Fibronectin containing extra domain A（EDA~＋ FN）,a functional glycoprotein participating in several cellular processes,correlates with chronic liver disease.Herein,we aim to investigate the expression and secretion ...Fibronectin containing extra domain A（EDA~＋ FN）,a functional glycoprotein participating in several cellular processes,correlates with chronic liver disease.Herein,we aim to investigate the expression and secretion of EDA~＋ FN from hepatocytes in nonalcoholic fatty liver disease（NAFLD） and the underlying mechanisms.Circulating levels of EDA~＋ FN were determined by ELISA in clinical samples.Western blotting and flow cytometry were performed on L02 and Hep G2 cell lines to analyze whether the levels of EDA~＋ FN were associated with endoplasmic reticulum（ER） stress-related cell death.Circulating levels of EDA~＋ FN in NAFLD patients were significantly higher than those in control subjects,and positively related with severity of ultrasonographic steatosis score.In cultured hepatocytes,palmitate up-regulated the expression of EDA~＋ FN in a dose-dependent manner.Conversely,when the cells were pretreated with 4-phenylbutyrate,a specific inhibitor of ER stress,up-regulation of EDA~＋ FN could be abrogated.Moreover,silencing CHOP by sh RNA enhanced the release of EDA~＋ FN from hepatocytes following palmitate treatment,which was involved in ER stress-related cell damage.These findings suggest that the up-regulated level of EDA~＋ FN is associated with liver damage in NAFLD,and ER stress-mediated cell damage contributes to the release of EDA~＋ FN from hepatocytes.展开更多
目的观察利拉鲁肽对2型糖尿病(T2DM)合并非酒精性脂肪肝(NAFLD)患者内质网应激(ERS)的影响,并分析其临床疗效。方法选取我院2017年6月—2019年2月收治的T2DM伴发NAFLD患者144例,使用数字表法随机分为对照组和观察组,每组72例。对照组给...目的观察利拉鲁肽对2型糖尿病(T2DM)合并非酒精性脂肪肝(NAFLD)患者内质网应激(ERS)的影响,并分析其临床疗效。方法选取我院2017年6月—2019年2月收治的T2DM伴发NAFLD患者144例,使用数字表法随机分为对照组和观察组,每组72例。对照组给二甲双胍,0.5g/次,2次/d,观察组给予利拉鲁肽,0.6mg/d,连用1周,以后1.2 mg/d,疗程12周。使用荧光定量PCR法检测内质网应激蛋白(CHOP)、激活转录因子6(ATF6)和分子伴侣葡萄糖调节蛋白78(GRP78)基因表达。比较两组临床疗效和不良反应。结果治疗前两组FBG、2 h PBG、HbA1c、HOMA-IR、TG、TC和LDL-C无显著性差异(P>0.05),治疗后观察组FBG、2 h PBG、HbA1c、HOMA-IR、TG、TC和LDL-C显著低于对照组(P<0.05)。治疗前两组CHOP、ATF6和GRP78基因表达2-△△Ct值无显著性差异(P>0.05),治疗后观察组CHOP、ATF6和GRP78基因表达2-△△Ct值显著低于对照组(P<0.05)。观察组临床治疗有效率为81.9%(59/72),显著高于对照组的62.5%(45/72)(P<0.05)。对照组不良反应发生率为2.8%(2/72),观察组不良反应发生率为4.2%(3/72),两组不良反应发生率无显著性差异(P>0.05)。结论利拉鲁肽可以降低T2DM伴发NAFLD患者的ERS,降低血糖和血脂,临床疗效显著,使用安全。展开更多
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 the National Natural Science Foundation of China(No.81300304 and No.31271855)
文摘Fibronectin containing extra domain A（EDA~＋ FN）,a functional glycoprotein participating in several cellular processes,correlates with chronic liver disease.Herein,we aim to investigate the expression and secretion of EDA~＋ FN from hepatocytes in nonalcoholic fatty liver disease（NAFLD） and the underlying mechanisms.Circulating levels of EDA~＋ FN were determined by ELISA in clinical samples.Western blotting and flow cytometry were performed on L02 and Hep G2 cell lines to analyze whether the levels of EDA~＋ FN were associated with endoplasmic reticulum（ER） stress-related cell death.Circulating levels of EDA~＋ FN in NAFLD patients were significantly higher than those in control subjects,and positively related with severity of ultrasonographic steatosis score.In cultured hepatocytes,palmitate up-regulated the expression of EDA~＋ FN in a dose-dependent manner.Conversely,when the cells were pretreated with 4-phenylbutyrate,a specific inhibitor of ER stress,up-regulation of EDA~＋ FN could be abrogated.Moreover,silencing CHOP by sh RNA enhanced the release of EDA~＋ FN from hepatocytes following palmitate treatment,which was involved in ER stress-related cell damage.These findings suggest that the up-regulated level of EDA~＋ FN is associated with liver damage in NAFLD,and ER stress-mediated cell damage contributes to the release of EDA~＋ FN from hepatocytes.
文摘目的观察利拉鲁肽对2型糖尿病(T2DM)合并非酒精性脂肪肝(NAFLD)患者内质网应激(ERS)的影响,并分析其临床疗效。方法选取我院2017年6月—2019年2月收治的T2DM伴发NAFLD患者144例,使用数字表法随机分为对照组和观察组,每组72例。对照组给二甲双胍,0.5g/次,2次/d,观察组给予利拉鲁肽,0.6mg/d,连用1周,以后1.2 mg/d,疗程12周。使用荧光定量PCR法检测内质网应激蛋白(CHOP)、激活转录因子6(ATF6)和分子伴侣葡萄糖调节蛋白78(GRP78)基因表达。比较两组临床疗效和不良反应。结果治疗前两组FBG、2 h PBG、HbA1c、HOMA-IR、TG、TC和LDL-C无显著性差异(P>0.05),治疗后观察组FBG、2 h PBG、HbA1c、HOMA-IR、TG、TC和LDL-C显著低于对照组(P<0.05)。治疗前两组CHOP、ATF6和GRP78基因表达2-△△Ct值无显著性差异(P>0.05),治疗后观察组CHOP、ATF6和GRP78基因表达2-△△Ct值显著低于对照组(P<0.05)。观察组临床治疗有效率为81.9%(59/72),显著高于对照组的62.5%(45/72)(P<0.05)。对照组不良反应发生率为2.8%(2/72),观察组不良反应发生率为4.2%(3/72),两组不良反应发生率无显著性差异(P>0.05)。结论利拉鲁肽可以降低T2DM伴发NAFLD患者的ERS,降低血糖和血脂,临床疗效显著,使用安全。
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.
