Importantly, metabolic stress further aggravated NASH progression in the absence of Fbxw7, resulting from deregulated hepatic and peripheral stress responses mediated by drastic alteration of liver-derived secreted factors known to participate in peripheral glucose and lipid metabolism as well as liver fibrogenesis, including Apoa4, Apcs and Igfbp1. The gene discussed is APOA4; the disease is metabolic dysfunction-associated steatohepatitis.