8月3日，國際權(quán)威學(xué)術(shù)期刊《細(xì)胞代謝》（Cell Metabolism）在線發(fā)表了中國科學(xué)院上海生命科學(xué)研究院生物化學(xué)與細(xì)胞生物學(xué)研究所宋保亮研究組與李伯良研究組的最新研究成果,，揭示了泛素連接酶gp78調(diào)控脂質(zhì)代謝的機(jī)理,，為治療肥胖等一系列代謝疾病提供了新的途徑。
膽固醇等脂質(zhì)小分子具有重要的生物學(xué)功能,，但過量的膽固醇會(huì)引起動(dòng)脈粥樣硬化,，進(jìn)而導(dǎo)致冠心病和腦中風(fēng)等一系列嚴(yán)重的疾病。因此,，體內(nèi)脂質(zhì)水平必須受到嚴(yán)密而精準(zhǔn)的調(diào)控,。
gp78作為一個(gè)泛素連接酶，能調(diào)控膽固醇代謝過程中的一些重要蛋白質(zhì)的降解,。泛素連接酶,，是將泛素分子（一種小蛋白，它的主要功能是標(biāo)記需要分解掉的蛋白質(zhì)）連接到目的蛋白質(zhì),，使其被降解的酶,。由于肝臟是脂質(zhì)代謝的重要器官，為探究gp78的生理功能,，宋保亮研究組與李伯良研究組在小鼠肝臟中特異性敲除了gp78基因,。
博士研究生柳童斐等研究發(fā)現(xiàn)，gp78基因缺失的小鼠消瘦,，脂肪含量減少,，能夠顯著抵抗高脂飲食和年齡誘導(dǎo)的肥胖，并且表現(xiàn)為胰島素敏感性增強(qiáng),。其分子機(jī)制在于一方面減少了膽固醇與脂肪酸等脂質(zhì)合成,，另一方面促進(jìn)大量葡萄糖和脂肪酸等營養(yǎng)物質(zhì)的消耗。這項(xiàng)研究發(fā)現(xiàn)了脂質(zhì)合成與能量代謝之間的聯(lián)系,，并提示gp78可作為治療肥胖,、糖尿病等代謝疾病的靶標(biāo)。
該課題獲得了國家科技部,、國家自然科學(xué)基金委和上海市科委的經(jīng)費(fèi)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.
