Evidence that Hyperinsulinemia, known to Accelerate Diabetes Progression, may also Contribute to Dyslipidemia via Impairing ApoA1/ABCA1-Mediated Cholesterol Efflux

poster abstractLow levels of plasma high-density lipoprotein cholesterol (HDL-C) are associated with insulin resistance and type 2 diabetes (T2D). As it is well appreciated that hyperinsulinemia contributes to the progression/worsening of insulin resistance, we tested here if this key metabolic derangement impaired cellular mechanisms of HDL-C generation. An initial event in this process is the binding of apolipoprotein A1 (ApoA1) to the plasma membrane (PM)-localized ATPbinding cassette cholesterol transporter protein ABCA1. Subcellular fractionation analyses revealed that 3T3-L1 adipocytes exposed to chronic insulin (12h, 5nM) displayed a 25% decrease (P<0.05) in PM ABCA1 content and a reciprocal increase in endosomal ABCA1 content. These insulin-induced changes in cellular ABCA1 distribution occurred concomitantly with a decrease in ApoA1-mediated cellular cholesterol efflux. Consistent with endosomal/cytosolic cycling of the small molecular GTPase Rab8 playing a functional role in ABCA1 vesicle trafficking, we found a 50% increase (P<0.05) in endosomal Rab8 content and a 30% decrease (P