Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.
Arterioscler Thromb Vasc Biol. 2012 Aug;32(8):1824-31. doi: 10.1161/ATVBAHA.111.240754. Epub 2012 Jun 14.
3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) catalyzes the rate-limiting step in cholesterol biosynthesis and has proven to be an effective target of lipid-lowering drugs, statins. The aim of this study was to understand the role of hepatic HMGCR in vivo.
To disrupt the HMGCR gene in liver, we generated mice homozygous for a floxed HMGCR allele and heterozygous for a transgene encoding Cre recombinase under the control of the albumin promoter (liver-specific HMGCR knockout mice). Ninety-six percent of male and 71% of female mice died by 6 weeks of age, probably as a result of liver failure or hypoglycemia. At 5 weeks of age, liver-specific HMGCR knockout mice showed severe hepatic steatosis with apoptotic cells, hypercholesterolemia, and hypoglycemia. The hepatic steatosis and death were completely reversed by providing the animals with mevalonate, indicating its essential role in normal liver function. There was a modest decrease in hepatic cholesterol synthesis in liver-specific HMGCR knockout mice. Instead, they showed a robust increase in the fatty acid synthesis, independent of sterol regulatory element binding protein-1c.
Hepatocyte HMGCR is essential for the survival of mice, and its abrogation elicits hepatic steatosis with jaundice and hypoglycemia.
3-羟-3-甲基戊二酰基辅酶 A 还原酶（HMGCR）催化胆固醇生物合成的限速步骤，已被证明是降脂药物他汀类药物的有效靶点。本研究旨在了解肝内 HMGCR 的作用。
为了在肝脏中破坏 HMGCR 基因，我们生成了 HMGCR 基因纯合缺失且白蛋白启动子控制下的 Cre 重组酶转基因杂合的小鼠（肝特异性 HMGCR 敲除小鼠）。96%的雄性和 71%的雌性小鼠在 6 周龄时死亡，可能是由于肝功能衰竭或低血糖。在 5 周龄时，肝特异性 HMGCR 敲除小鼠表现出严重的肝脂肪变性伴凋亡细胞、高胆固醇血症和低血糖。用甲羟戊酸喂养动物可完全逆转肝脂肪变性和死亡，表明其在正常肝功能中的重要作用。肝特异性 HMGCR 敲除小鼠的肝胆固醇合成略有下降。相反，它们表现出脂肪酸合成的显著增加，这与固醇调节元件结合蛋白-1c 无关。
肝细胞 HMGCR 对小鼠的生存至关重要，其缺失会导致肝脂肪变性、黄疸和低血糖。
