Visceral obesity is a feature of the metabolic syndrome (MetS), which predisposes to insulin resistance and type 2 diabetes mellitus (T2DM)?two major risk factors for cardiovascular disease (CVD). MetS and T2DM are characterized by adipose tissue inflammation, hypertriglyceridemia and low levels of HDL-cholesterol (HDL-C), a classical risk factor for CVD. However, recent studies have cast doubt on HDL-cholesterol as an anti-atherogenic factor, suggesting that HDL function may be more important than HDL cholesterol level. In addition to promoting cholesterol efflux, HDL has important anti-inflammatory effects, including on adipose tissue. Our preliminary data suggest that HDL can become dysfunctional as a result of diabetes and inflammation. Therefore, we hypothesize that the inflammation of adipose tissue that accompanies visceral obesity in the MetS and T2DM is due, at least in part, to impaired HDL function. We also hypothesize that dysfunctional HDL is instrumental in causing low-grade inflammation, which increases the risk of CVD. One key mediator of HDL dysfunction is serum amyloid A (SAA), which is induced during inflammation. Circulating SAA derives mainly from the liver and is transported through plasma, primarily on HDL. Recent preliminary data also show that oxidation of apoA-I results in loss of it anti-inflammatory properties on adipocytes. Therefore, we hypothesize that SAA-loaded HDL and apoA-I oxidation are two important mediators of dysfunctional HDL in the MetS and T2DM, which in turn fails to inhibit inflammation of adipose tissue. To investigate mechanisms by which dysfunctional HDL influences adipose tissue inflammation, we will determine whether ?inflammatory HDL? loses its anti-inflammatory effect on adipocytes by failing to reduce plasma membrane cholesterol content, and investigate the roles of SAA on HDL and/or apoA-I oxidation on the loss of anti-inflammatory properties of HDL on adipocytes. We also will investigate mechanisms by which HDL becomes dysfunctional as a result of obesity, the MetS and diabetes by (i) determining the effect of SAA- loading of HDL on its anti-inflammatory actions on adipose tissue in mouse models, (ii) establishing whether expression of oxidation-resistant apoA-I will reverse the adverse effects of adipose tissue inflammation, and (iii) investigating whether SAA-loading of HDL and apoA-I oxidation correlate with adipose tissue inflammation and insulin resistance in human subjects with inflamed adipose tissue. Collectively these studies will provide important new information concerning the role of obesity, and particularly of SAA in determining HDL dysfunction and its role in promoting CVD in the MetS and diabetes.
Diabetes and the metabolic syndrome (MetS) are two major risk factors for the development of cardiovascular disease (CVD). Low levels of high density lipoprotein (HDL) cholesterol are present in the MetS and diabetes. However, HDL also might be dysfunctional in these disorders, and contribute to the increased risk of CVD. The proposed studies will provide important new information concerning the role of HDL dysfunction in promoting inflammation and cardiovascular complications in the MetS and diabetes mellitus.
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