Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH
Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH.
Diabetes Care. 2019 Mar;42(3):466-475. doi: 10.2337/dc18-0870. Epub 2019 Jan 18.
Components of the adipose tissue (AT) extracellular matrix (ECM) are recently discovered contributors to obesity-related cardiometabolic disease. We identified increased adipocyte expression of ECM-related clusterin (apolipoprotein J) in obese versus lean women by microarray. Our objective was to determine ) whether subcutaneous AT adipocyte (SAd) clusterin and serum clusterin are associated with insulin resistance (IR) and known markers of cardiometabolic risk and ) how clusterin may contribute to increased risk.
We validated increased clusterin expression in adipocytes from a separate group of 18 lean and 54 obese individuals. The relationship of clusterin gene expression and plasma clusterin with IR, cardiovascular biomarkers, and risk of cardiovascular disease (CVD) was then determined. Further investigations in human cultured cells and in aged LDLR mice prone to development of obesity-associated complications were performed.
SAd clusterin correlated with IR, multiple CVD biomarkers, and CVD risk, independent of traditional risk factors. Circulating human clusterin exhibited similar associations. In human adipocytes, palmitate enhanced clusterin secretion, and in human hepatocytes, clusterin attenuated insulin signaling and APOA1 expression and stimulated hepatic gluconeogenesis. LRP2 (megalin), a clusterin receptor, highly expressed in liver, mediated these effects, which were inhibited by LRP2 siRNA. In response to Western diet feeding, an increase in adipocyte clusterin expression was associated with a progressive increase in liver fat, steatohepatitis, and fibrosis in aged LDLR mice.
Adipocyte-derived clusterin is a novel ECM-related protein linking cardiometabolic disease and obesity through its actions in the liver.
脂肪组织（AT）细胞外基质（ECM）的成分最近被发现是肥胖相关心血管代谢疾病的致病因素。我们通过微阵列鉴定出肥胖女性脂肪细胞中 ECM 相关载脂蛋白 J（簇蛋白）的表达增加。我们的目的是确定皮下脂肪组织（SAd）脂肪细胞簇蛋白和血清簇蛋白是否与胰岛素抵抗（IR）以及已知的心血管代谢风险标志物相关，以及簇蛋白如何增加风险。
我们在另一组 18 名瘦人和 54 名肥胖个体的脂肪细胞中验证了簇蛋白表达的增加。然后确定簇蛋白基因表达和血浆簇蛋白与 IR、心血管生物标志物和心血管疾病（CVD）风险的关系。在人类培养细胞和易发生肥胖相关并发症的老年 LDLR 小鼠中进行了进一步的研究。
SAd 簇蛋白与 IR、多种 CVD 生物标志物和 CVD 风险相关，与传统危险因素无关。循环人簇蛋白表现出相似的关联。在人类脂肪细胞中，棕榈酸增强了簇蛋白的分泌，在人类肝细胞中，簇蛋白减弱了胰岛素信号和 APOA1 表达，并刺激了肝糖异生。LRP2（megalin），一种在肝脏中高表达的簇蛋白受体，介导了这些效应，这些效应被 LRP2 siRNA 抑制。在对西方饮食的反应中，脂肪细胞簇蛋白表达的增加与老年 LDLR 小鼠肝脏脂肪、脂肪性肝炎和纤维化的进行性增加有关。
脂肪细胞衍生的簇蛋白是一种新型 ECM 相关蛋白，通过其在肝脏中的作用将心血管代谢疾病与肥胖联系起来。
