Cell Metabolism
Volume 32, Issue 6, 1 December 2020, Pages 1012-1027.e7
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Article
TANK-Binding Kinase 1 Regulates the Localization of Acyl-CoA Synthetase ACSL1 to Control Hepatic Fatty Acid Oxidation

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Highlights

  • Hepatic TBK1 activity is reduced by fasting while elevated by obesity

  • Liver-specific TBK1 KO mice exhibit increased liver lipid due to less fat oxidation

  • Fasting-stimulated mitochondrial localization of ACSL1 is impaired in TBK1 KO mice

  • Inactive TBK1 rescues fatty acid oxidation, suggesting a scaffolding function

Summary

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.

Keywords

tank-binding kinase 1 (TBK1)
acyl-CoA synthetase long-chain family member 1 (ACSL1)
hepatic lipid metabolism
fasting
mitochondria
β-oxidation
re-esterification
nonalcoholic fatty liver disease (NAFLD)

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