NEFA介导内质网应激对奶牛肝细胞自噬和脂质代谢的调控机制

项目名称： NEFA介导内质网应激对奶牛肝细胞自噬和脂质代谢的调控机制

项目编号： No.31502129

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 农业科学

项目作者： 王建国

作者单位： 西北农林科技大学

项目金额： 20万元

中文摘要： 脂肪过度动员导致的高非酯化脂肪酸（NEFA）血症是诱发围产期奶牛能量代谢障碍性疾病的前提。申请者前期研究显示，高浓度NEFA可显著上调奶牛肝细胞中内质网应激（ERS）标志性分子表达。研究表明ERS与多种疾病发生有关，但NEFA介导的ERS是否参与奶牛肝细胞自噬和脂质代谢调节还不明确。本项目以“NEFA介导的ERS调控肝细胞自噬并促进肝脂沉积，进而促发奶牛能量代谢障碍性疾病”为理论假设，通过测定健康与高NEFA血症奶牛肝脏中ERS和自噬关键因子表达水平，并分析其与血液NEFA浓度和肝脂沉积的相关性，明确NEFA介导ERS并参与奶牛肝细胞自噬调控；通过体外培养奶牛肝细胞并模拟高NEFA血症，测定ERS、自噬和脂质代谢关键信号分子表达水平及其相互关系，探究NEFA介导ERS对奶牛肝细胞自噬和脂质代谢的调控机制，为进一步揭示奶牛能量代谢障碍性疾病的发病机理并探寻其防治的新靶标和途径奠定理论基础。

中文关键词： 奶牛；肝细胞；内质网应激；脂质代谢；致病机理

英文摘要： Negative energy balance (NEB) is considered as the pathological basis of energy metabolic disorders in periparturient dairy cows. Under the condition of NEB, excessive fat mobilization results in a marked influx of non-esterified fatty acids (NEFA) in blood, which is crucial to cause energy metabolic disorders, like fatty liver and ketosis etc. Preliminary experiment data showed that high NEFA concentrations increased the expression of endoplasmic reticulum stress (ERS) marker molecules in hepatocytes of dairy cows. Studies have shown that ERS occurs under various pathological conditions, and plays a vital role in pathologic processes of numerous diseases. However, molecular mechanisms of how NEFA-induced ERS is involved in the regulation of hepatocyte autophagy and lipid metabolism in dairy cows remain poorly understood. Therefore, we hypothesize that NEFA-induced ERS regulates hepatocyte autophagy and lipid accumulation, thereby promoting the occurrence of energy metabolic disorders in periparturient dairy cows. In order to make clear the involvement and regulation of NEFA-induced ERS in hepatocyte autophagy, expressions of several key indicators of ERS and autophagy are measured, and their correlation with blood NEFA concentration and liver TG content are as well analyzed in both healthy periparturient dairy cows and cows with high blood NEFA. Primary cultured cow hepatocytes with/without high NEFA are established as a experiment model in vitro. The expression of the key signal molecules of ERS, autophagy and lipid metabolism and their relationships are determined in cultured hepatocytes, which will explore the regulatory mechanism of hepatocyte autophagy and lipid metabolism by NEFA-induced ERS in dairy cows. The present project will further reveal the pathogenesis of energy metabolism disorders in dairy cows, and establish the theoretical basis for searching new targets and methods for prevention and treatment of those diseases.

英文关键词： Dairy cow;Hepatocytes;Endoplasmic reticulum stress;Lipid metabolism;Pathogenesis