Obesity is associated with chronic inflammation that exacerbates insulin resistance and metabolic disease. Inflammation drives the pathogenesis of nonalcoholic fatty liver disease (NAFLD), hepatic manifestations of obesity. Hepatic inflammatory microenvironments are believed to induce reprogramming of metabolic pathways; however, intracellular molecules coupling inflammation to metabolism remain poorly understood. Cytokines, damage-associated (DAMPs) and pathogen-associated molecular patterns (PAMPs) are known to activate Traf family members that in turn activate the NF-κB and other inflammatory pathways. We previously reported that hepatic Traf2 and Traf3 augment hepatic glucose production. Here, we demonstrate that hepatocyte Traf2, Traf3 and Traf6 act in concert to promote liver steatosis and insulin resistance. We ablated hepatocyte Traf2, Traf3, and Traf6 individually and in combination (Traf2,3,6Δhep) in adult Traf2flox/flox, Traf3flox/flox, Traf6flox/flox, and Traf2,3,6flox/flox mice, respectively, using AAV-TBG-Cre vectors. Metabolic abnormality was more severe in Traf2,3,6Δhep mice relative to Traf2Δhep, Traf3Δhep and Traf6Δhep mice. Remarkably, Traf2,3,6Δhep mice were resistant to high fat diet-induced liver steatosis, insulin resistance, and glucose intolerance. Hepatic PPARα, a master regulator of fatty acid β oxidation, was substantially elevated in Traf2,3,6Δhep mice. Conversely, in primary hepatocytes, overexpression of Traf3 markedly decreased PPARα stability and protein levels. Traf3 coimmunoprecipitated with PPARα and decreased PPARα transcriptional activity. In primary hepatocytes, ablation of Traf2, Traf3 and Traf6 significantly increased fatty acid β oxidation, and overexpression of Traf3 had the opposite effects. Together, our results unveil an unrecognized hepatocyte Traf/PPARα/fatty acid β oxidation pathway that couples inflammation to liver steatosis and insulin resistance in obesity.


Z. Zhang: None. H. Lin: None. X. Zhong: None. L. Rui: None.

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