK NIDDK NIH HHS; R01 NS087611 United States NS NINDS NIH HHS; R01 DK124496 United States DK NIDDK NIH HHS; P30 DK063491 United States DK NIDDK NIH HHS; K01 DK105075 United States DK NIDDK NIH HHS; R01 DK117551 United States DK NIDDK NIH HHS; R01 DK122804 United States DK NIDDK NIH HHS; R03 DK118195 United States DK NIDDK NIH HHS; I01 BX003934 United States BX BLRD VA Contributed Indexing: Keywords: acyl-CoA synthetase long-chain family member 1 (ACSL1); fasting; hepatic lipid metabolism; mitochondria; nonalcoholic fatty liver disease (NAFLD); re-esterification; tank-binding kinase 1 (TBK1); β-oxidation Substance Nomenclature: 0 (Fatty Acids) ; EC 2.7.1.- (Tbk1 protein, mouse) ; EC 2.7.11.1 (Protein Serine-Threonine Kinases) ; EC 6.2.1.- (ACSL1 protein, mouse) ; EC 6.2.1.- (Coenzyme A Ligases) Entry Date(s): Date Created: 20201105 Date Completed: 20211122 Latest Revision: 20211204 Update Code: 20231215 PubMed Central ID: PMC7710607

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TANK-Binding Kinase 1 Regulates the Localization of Acyl-CoA Synthetase ACSL1 to Control Hepatic Fatty Acid Oxidation.