biostudies-literatureChen YQFondation LeducqNHLBI NIH HHSHHS | NIH | National Heart, Lung, and Blood InstituteEli Lilly and Companye2322332121https://www.ebi.ac.uk/biostudies/studies/S-EPMC11046700biostudies-literatureUnknown121(17)Apolipoprotein AV (APOA5) lowers plasma triglyceride (TG) levels by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its capacity to inhibit lipoprotein lipase (LPL) catalytic activity and its ability to detach LPL from binding sites within capillaries. However, the sequences in APOA5 that are required for suppressing ANGPTL3/8 activity have never been defined. A clue to the identity of those sequences was the presence of severe hypertriglyceridemia in two patients harboring an <i>APOA5</i> mutation that truncates APOA5 by 35 residues ("APOA5Δ35"). We found that wild-type (WT) human APOA5, but not APOA5Δ35, suppressed ANGPTL3/8's ability to inhibit LPL catalytic activity. To pursue that finding, we prepared a mutant mouse APOA5 protein lacking 40 C-terminal Proceedings of the National Academy of Sciences of the United States of AmericaCarboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity.PMC1104670000R01 HL087228HL13972523CVD02P01 HL146358HL146358HL087228R35 HL13972512CVD04Wen YLiao ZLi HBirrane GSiegel RWPloug MJackson NKonrad RJJung HKumari AScheithauer JLChen YQYang YQian YXie KBalasubramaniam DZhen EYRussell AMBeyer TPEhsani MYoung SGfalseCarboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity.Apolipoprotein AV (APOA5) lowers plasma triglyceride (TG) levels by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its capacity to inhibit lipoprotein lipase (LPL) catalytic activity and its ability to detach LPL from binding sites within capillaries. However, the sequences in APOA5 that are required for suppressing ANGPTL3/8 activity have never been defined. A clue to the identity of those sequences was the presence of severe hypertriglyceridemia in two patients harboring an <i>APOA5</i> mutation that truncates APOA5 by 35 residues ("APOA5Δ35"). We found that wild-type (WT) human APOA5, but not APOA5Δ35, suppressed ANGPTL3/8's ability to inhibit LPL catalytic activity. To pursue that finding, we prepared a mutant mouse APOA5 protein lacking 40 C-terminal 2024-01-01T00:00:00Z2024 Apr2025-04-04T08:18:16.773Z2025-04-04T08:18:16.773ZS-EPMC110467003862594810.1073/pnas.2322332121