Absence of the intracellular lipolytic inhibitor G0S2 enhances intravascular triglyceride clearance and abolishes diet-induced hypertriglyceridemia
Yongbin Chen, … , Cailin E. McMahon, Jun Liu
Yongbin Chen, … , Cailin E. McMahon, Jun Liu
Published March 18, 2025
Citation Information: J Clin Invest. 2025;135(10):e181754. https://doi.org/10.1172/JCI181754.
View: Text | PDF
Research Article Endocrinology Metabolism

Absence of the intracellular lipolytic inhibitor G0S2 enhances intravascular triglyceride clearance and abolishes diet-induced hypertriglyceridemia

Abstract

The interplay between intracellular and intravascular lipolysis is crucial for maintaining circulating lipid levels and systemic energy homeostasis. Adipose triglyceride lipase (ATGL) and lipoprotein lipase (LPL), the primary triglyceride (TG) lipases responsible for these two spatially separate processes, are highly expressed in adipose tissue. Yet the mechanisms underlying their coordinated regulation remain undetermined. Here, we demonstrate that genetic ablation of G0S2, a specific inhibitory protein of ATGL, completely abolished diet-induced hypertriglyceridemia and significantly attenuated atherogenesis in mice. These effects were attributable to enhanced whole-body TG clearance, not altered hepatic TG secretion. Specifically, G0S2 deletion increased circulating LPL concentration and activity, predominantly through LPL production from white adipose tissue (WAT). Strikingly, transplantation of G0S2-deficient WAT normalized plasma TG levels in mice with hypertriglyceridemia. In conjunction with improved insulin sensitivity and decreased ANGPTL4 expression, the absence of G0S2 enhanced the stability of LPL protein in adipocytes, a phenomenon that could be reversed upon ATGL inhibition. Collectively, these findings highlight the pivotal role of adipocyte G0S2 in regulating both intracellular and intravascular lipolysis, and the possibility of targeting G0S2 as a viable pharmacological approach to reducing levels of circulating TGs.

Authors

Yongbin Chen, Scott M. Johnson, Stephanie D. Burr, Davide Povero, Aaron M. Anderson, Cailin E. McMahon, Jun Liu

×

Figure 6

Transplantation with G0s2–/– WAT alleviates hypertriglyceridemia in WT recipient mice.

Options: View larger image (or click on image) Download as PowerPoint
Transplantation with G0s2–/– WAT alleviates hypertriglyceridemia in WT r...
(A) Experimental scheme: After 3 weeks of treatment with Western diet (WD) and Ldlr-ASO, epididymal WAT dissected from chow-fed WT or G0s2–/– donor mice was transplanted in situ into WT recipient mice. (B) Plasma TG concentrations prior to and after transplantation at the indicated time points (n = 9–10). (C and D) Circulating lipase activity 10 minutes after heparin administration, as determined following a 15-minute reaction of plasma with the artificial substrate (C), and LPL protein concentration (D) during fasting or refeeding 4 weeks after transplantation (n = 9–10). (E–G) Fasting plasma levels or free FA (E), total cholesterol (F), and glucose (G) at the end point (n = 9–10). (H) Liver TG content normalized to liver weight at the end point (n = 9–10). (I). Fasting plasma β-hydroxybutyrate (BHB) levels (n = 9–10). Data represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by unpaired 2-tailed t tests (B, and E–I) or 2-way ANOVA (C and D).