Serum palmitic acid(PA), a type of saturated fatty acid, causes lipid accumulation and induces toxicity in hepatocytes.Ethanol(Et OH) is metabolized by the liver and induces hepatic injury and inflammation. Herein, we...Serum palmitic acid(PA), a type of saturated fatty acid, causes lipid accumulation and induces toxicity in hepatocytes.Ethanol(Et OH) is metabolized by the liver and induces hepatic injury and inflammation. Herein, we analyzed the effects of Et OH on PA-induced lipotoxicity in the liver. Our results indicated that Et OH aggravated PA-induced apoptosis and lipid accumulation in primary rat hepatocytes in dose-dependent manner. Et OH intensified PA-caused endoplasmic reticulum(ER) stress response in vitro and in vivo, and the expressions of CHOP, ATF4, and XBP-1 in nucleus were significantly increased. Et OH also increased PA-caused cleaved caspase-3 in cytoplasm. In wild type and CHOP–/– mice treated with Et OH and high fat diet(HFD), Et OH worsened the HFD-induced liver injury and dyslipidemia, while CHOP knockout blocked toxic effects of Et OH and PA. Our study suggested that targeting UPR-signaling pathways is a promising, novel approach to reducing Et OH and saturated fatty acid-induced metabolic complications.展开更多
基金supported by National Natural Science Foundation of China(Nos.81273569,81001465)Natural Science Foundation of Jiangsu Province,China(No.BK2012726)the Ph.D. Programs Foundation of Ministry of Education of China(No.20100091120028)
文摘Serum palmitic acid(PA), a type of saturated fatty acid, causes lipid accumulation and induces toxicity in hepatocytes.Ethanol(Et OH) is metabolized by the liver and induces hepatic injury and inflammation. Herein, we analyzed the effects of Et OH on PA-induced lipotoxicity in the liver. Our results indicated that Et OH aggravated PA-induced apoptosis and lipid accumulation in primary rat hepatocytes in dose-dependent manner. Et OH intensified PA-caused endoplasmic reticulum(ER) stress response in vitro and in vivo, and the expressions of CHOP, ATF4, and XBP-1 in nucleus were significantly increased. Et OH also increased PA-caused cleaved caspase-3 in cytoplasm. In wild type and CHOP–/– mice treated with Et OH and high fat diet(HFD), Et OH worsened the HFD-induced liver injury and dyslipidemia, while CHOP knockout blocked toxic effects of Et OH and PA. Our study suggested that targeting UPR-signaling pathways is a promising, novel approach to reducing Et OH and saturated fatty acid-induced metabolic complications.
