Roles of IκB kinases and TANK-binding kinase 1 in hepatic lipid metabolism and nonalcoholic fatty liver disease

Abstract Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is strongly associated with obesity-related ectopic fat accumulation in the liver. Hepatic lipid accumulation encompasses a histological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma. Given that dysregulated hepatic lipid metabolism may be an onset factor in NAFLD, understanding how hepatic lipid metabolism is modulated in healthy subjects and which steps are dysregulated in NAFLD subjects is crucial to identify effective therapeutic targets. Additionally, hepatic inflammation is involved in chronic hepatocyte damage during NAFLD progression. As a key immune signaling hub that mediates NF-κB activation, the IκB kinase (IKK) complex, including IKKα, IKKβ, and IKKγ (NEMO), has been studied as a crucial regulator of the hepatic inflammatory response and hepatocyte survival. Notably, TANK-binding kinase 1 (TBK1), an IKK-related kinase, has recently been revealed as a potential link between hepatic inflammation and energy metabolism. Here, we review (1) the biochemical steps of hepatic lipid metabolism; (2) dysregulated lipid metabolism in obesity and NAFLD; and (3) the roles of IKKs and TBK1 in obesity and NAFLD.