8月3日，国际权威学术期刊《细胞代谢》（Cell Metabolism）在线发表了中国科学院上海生命科学研究院生物化学与细胞生物学研究所宋保亮研究组与李伯良研究组的最新研究成果，揭示了泛素连接酶gp78调控脂质代谢的机理，为治疗肥胖等一系列代谢疾病提供了新的途径。
胆固醇等脂质小分子具有重要的生物学功能，但过量的胆固醇会引起动脉粥样硬化，进而导致冠心病和脑中风等一系列严重的疾病。因此，体内脂质水平必须受到严密而精准的调控。
gp78作为一个泛素连接酶，能调控胆固醇代谢过程中的一些重要蛋白质的降解。泛素连接酶，是将泛素分子（一种小蛋白，它的主要功能是标记需要分解掉的蛋白质）连接到目的蛋白质，使其被降解的酶。由于肝脏是脂质代谢的重要器官，为探究gp78的生理功能，宋保亮研究组与李伯良研究组在小鼠肝脏中特异性敲除了gp78基因。
博士研究生柳童斐等研究发现，gp78基因缺失的小鼠消瘦，脂肪含量减少，能够显著抵抗高脂饮食和年龄诱导的肥胖，并且表现为胰岛素敏感性增强。其分子机制在于一方面减少了胆固醇与脂肪酸等脂质合成，另一方面促进大量葡萄糖和脂肪酸等营养物质的消耗。这项研究发现了脂质合成与能量代谢之间的联系，并提示gp78可作为治疗肥胖、糖尿病等代谢疾病的靶标。
该课题获得了国家科技部、国家自然科学基金委和上海市科委的经费支持。（生物谷Bioon.com）
doi:10.1016/j.cmet.2012.06.014
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Ablation of gp78 in Liver Improves Hyperlipidemia and Insulin Resistance by Inhibiting SREBP to Decrease Lipid Biosynthesis
Tong-Fei Liu, Jing-Jie Tang, Pei-Shan Li, Yang Shen, Jia-Gui Li, Hong-Hua Miao, Bo-Liang Li, Bao-Liang Song
gp78 is a membrane-anchored ubiquitin ligase mediating the degradation of HMG-CoA reductase (HMGCR) and Insig-1. As a rate-limiting enzyme in cholesterol biosynthesis, HMGCR undergoes rapid sterol-promoted degradation. In contrast, destruction of Insig-1 releases its inhibition on SREBP and stimulates the expression of lipogenic genes. Thus, gp78 has opposite effects on lipid biosynthesis. We here generated liver-specific gp78 knockout (L-gp78?/?) mice and showed that although the degradation of HMGCR was blunted, SREBP was suppressed due to the elevation of Insig-1/-2, and therefore the lipid biosynthesis was decreased. The L-gp78?/? mice were protected from diet-/age-induced obesity and glucose intolerance. The livers of L-gp78?/? mice produced more FGF21, which activated thermogenesis in brown adipocytes and enhanced energy expenditure. Together, the major function of gp78 in liver is regulating lipid biosynthesis through SREBP pathway. Ablation of gp78 decreases the lipid levels and increases FGF21, and is beneficial to patients with metabolic diseases.
