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.

Obesity: tracing the inflammation underlying liver disease

A deeper understanding of the molecular processes underlying dysfunctional fatty-acid metabolism in nonalcoholic fatty liver disease (NAFLD) could help protect patients from severe liver damage. NAFLD is a common consequence of obesity, and severe disease can ultimately give rise to liver cancer or cirrhosis. Alan Saltiel of the University of California, San Diego, USA, and Jin Young Huh of Seoul National University, South Korea, have reviewed current knowledge of the mechanisms governing fatty acid metabolism in the liver, and how they are disturbed in obesity and NAFLD. The various IκB kinase (IKK) complexes and a protein known as TANK-binding kinase 1 (TBK1) play particularly prominent roles in the inflammatory response associated with NAFLD pathogenesis. Better insights into IKK- and TBK1-associated regulatory pathways could inform the development of new interventions for this currently untreatable condition.