Abstract 16198: Human Resistin Stimulates Hepatic Overproduction of Atherogenic Apolipoprotein B - Containing Lipoprotein Particles by Increasing MTP Activity and Hepatocyte Neutral Lipid Content
Obese individuals are at high risk of developing atherosclerotic cardiovascular disease (ASCVD), due in large part to elevated plasma concentrations of apolipoprotein B (apoB)-containing particles, including very-low-density lipoprotein (VLDL). Resistin is a candidate molecule that may play a role in the increased VLDL in obesity. Plasma levels of resistin are increased in human obesity and resistin expression in humans is positively correlated with plasma VLDL levels and coronary ASCVD. The mechanisms responsible for these resistin-associated changes in humans have not been delineated. We wished to determine whether resistin directly stimulates human hepatic production of apoB-containing particles. Treatment of HepG2 cells with physiological levels of resistin observed in human obesity (50 ng/mL) for 24 hrs resulted in a marked 10-fold increase in expression and secretion of apoB protein. The cholesterol and triglyceride contents of secreted VLDL, assessed by FPLC analyses, increased by over 8-fold and electron microscopy analyses showed smaller, more numerous VLDL particles. We further found that apoB protein stability was enhanced in resistin-treated (50 ng/mL, 24hrs) HepG2 cells due to a significant increase in the activity of the ER chaperone, microsomal triglyceride transfer protein (MTP), by 26%, and to increased cellular neutral lipid content (triglycerides and cholesteryl esters) by 20–25%. The increase in neutral lipids was accounted for by increased intracellular de novo lipogenesis via the SREBP1 and SREBP2 intracellular pathways. Thus, we have shown for the first time that resistin has a direct deleterious impact on human hepatic lipoprotein biosynthesis. Resistin treatment markedly increased VLDL apoB protein and lipid secretion by human hepatic cells. This is due to enhanced intracellular apoB stability due to increases in both intracellular MTP activity and neutral lipid content. The resulting elevation in VLDL by resistin is directly atherogenic and contributes to increased ASCVD prevalence in obese individuals.
- © 2010 by American Heart Association, Inc.