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TANK-Binding Kinase 1 Regulates the Localization of Acyl-CoA Synthetase ACSL1 to Control Hepatic Fatty Acid Oxidation
| Content Provider | eScholarship Repository: University of California |
|---|---|
| Author | 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 |
| Abstract | 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. |
| File Format | |
| DOI | 10.1016/j.cmet.2020.10.010 |
| Alternate Webpage(s) | https://escholarship.org/uc/item/159582qr |
| Journal | Cell Metabolism |
| Issue Number | 6 |
| Volume Number | 32 |
| Language | English |
| Publisher Date | 2020-12-01 |
| Access Restriction | Open |
| Subject Keyword | Fasting Hepatic Lipid Metabolism Mitochondria Nonalcoholic Fatty Liver Disease Re-Esterification Β-Oxidation Biochemistry and Cell Biology Biological Sciences Digestive Diseases Chronic Liver Disease and Cirrhosis Liver Disease Nutrition Obesity Oral and gastrointestinal Animals Coenzyme A Ligases Fatty Acids HEK293 Cells Humans Male Mice Inbred C57BL Knockout Non-alcoholic Fatty Liver Disease Oxidation-Reduction Protein Serine-Threonine Kinases acyl-CoA synthetase long-chain family member 1 tank-binding kinase 1 Medical Biochemistry and Metabolomics Endocrinology & Metabolism |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Molecular Biology Physiology |
