Abstract
Hepatocyte apoptosis is a hallmark of nonalcoholic steatohepatitis (NASH) and contributes to liver injury, fibrosis, and inflammation. However, the molecular mechanisms underlying excessive hepatocyte apoptosis in NASH remain largely unknown. This study aimed to explore whether and how the v-ets avian erythroblastosis virus E26 oncogene homolog 1 (Ets-1) is involved in diet-induced hepatocyte apoptosis in mice. The study found that the expression level of hepatic Ets-1 was elevated in a NASH mouse model as a result of the activation of transforming growth factor beta1 (TGF-β1) signaling. In the presence of TGF-β1, phosphorylated mothers against decapentaplegic homolog 2/3 (p-Smad2/3) translocated to the binding sites of the Ets-1 promoter to upregulate the expression of Ets-1 in primary hepatocytes. In addition, Ets-1 bound directly to phosphorylated Smad3 (p-Smad3), thereby preventing the ubiquitination and proteasomal degradation of p-Smad3 and enhancing the activity of TGF-β1/Smad3 signaling. Consequently, elevated Ets-1 stimulated TGF-β1-induced hepatocyte apoptosis. However, Ets-1 knockdown alleviated diet-induced hepatocyte apoptosis and NASH with reduced liver injury, inflammation, and fibrosis. Taken together, Ets-1 had an adverse impact on hepatocyte survival under TGF-β1 treatment and accelerated the development of NASH in mice.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is both common and chronic and occurs in ~25% of the general population in the world[1]
Among the cytokines, transforming growth factor beta[1] (TGF-β1) is closely associated with fibrosis and apoptosis, which plays a major role in the progression of NASH11
The forced expression of Ets-1 reinforced the effect of TGF-β1, and it increased the expressions of BCL-2-interacting mediator of cell death (Bim) and cleaved caspase-3 in hepatocytes (Fig. 5f). These results demonstrated that Ets[1] participated in apoptosis, mediated by TGF-β1/ Smad[3] signaling, which promoted the progression of nonalcoholic steatohepatitis (NASH)
Summary
Nonalcoholic fatty liver disease (NAFLD) is both common and chronic and occurs in ~25% of the general population in the world[1]. NAFLD includes a wide spectrum of disorders ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). NASH is characterized by liver injury, inflammation, fibrosis and a high risk of cirrhosis and eventual hepatocellular carcinoma[3]. During the development of NASH, hepatocellular apoptosis activates the aberration of the liver’s regenerative responses, including fibrosis and inflammation[8,9]. Chronic inflammation in liver tissues stimulates macrophages to produce cytokines, which further promote hepatocyte apoptosis, thereby aggravating NASH10. Among the cytokines, transforming growth factor beta[1] (TGF-β1) is closely associated with fibrosis and apoptosis, which plays a major role in the progression of NASH11. Besides activating hepatic star cells (HSCs) for extracellular matrix deposition[12], TGF-β1 signaling was over-activated in hepatocytes of patients with NASH13. It has been proven that the hepatocyte specific knockdown of TGF-β type II receptor (TβRII) preserves hepatocyte survival and protects against diet-induced
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