Department of Internal Medicine I, Regensburg University Hospital, D-93042, Regensburg, Germany.
Department of Visceral Surgery and Medicine, University Inselspital, Bern, Switzerland.
Lipids Health Dis. 2021 Jan 18;20(1):6. doi: 10.1186/s12944-021-01431-x.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is of particular importance in cholesterol metabolism with high levels contributing to hypercholesterolemia. Cholesterol and sphingolipids are low in patients with liver cirrhosis. Purpose of this study was to find associations of plasma PCSK9 with circulating cholesterol and sphingolipid species and measures of liver disease severity in patients with liver cirrhosis.
PCSK9 protein levels were determined by ELISA in systemic vein (SVP), hepatic vein (HVP) and portal vein plasma of patients with mostly alcoholic liver cirrhosis. PCSK9 and LDL-receptor protein expression were analysed in cirrhotic and non-cirrhotic liver tissues.
Serum PCSK9 was reduced in patients with liver cirrhosis in comparison to non-cirrhotic patients. In liver cirrhosis, plasma PCSK9 was not correlated with Child-Pugh score, Model for End-Stage Liver Disease score, bilirubin or aminotransferases. A negative association of SVP PCSK9 with albumin existed. PCSK9 protein in the liver did not change with fibrosis stage and was even positively correlated with LDL-receptor protein levels. Ascites volume and variceal size were not related to PCSK9 levels. Along the same line, transjugular intrahepatic shunt to lower portal pressure did not affect PCSK9 concentrations in the three blood compartments. Serum cholesterol, sphingomyelin and ceramide levels did not correlate with PCSK9. Stratifying patients by high versus low PCSK9 levels using the median as cut-off, several cholesteryl ester species were even low in the subgroup with high PCSK9 levels. A few sphingomyelin species were also reduced in the patients with PCSK9 levels above the median. PCSK9 is highly expressed in the liver but systemic, portal and hepatic vein levels were similar. PCSK9 was not correlated with the inflammatory proteins C-reactive protein, IL-6, galectin-3, resistin or pentraxin 3. Of note, HVP PCSK9 was positively associated with HVP chemerin and negatively with HVP adiponectin levels.
In the cohort of patients with liver cirrhosis mostly secondary to alcohol consumption high PCSK9 was associated with low levels of certain cholesteryl ester and sphingomyelin species. Positive correlations of PCSK9 and LDL-receptor protein in the liver of patients with chronic liver injury are consistent with these findings.
前蛋白转化酶枯草溶菌素 9（PCSK9）在胆固醇代谢中尤为重要，高水平的 PCSK9 会导致高胆固醇血症。肝硬化患者的胆固醇和神经鞘脂类含量较低。本研究旨在寻找肝硬化患者血浆 PCSK9 与循环胆固醇和神经鞘脂类种类及肝脏疾病严重程度指标的相关性。
采用酶联免疫吸附法（ELISA）测定大多数酒精性肝硬化患者的静脉血（SVP）、肝静脉（HVP）和门静脉血浆中的 PCSK9 蛋白水平。分析肝硬化和非肝硬化肝组织中的 PCSK9 和 LDL 受体蛋白表达。
与非肝硬化患者相比，肝硬化患者的血清 PCSK9 降低。在肝硬化患者中，血浆 PCSK9 与 Child-Pugh 评分、终末期肝病模型评分、胆红素或氨基转移酶均无相关性。SVP PCSK9 与白蛋白呈负相关。肝脏中 PCSK9 蛋白的变化与纤维化分期无关，甚至与 LDL 受体蛋白水平呈正相关。腹水体积和静脉曲张大小与 PCSK9 水平无关。同样，经颈静脉肝内门体分流术（TIPS）降低门静脉压力也不会影响 3 个血液腔室中的 PCSK9 浓度。血清胆固醇、神经鞘氨醇和神经酰胺水平与 PCSK9 不相关。按中位数作为截断值将患者分为高 PCSK9 水平和低 PCSK9 水平亚组，发现高 PCSK9 水平亚组中几种胆固醇酯种类甚至较低。少数神经鞘氨醇种类在 PCSK9 水平高于中位数的患者中也减少。PCSK9 在肝脏中高度表达，但系统、门静脉和肝静脉水平相似。PCSK9 与炎症蛋白 C 反应蛋白、白细胞介素 6、半乳糖凝集素 3、抵抗素或五聚素 3 不相关。值得注意的是，HVP PCSK9 与 HVP 趋化素呈正相关，与 HVP 脂联素呈负相关。
在主要由酒精引起的肝硬化患者队列中，高 PCSK9 与某些胆固醇酯和神经鞘氨醇种类的低水平相关。慢性肝损伤患者肝脏中 PCSK9 与 LDL 受体蛋白的正相关与其发现一致。
