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TBK1通过调节ACSL1定位来控制肝脂肪酸氧化
作者:小柯机器人 发布时间:2020/11/6 20:05:34

美国加州大学圣地亚哥分校Alan R. Saltiel课题组在研究中取得进展。他们提出TANK(与TRAF家族成员相关的NFκB激活剂)结合激酶1(TBK1)调节酰基辅酶A合成酶长链家族成员1(ACSL1)的定位,以控制肝脂肪酸氧化。该项研究成果发表在2020年11月4日出版的《细胞-代谢》杂志上。

肥胖期间肝TBK1活性增加,而给予TBK1抑制剂可减少脂肪肝。出人意料的是,小鼠肝脏特异性TBK1基因敲除会通过减少脂肪酸氧化导致脂肪肝。TBK1充当脚手架蛋白,将ACSL1定位于线粒体,因此线粒体能够产生可引导β-氧化的酰基辅酶A。禁食期间可诱导TBK1,并使其保持未磷酸化的非活性状态,从而使其与线粒体中的ACSL1具有高亲和力。

在缺乏TBK1的肝脏中,ACSL1转移到内质网以促进脂肪酸的再酯化,以代替对禁食的氧化,从而加速了肝脂质的积累。激酶失活的TBK1的表达可以挽救TBK1缺陷型肝细胞中受损的脂肪酸氧化。因此,TBK1充当变阻器,以指导肝细胞中脂肪酸的命运,在禁食中无活性时支持氧化,而在肥胖症中激活时则促进重新酯化。

附:英文原文

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

Author: Jin Young Huh, Shannon M. Reilly, Mohammad Abu-Odeh, Anne N. Murphy, Sushil K. Mahata, Jinyu Zhang, Yoori Cho, Jong Bae Seo, Chao-Wei Hung, Courtney R. Green, Christian M. Metallo, Alan R. Saltiel

Issue&Volume: 2020-11-04

Abstract: Hepatic TANK (TRAF family member associated NFκB activator)-binding kinase 1 (TBK1)activity is increased during obesity, and administration of a TBK1 inhibitor reducesfatty liver. Surprisingly, liver-specific TBK1 knockout in mice produces fatty liverby reducing fatty acid oxidation. TBK1 functions as a scaffolding protein to localizeacyl-CoA synthetase long-chain family member 1 (ACSL1) to mitochondria, which generatesacyl-CoAs that are channeled for β-oxidation. TBK1 is induced during fasting and maintainedin the unphosphorylated, inactive state, enabling its high affinity binding to ACSL1in mitochondria. In TBK1-deficient liver, ACSL1 is shifted to the endoplasmic reticulumto 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 theexpression of kinase-dead TBK1. Thus, TBK1 operates as a rheostat to direct the fateof fatty acids in hepatocytes, supporting oxidation when inactive during fasting andpromoting re-esterification when activated during obesity.

DOI: 10.1016/j.cmet.2020.10.010

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30543-X

期刊信息

Cell Metabolism:《细胞—代谢》,创刊于2005年。隶属于细胞出版社,最新IF:22.415
官方网址:https://www.cell.com/cell-metabolism/home
投稿链接:https://www.editorialmanager.com/cell-metabolism/default.aspx