Although numerous functions of extracellular signal-regulated kinase 1/2 (ERK1/2) are identified, a direct effect of ERK1/2 on liver steatosis has not been reported. Here, we show that ERK1/2 activity is compromised in livers of leptin receptor-deficient (db/db) mice. Adenovirus-mediated activation of mitogen-activated protein kinase kinase 1 (MEK1), the upstream regulator of ERK1/2, significantly ameliorated liver steatosis in db/db mice, increased expression of genes related to fatty acid β-oxidation and triglyceride (TG) export and increased serum β-hydroxybutyrate (3-HB) levels. Opposite effects were observed in adenovirus-mediated ERK1/2 knockdown C57/B6J wild-type mice. Furthermore, autophagy and autophagy-related protein 7 (ATG7) expression were decreased or increased by ERK1/2 knockdown or activation, respectively, in primary hepatocytes and liver. Blockade of autophagy by the autophagy inhibitor chloroquine or adenovirus-mediated ATG7 knockdown reversed the ameliorated liver steatosis in recombinant adenoviruses construct expressing rat constitutively active MEK1 Ad-CA MEK1 db/db mice, decreased expression of genes related to fatty acid β-oxidation and TG export, and decreased serum 3-HB levels. Finally, ERK1/2 regulated ATG7 expression in a p38-dependent pathway. Taken together, these results identify a novel beneficial role for ERK1/2 in liver steatosis via promoting ATG7-dependent autophagy, which provides new insights into the mechanisms underlying liver steatosis and important hints for targeting ERK1/2 in treating liver steatosis.
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