坦克结合激酶1
β氧化
脂肪酸
内质网
生物化学
脂肪肝
线粒体
激活剂(遗传学)
激酶
内科学
内分泌学
化学
生物
蛋白激酶A
受体
医学
MAP激酶激酶激酶
疾病
作者
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
出处
期刊:Cell Metabolism
[Elsevier]
日期:2020-12-01
卷期号:32 (6): 1012-1027.e7
被引量:44
标识
DOI:10.1016/j.cmet.2020.10.010
摘要
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.
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