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Hypertriglyceridemia in [Apoa5.sup.-/-] mice results from reduced amounts of lipoprotein lipase in the capillary lumen
- Source :
- Journal of Clinical Investigation. December, 2023, Vol. 133 Issue 23
- Publication Year :
- 2023
-
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.sup.-/-] 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.sup.-/-] mice. LPL levels in the postheparin plasma were also lower in [Apoa5.sup.-/-] 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.sup.-/-] mice. We showed that an ANGPTL3/8-specific mAb (IBA490) and APOA5 normalized plasma triglyceride (TG) levels and intracapillary LPL levels in [Apoa5.sup.-/-] 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.sup.-/-] mice and further illuminate the molecular mechanisms that regulate plasma TG metabolism.<br />Introduction Apolipoprotein AV (APOA5), uncovered by comparative sequencing of the mouse and human APOAI/CIII/AIV gene cluster (1), has substantial effects on plasma triglyceride (TG) metabolism. [Apoa5.sup.-/-] mice have markedly elevated [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 133
- Issue :
- 23
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.777600285
- Full Text :
- https://doi.org/10.1172/JCI172600