Clusterin Impairs Hepatic Insulin Sensitivity and Adipocyte Clusterin Associates With Cardiometabolic Risk

Abstract

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 2/2 mice prone to development of obesityassociated 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 2/2 mice. CONCLUSIONS Adipocyte-derived clusterin is a novel ECM-related protein linking cardiometabolic disease and obesity through its actions in the liver. Obesity is associated with a heightened cardiovascular disease (CVD) risk profile that encompasses insulin resistance (IR), type 2 diabetes, hypertension, dyslipidemia, and hepatic steatosisdall components of the well-described metabolic syndrome (1,2). These factors act synergistically to accelerate morbidity and mortality in obesity (3). IR stems from adipocyte lipolysis and lipid deposition into insulin target tissues, as well

Apolipoprotein J is a hepatokine regulating muscle glucose metabolism and insulin sensitivity

“…Similarly, liver-specific overexpression of ApoJ prevents the development of diet-induced hepatic steatosis 48 , suggesting a sufficiency of hepatic ApoJ in modulating hepatic lipid metabolism. Other studies revealed that treatment of HepG2 cells with recombinant ApoJ protein increased gene expression of key molecules involved in gluconeogenesis 49 . Thus, the importance of hepatic ApoJ in hepatic lipid metabolism will require further investigations.…”

“…Thus, the importance of hepatic ApoJ in hepatic lipid metabolism will require further investigations. Of note, a recent study demonstrated that ApoJ is secreted from human adipocytes in vitro and its production is increased in 49 . However, a lack of detailed experimental conditions is found in this report, even no information of ApoJ antibody is provided.…”

Clusterin as a Potential Biomarker of Obesity-Related Alzheimer’s Disease Risk

“…110 On array analysis, we have previously identified subcutaneous adipocyte CLU as one of the top 15 extracellular matrix-related genes overexpressed in human obesity. 104 In addition, we found in 54 obese patients compared to 18 lean patients that human adipocyte expression, protein levels and serum concentrations of clusterin were higher in obesity and directly associated with multiple sequelae of obesity-related cardiometabolic disease: systemic insulin resistance, dyslipidemia, elevated blood pressure, hepatic steatosis/ steatohepatitis, key biomarkers of cardiovascular disease and risk, and atherosclerotic lesions. 104 We also demonstrated that clusterin in vivo has a progressive abrogating effect on hepatic ApoA1 expression (HepG2 cells cultured with increasing levels of recombinant clusterin).…”

“…104 In addition, we found in 54 obese patients compared to 18 lean patients that human adipocyte expression, protein levels and serum concentrations of clusterin were higher in obesity and directly associated with multiple sequelae of obesity-related cardiometabolic disease: systemic insulin resistance, dyslipidemia, elevated blood pressure, hepatic steatosis/ steatohepatitis, key biomarkers of cardiovascular disease and risk, and atherosclerotic lesions. 104 We also demonstrated that clusterin in vivo has a progressive abrogating effect on hepatic ApoA1 expression (HepG2 cells cultured with increasing levels of recombinant clusterin). ApoA1 a major component of HDL cholesterol and a biomarker of reduced myocardial infarction risk, 111 through binding to low density lipoprotein-related protein 2 (LRP2/Megalin).…”

“…Several adipokines, comprised of a number of cell signaling proteins secreted by AT, 101 have been proposed as biomarkers of AD. 102,103 Clusterin is not only expressed by astrocytes and neurons, but by a large number of peripheral tissues, including AT 104 and it readily crosses the BBB. 105 Indeed, the cognitive decline in MCI and AD has been related to circulating, and not CNS clusterin, 106 and the meta-analysis of 12 studies comparing patients with AD to controls showed that plasma clusterin was increased, but not CSF clusterin.…”