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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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 5

Reduced amounts of LPL in capillaries of Apoa5–/– mice, as judged by infrared scanning of sections spanning the entire heart or an entire BAT pad.

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Reduced amounts of LPL in capillaries of Apoa5–/– mice, as judged by inf...
Apoa5+/+, Apoa5–/–, and ΔLPL mice were given an intravenous injection of IRDye 680-27A7 and IRDye 800-11A12. Ten minutes later, the mice were euthanized, and the vasculature was perfused with PBS. (A and B) Infrared scans of heart (A) and BAT (B) sections revealing reduced amounts of intracapillary LPL, relative to GPIHBP1, in the heart and BAT of Apoa5–/– mice. Scale bars: 5 mm. (C and D) LPL/GPIHBP1 ratios in the hearts (C) and BAT (D) of Apoa5–/– (n = 4) and Apoa5+/+ (n = 3) mice. Signal intensities were measured in 10 tissue sections per mouse. Each dot represents the mean LPL/GPIHBP1 signal intensity ratio in 10 sections from 1 mouse; data in Apoa5–/– and ΔLPL mice were normalized to the mean ratio in Apoa5+/+ mice (set at 1.0). Data show the mean ± SEM. *P < 0.05 and **P < 0.01, by unpaired, 2-tailed Student’s t test for differences between Apoa5–/– and Apoa5+/+ mice.