Zaid Ahmed, Roubtsova Anna, Essalmani Rachid, Marcinkiewicz Jadwiga, Chamberland Ann, Hamelin Josée, Tremblay Michel, Jacques Hélène, Jin Weijun, Davignon Jean, Seidah Nabil G, Prat Annik
Laboratorie of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, affiliated to the University of Montreal, Montreal, Quebec, Canada.
Hepatology. 2008 Aug;48(2):646-54. doi: 10.1002/hep.22354.
The gene encoding the proprotein convertase subtilisin/kexin type 9 (PCSK9) is linked to familial hypercholesterolemia, as are those of the low-density lipoprotein receptor (LDLR) and apolipoprotein B. PCSK9 enhances LDLR degradation, resulting in low-density lipoprotein accumulation in plasma. To analyze the role of hepatic PCSK9, total and hepatocyte-specific knockout mice were generated. They exhibit 42% and 27% less circulating cholesterol, respectively, showing that liver PCSK9 was responsible for two thirds of the phenotype. We also demonstrated that, in liver, PCSK9 is exclusively expressed in hepatocytes, representing the main source of circulating PCSK9. The data suggest that local but not circulating PCSK9 regulates cholesterol levels. Although transgenic mice overexpressing high levels of liver and circulating PCSK9 led to the almost complete disappearance of the hepatic LDLR, they did not recapitulate the plasma cholesterol levels observed in LDLR-deficient mice. Single LDLR or double LDLR/PCSK9 knockout mice exhibited similar cholesterol profiles, indicating that PCSK9 regulates cholesterol homeostasis exclusively through the LDLR. Finally, the regenerating liver of PCSK9-deficient mice exhibited necrotic lesions, which were prevented by a high-cholesterol diet. However, lipid accumulation in hepatocytes of these mice was markedly reduced under both chow and high-cholesterol diets, revealing that PCSK9 deficiency confers resistance to liver steatosis.
Although PCSK9 is a target for controlling hypercholesterolemia, our data indicate that upon hepatic damage, patients lacking PCSK9 could be at risk.
编码前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK9）的基因与家族性高胆固醇血症相关，低密度脂蛋白受体（LDLR）和载脂蛋白B的基因也是如此。PCSK9增强LDLR降解，导致血浆中低密度脂蛋白积聚。为了分析肝脏PCSK9的作用，构建了全身和肝细胞特异性敲除小鼠。它们的循环胆固醇分别减少了42%和27%，表明肝脏PCSK9导致了三分之二的表型。我们还证明，在肝脏中，PCSK9仅在肝细胞中表达，是循环PCSK9的主要来源。数据表明，是局部而非循环中的PCSK9调节胆固醇水平。尽管过表达高水平肝脏和循环PCSK9的转基因小鼠导致肝脏LDLR几乎完全消失，但它们并未重现LDLR缺陷小鼠中观察到的血浆胆固醇水平。单LDLR或双LDLR/PCSK9敲除小鼠表现出相似的胆固醇谱，表明PCSK9仅通过LDLR调节胆固醇稳态。最后，PCSK9缺陷小鼠再生的肝脏出现坏死性病变，高胆固醇饮食可预防这种病变。然而，在普通饮食和高胆固醇饮食条件下，这些小鼠肝细胞中的脂质积累均显著减少，表明PCSK9缺陷赋予了对肝脏脂肪变性的抗性。
尽管PCSK9是控制高胆固醇血症的靶点，但我们的数据表明，肝脏受损时，缺乏PCSK9的患者可能有风险。
