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 6

Amounts of LPL in the postheparin plasma are lower in Apoa5–/– mice than in Apoa5+/+ mice.

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Amounts of LPL in the postheparin plasma are lower in Apoa5–/– mice than...
Apoa5–/– and Apoa5+/+ mice were given an intravenous injection of heparin (500 U/kg), and plasma samples were collected 2 minutes later. (A and B) LPL mass and activity levels in the postheparin plasma of individual Apoa5–/– and Apoa5+/+ mice during ad libitum feeding (A) and during fasting (B). Apoa5–/– mice, n = 5 in A and n = 6 in B; Apoa5+/+ mice, n = 7 in A and n = 9 in B. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by unpaired, 2-tailed Student’s t test. (C–E) Amounts of LPL in postheparin plasma from Apoa5–/– and Apoa5+/+ mice (n = 3 mice/group), as assessed by HS chromatography. LPL appeared in the “high-salt” fractions (fractions 21–27; 1.13–1.38 M NaCl). (C) LPL mass and activity levels in the HS fractions from the postheparin plasma of Apoa5–/– and Apoa5+/+ mice during ad libitum feeding. (D) Western blots (WB) of LPL in fractions 21–27 from fasted Apoa5–/– and Apoa5+/+ mice. Band intensity was measured with an infrared scanner. (E) Levels of LPL mass and activity in fractions 21–27 from fasted Apoa5–/– and Apoa5+/+ mice. The reported results were confirmed in 2 independent experiments.