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

• Published in: Cell metabolism 2020-12, Vol.32 (6), p.1012-1027.e7
• Main Authors: Huh, Jin Young, Reilly, Shannon M., Abu-Odeh, Mohammad, Murphy, Anne N., Mahata, Sushil K., Zhang, Jinyu, Cho, Yoori, Seo, Jong Bae, Hung, Chao-Wei, Green, Courtney R., Metallo, Christian M., Saltiel, Alan R.
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2020.10.010

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. [Display omitted] •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 Huh et al. demonstrate that TBK1 is necessary for fasting-induced fat oxidation in liver via channeling substrates to mitochondria. While obesity increases the kinase activity of TBK1, fasting reduces its activity, which elevates the inactive TBK1 to support more efficient fat oxidation. This pathway may contribute to the mechanism by which TBK1 inhibitors improve fatty liver.