Ablation of gp78 in Liver Improves Hyperlipidemia and Insulin Resistance by Inhibiting SREBP to Decrease Lipid Biosynthesis
Ablation of gp78 in Liver Improves Hyperlipidemia and Insulin Resistance by Inhibiting SREBP to Decrease Lipid Biosynthesis
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肝脏中 gp78 的消除通过抑制 SREBP 减少脂质生物合成改善高脂血症和胰岛素抵抗
DOI：
10.1016/j.cmet.2012.06.014
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发表时间：
2012-08-08
期刊：
影响因子：
29
通讯作者：
Song, Bao-Liang
中科院分区：
文献类型：
--
作者：
Liu, Tong-Fei;Tang, Jing-Jie;Song, Bao-Liang
gp78 是一种膜锚定泛素连接酶，介导 HMG-CoA 还原酶 (HMGCR) 和 Insig-1 的降解。作为胆固醇生物合成中的限速酶，HMGCR 会经历甾醇促进的快速降解。相反，Insig-1 的破坏释放了其对 SREBP 的抑制并刺激脂肪生成基因的表达。因此，gp78 对脂质生物合成具有相反的作用。我们在这里生成了肝脏特异性 gp78 敲除 (L-gp78(-/-)) 小鼠，结果表明，尽管 HMGCR 的降解减弱，但由于 Insig-1/-2 的升高，SREBP 受到抑制，因此脂质生物合成减少。 L-gp78(-/-) 小鼠免受饮食/年龄诱导的肥胖和葡萄糖不耐受的影响。 L-gp78(-/-)小鼠的肝脏产生更多的FGF21，激活棕色脂肪细胞的生热作用并增加能量消耗。总之，gp78 在肝脏中的主要功能是通过 SREBP 途径调节脂质生物合成。消除gp78可降低脂质水平并增加FGF21，对患有代谢性疾病的患者有益。
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.