David Bradley1, Alecia Blaszczak2, Zheng Yin3, Joey Liu2, Joshua J Joseph2, Valerie Wright2, Kajol Anandani2, Bradley Needleman4, Sabrena Noria4, David Renton4, Martha Yearsley5, Stephen T C Wong6, Willa A Hsueh1. 1. Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH david.bradley@osumc.edu willa.hsueh@osumc.edu stwong@houstonmethodist.org. 2. Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH. 3. Department of Systems Medicine and Bioengineering, Institute for Academic Medicine, Houston Methodist Hospital, Weill Cornell Medicine, Houston, TX. 4. Center for Minimally Invasive Surgery, Department of Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH. 5. Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH. 6. Department of Systems Medicine and Bioengineering, Institute for Academic Medicine, Houston Methodist Hospital, Weill Cornell Medicine, Houston, TX david.bradley@osumc.edu willa.hsueh@osumc.edu stwong@houstonmethodist.org.
Abstract
OBJECTIVE: 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 1) whether subcutaneous AT adipocyte (SAd) clusterin and serum clusterin are associated with insulin resistance (IR) and known markers of cardiometabolic risk and 2) how clusterin may contribute to increased risk. RESEARCH DESIGN AND METHODS: 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. RESULTS: 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. CONCLUSIONS: Adipocyte-derived clusterin is a novel ECM-related protein linking cardiometabolic disease and obesity through its actions in the liver.
OBJECTIVE: 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 1) whether subcutaneous AT adipocyte (SAd) clusterin and serum clusterin are associated with insulin resistance (IR) and known markers of cardiometabolic risk and 2) how clusterin may contribute to increased risk. RESEARCH DESIGN AND METHODS: 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. RESULTS: SAd clusterin correlated with IR, multiple CVD biomarkers, and CVD risk, independent of traditional risk factors. Circulating humanclusterin 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. CONCLUSIONS: Adipocyte-derived clusterin is a novel ECM-related protein linking cardiometabolic disease and obesity through its actions in the liver.
Authors: Daniel Veyel; Kathrin Wenger; Andre Broermann; Tom Bretschneider; Andreas H Luippold; Bartlomiej Krawczyk; Wolfgang Rist; Eric Simon Journal: Sci Rep Date: 2020-01-28 Impact factor: 4.379
Authors: Ji A Seo; Min-Cheol Kang; Won-Mo Yang; Won Min Hwang; Sang Soo Kim; Soo Hyun Hong; Jee-In Heo; Achana Vijyakumar; Leandro Pereira de Moura; Aykut Uner; Hu Huang; Seung Hwan Lee; Inês S Lima; Kyong Soo Park; Min Seon Kim; Yossi Dagon; Thomas E Willnow; Vanita Aroda; Theodore P Ciaraldi; Robert R Henry; Young-Bum Kim Journal: Nat Commun Date: 2020-04-24 Impact factor: 14.919