Hypertriglyceridemia in Apoa5–/– mice results from reduced amounts of lipoprotein lipase in the capillary lumen
Ye Yang, … , Loren G. Fong, Stephen G. Young
Ye Yang, … , Loren G. Fong, Stephen G. Young
Published October 12, 2023
Citation Information: J Clin Invest. 2023;133(23):e172600. https://doi.org/10.1172/JCI172600.
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Research Article Metabolism Vascular biology

Hypertriglyceridemia in Apoa5–/– mice results from reduced amounts of lipoprotein lipase in the capillary lumen

Abstract

Why apolipoprotein AV (APOA5) deficiency causes hypertriglyceridemia has remained unclear, but we have suspected that the underlying cause is reduced amounts of lipoprotein lipase (LPL) in capillaries. By routine immunohistochemistry, we observed reduced LPL staining of heart and brown adipose tissue (BAT) capillaries in Apoa5–/– mice. Also, after an intravenous injection of LPL-, CD31-, and GPIHBP1-specific mAbs, the binding of LPL Abs to heart and BAT capillaries (relative to CD31 or GPIHBP1 Abs) was reduced in Apoa5–/– mice. LPL levels in the postheparin plasma were also lower in Apoa5–/– mice. We suspected that a recent biochemical observation — that APOA5 binds to the ANGPTL3/8 complex and suppresses its capacity to inhibit LPL catalytic activity — could be related to the low intracapillary LPL levels in Apoa5–/– mice. We showed that an ANGPTL3/8-specific mAb (IBA490) and APOA5 normalized plasma triglyceride (TG) levels and intracapillary LPL levels in Apoa5–/– mice. We also showed that ANGPTL3/8 detached LPL from heparan sulfate proteoglycans and GPIHBP1 on the surface of cells and that the LPL detachment was blocked by IBA490 and APOA5. Our studies explain the hypertriglyceridemia in Apoa5–/– mice and further illuminate the molecular mechanisms that regulate plasma TG metabolism.

Authors

Ye Yang, Anne P. Beigneux, Wenxin Song, Le Phuong Nguyen, Hyesoo Jung, Yiping Tu, Thomas A. Weston, Caitlyn M. Tran, Katherine Xie, Rachel G. Yu, Anh P. Tran, Kazuya Miyashita, Katsuyuki Nakajima, Masami Murakami, Yan Q. Chen, Eugene Y. Zhen, Joonyoung R. Kim, Paul H. Kim, Gabriel Birrane, Peter Tontonoz, Michael Ploug, Robert J. Konrad, Loren G. Fong, Stephen G. Young

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Figure 7

IBA490, an inhibitory ANGPTL3/8-specific mAb, lowers plasma TG levels in Apoa5–/– mice.

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IBA490, an inhibitory ANGPTL3/8-specific mAb, lowers plasma TG levels in...
Apoa5–/– and Apoa5+/+ mice were given a subcutaneous injection of IBA490 or a control mAb (10 mg/kg; n = 5/group). Plasma samples were obtained at baseline (t0) and 4, 24, 72, and 168 hours after administration of the mAbs. Data represent the mean ± SEM. **P < 0.01 and ***P < 0.001, by 2-way ANOVA, for comparisons of plasma TG levels in IBA490- and control mAb–treated Apoa5–/– mice; #P < 0.05 and ##P < 0.01, for comparisons of TG levels in IBA490- and control mAb–treated Apoa5+/+ mice. There were no significant differences in plasma TG levels in IBA490-treated Apoa5–/– or IBA490-treated Apoa5+/+ mice at 4, 24, and 72 hours.