Abstract 161: Ablation Of Intracellular Lipolytic Inhibitor G0S2 Promotes Vascular Lipolysis And Alleviates Diet-induced Atherosclerosis

Abstract

Adipose tissue plays a central role in the regulation of plasma triglyceride (TG) and fatty acid (FA) levels, whose elevation is associated with atherosclerotic cardiovascular disease (ASCVD). Circulating TGs are hydrolyzed by lipoprotein lipase (LPL), releasing FAs that are taken up by adipocytes. Conversely, lipolytic action of adipose tissue triglyceride lipase (ATGL) mobilizes intracellular TG storage, supplying FAs via circulation for utilization by other tissues. However, how intracellular lipolysis influences intravascular lipolysis and atherosclerotic development remains largely unknown. Herein, the current study aimed to explore the role of G0S2, a selective protein inhibitor of ATGL, in this particular context. When treated with a Western diet and antisense oligonucleotides (ASOs) targeting LDLR, mice with a global ablation of G0S2 exhibited a significantly reduced lesion formation in aorta and brachiocephalic artery than their wild type (WT) littermates. Despite of little to no impact on hypercholesterolemia, total plasma and lipoprotein-specific TG content were normalized in G0S2 -/- mice. While it did not elicit any effects on intestinal lipid adsorption and hepatic TG secretion, the G0S2 ablation resulted in considerable elevation of LPL activity and protein levels in both plasma and adipose tissue. Accordingly, these G0S2 -/- mice showed a greatly improved TG clearance upon an oral lipid challenge. Interestingly, transplantation of G0S2 -/- adipose tissue increased circulating LPL in the WD-treated WT mice, which subsequently displayed a profound reduction of plasma TG levels as well as alleviation of hepatic steatosis. By studying adipose tissue explants and primary adipocytes, we observed that the G0S2 ablation led to markedly improved insulin sensitivity, resulting in increased FOXO1 phosphorylation and decreased expression of the LPL inhibitor ANGPTL4. Together, our data indicate that in the absence of G0S2, upregulation of adipose tissue LPL plays an important role in the clearance of circulating TGs and alleviation of diet-induced hypertriglyceridemia and atherosclerosis. We thus conclude that adipocyte G0S2 acts as a critical switch of both intracellular and vascular lipolysis.