Abstract 14589: Adiponectin Inhibits Hepatic Production of Triglyceride-Rich Apolipoprotein B Lipoproteins Through Both LDL-Receptor Dependent and Independent Mechanisms
Background and Rationale: Increasing plasma concentrations of the anti-inflammatory protein, adiponectin, are significantly and independently associated with a lower risk of coronary heart disease (CHD), while hypoadiponectinemia, conversely, is a strong risk factor for CHD. The mechanisms by which adiponectin mediates its cardioprotective role are not clearly understood. Here, we have elucidated a key cause of the cardioprotective effect of adiponectin, involving a direct inhibitory action on hepatic production of pro-atherogenic triglyceride-rich apolipoprotein B (apoB) lipoproteins, mediated through both LDL-receptor dependent mechanisms, involving PCSK9, and LDL-receptor independent mechanisms.
Methods and Results: Cultured human hepatocytes (HepG2 cells) and primary human hepatocytes were treated with physiological concentrations of purified recombinant human adiponectin (10 μg/mL) for 24 hours. Adiponectin treatment reduced endogenous apoB cellular expression and secretion markedly by 60% and 30%, respectively, (P<0.01). Adiponectin also reduced apoB production stimulated by prior treatment of cells with oleate or with pro-inflammatory obese human serum (25% reduction for both, P<0.01). Adiponectin-mediated inhibition of cellular apoB production occurred through a substantial increase in levels of hepatocyte LDL-receptors (70%, P<0.01), which promote proteasome-mediated apoB degradation, and which resulted from a 50% reduction in cellular PCSK9 levels (P<0.01 for both). Multiple LDL-receptor independent effects of adiponectin involved mechanisms which reduce cellular apoB stability: (1) a decrease in cellular microsomal triglyceride transfer protein (MTP) (by 25%, (P<0.01); (2) an increase in AMP kinase (by 40%, P<0.01); and (3) marked stimulation of the Akt/Erk insulin signaling pathways.
Conclusions: Adiponectin has a direct mitigating effect on hepatic apoB production through mechanisms mediated in part by the LDL-receptor and PCSK9, MTP and the insulin signaling pathway. These findings indicate that that inhibition of apoB may explain in large part adiponectin’s cardioprotective role. Furthermore, targeted adiponectin-based therapies may be a novel approach to inhibit hepatic apoB production.
Author Disclosures: M. Melone: None. S. Rashid: None.
- © 2015 by American Heart Association, Inc.