Abstract 1610: The Pathophysiological Role of Resistin in Impaired Lipoprotein Metabolism in Obesity
Obese individuals are at high risk of developing cardiovascular disease, due in large part to elevated plasma concentrations of atherogenic apolipoprotein B (apoB)-containing particles, very low density lipoprotein (VLDL) and low density lipoprotein (LDL). Resistin is a candidate molecule that may play a role in the increased VLDL and LDL in obesity. Plasma levels of resistin are increased in genetically obese mice and in human obesity and resistin expression in humans is positively correlated with plasma apoB-containing particle levels. The mechanisms responsible for these resistin-induced lipoprotein changes in humans, however, have not been precisely delineated. We therefore wished to determine whether resistin directly impairs human hepatic production of apoB-containing particles. Human hepatic HepG2 cells were treated with recombinant resistin at varying concentrations (0 to 100 ng/mL) for 24 hrs. The effect of the treatment on cellular apoB protein and mRNA were determined. The lipid components of cell-secreted VLDL/LDL particles were determined via FPLC analyses and the effect on cellular accumulation of neutral lipids were determined by gas chromatography and Oil-Red-O analyses. Treatment of HepG2 cells with physiological levels of resistin (50 ng/mL) for 24 hrs resulted in a marked 25-fold increase in cellular expression and secretion of apoB protein. The cholesterol and triglyceride content of secreted VLDL increased by 8-fold. There was a 2-fold elevation of cellular apoB and microsomal triglyceride transfer protein (MTTP) mRNA, consistent with the increased cellular apoB protein expression. Concomitantly, there was a significant increase in cellular neutral lipid content with resistin treatment. Thus, we have shown for the first time that resistin has a direct deleterious impact on human hepatic lipoprotein biosynthesis. Resistin treatment increased VLDL/LDL apoB expression and secretion by human hepatic cells. Increased hepatic cellular neutral lipids with resistin reflects the fatty liver observed with elevated plasma resistin in humans. The resulting elevation in VLDL and LDL by resistin is directly atherogenic and contributes to increased cardiovascular disease prevalence in obese individuals.