Abstract P3073: Altered Mitochondrial Mg 2+ Homeostasis In Liver Links Lipid Metabolism, Inflammation And Atherogenesis

Abstract

Although evidences show the role of Mg 2+ in lipid metabolism and atherosclerosis, the molecular mechanism by which loss of Mg 2+ homeostasis promotes cardiovascular disease (CVD) is not known. Mg 2+ homeostasis is regulated by mitochondria and Mrs2 is the only known molecular machinery associated with mitochondrial Mg 2+ influx. To begin elucidating the importance of Mg 2+ homeostasis in lipid metabolism and CVD we made liver-specific Mrs2 KO mouse (Mrs2 Δhep ). Liver being the central hub of lipid metabolism, we asked whether loss of Mrs2 alters lipid metabolism and lipoprotein profile. Our results show increased accumulation of hepatic triacylglycerol (TG) and cholesterol in Mrs2 Δhep . Consistent with increased TG/cholesterol, plasma cholesterol and oxidized low density lipoprotein (ox-LDL) levels significantly differed between control and KO. Because ox-LDL contribute to atherosclerosis, we hypothesized altered hepatic lipid metabolism to induce inflammation, immune imbalance and accelerate lesions through modified atherogenic lipoprotein and cytokine profile. Quantification of plasma cytokines and chemokines were performed using the proteome profiler. Because T cells are critical drivers and modifiers of atherosclerosis, we quantified the lymphocyte and monocyte subsets by flow cytometry. Because T regulatory cells have anti-antherogenic roles, we studied the effect of ox-LDL on Tregs. Our results show increased and decreased levels of inflammatory and anti-inflammatory cytokines respectively in Mrs2 Δhep . In Mrs2 Δhep stimulation with ox-LDL showed an increased antigen specific proliferation of T-cells. We also observed increased and decreased population of Th17 and Tregs respectively. The decrease in Tregs population was attributed to increased apoptosis. In conclusion our observation suggests that high levels of ox-LDL in Mrs2 Δhep to induce inflammation and inflammatory cell expansion accompanied by apoptosis in Tregs. Our results conclude dysregulated Mg 2+ homeostasis to alter lipid metabolism and atherogenesis by inducing inflammation and compromised Tregs population. Our study will be the first of its kind to establish a triangular molecular link between Mg 2+ homeostasis, lipid metabolism, and atherogenesis.