Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity

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Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity. / Chen, Yan Q.; Yang, Ye; Zhen, Eugene Y.; Beyer, Thomas P.; Li, Hongxia; Wen, Yi; Ehsani, Mariam; Jackson, Nicholas; Xie, Katherine; Jung, Hyesoo; Scheithauer, Julia L.; Kumari, Anni; Birrane, Gabriel; Russell, Anna M.; Balasubramaniam, Deepa; Liao, Zhongping; Siegel, Robert W.; Qian, Yuewei; Ploug, Michael; Young, Stephen G.; Konrad, Robert J.

I: Proceedings of the National Academy of Sciences of the United States of America, Bind 121, Nr. 17, e2322332121, 2024.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Chen, YQ, Yang, Y, Zhen, EY, Beyer, TP, Li, H, Wen, Y, Ehsani, M, Jackson, N, Xie, K, Jung, H, Scheithauer, JL, Kumari, A, Birrane, G, Russell, AM, Balasubramaniam, D, Liao, Z, Siegel, RW, Qian, Y, Ploug, M, Young, SG & Konrad, RJ 2024, 'Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity', Proceedings of the National Academy of Sciences of the United States of America, bind 121, nr. 17, e2322332121. https://doi.org/10.1073/pnas.2322332121

APA

Chen, Y. Q., Yang, Y., Zhen, E. Y., Beyer, T. P., Li, H., Wen, Y., Ehsani, M., Jackson, N., Xie, K., Jung, H., Scheithauer, J. L., Kumari, A., Birrane, G., Russell, A. M., Balasubramaniam, D., Liao, Z., Siegel, R. W., Qian, Y., Ploug, M., ... Konrad, R. J. (2024). Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity. Proceedings of the National Academy of Sciences of the United States of America, 121(17), [e2322332121]. https://doi.org/10.1073/pnas.2322332121

Vancouver

Chen YQ, Yang Y, Zhen EY, Beyer TP, Li H, Wen Y o.a. Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity. Proceedings of the National Academy of Sciences of the United States of America. 2024;121(17). e2322332121. https://doi.org/10.1073/pnas.2322332121

Author

Chen, Yan Q. ; Yang, Ye ; Zhen, Eugene Y. ; Beyer, Thomas P. ; Li, Hongxia ; Wen, Yi ; Ehsani, Mariam ; Jackson, Nicholas ; Xie, Katherine ; Jung, Hyesoo ; Scheithauer, Julia L. ; Kumari, Anni ; Birrane, Gabriel ; Russell, Anna M. ; Balasubramaniam, Deepa ; Liao, Zhongping ; Siegel, Robert W. ; Qian, Yuewei ; Ploug, Michael ; Young, Stephen G. ; Konrad, Robert J. / Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity. I: Proceedings of the National Academy of Sciences of the United States of America. 2024 ; Bind 121, Nr. 17.

Bibtex

@article{56b4e410d8e74f609f8da8db5eaab471,
title = "Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity",
abstract = "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 APOA5 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 amino acids ({"}APOA5Δ40{"}). Mouse WT-APOA5, but not APOA5Δ40, suppressed ANGPTL3/8's capacity to inhibit LPL catalytic activity and sharply reduced plasma TG levels in mice. WT-APOA5, but not APOA5Δ40, increased intracapillary LPL levels and reduced plasma TG levels in Apoa5-/- mice (where TG levels are high and intravascular LPL levels are low). Also, WT-APOA5, but not APOA5Δ40, blocked the ability of ANGPTL3/8 to detach LPL from cultured cells. Finally, an antibody against a synthetic peptide corresponding to the last 26 amino acids of mouse APOA5 reduced intracapillary LPL levels and increased plasma TG levels in WT mice. We conclude that C-terminal sequences in APOA5 are crucial for suppressing ANGPTL3/8 activity in vitro and for regulating intracapillary LPL levels and plasma TG levels in vivo.",
keywords = "ANGPTL3/8, apolipoprotein AV, lipoprotein lipase, triglycerides",
author = "Chen, {Yan Q.} and Ye Yang and Zhen, {Eugene Y.} and Beyer, {Thomas P.} and Hongxia Li and Yi Wen and Mariam Ehsani and Nicholas Jackson and Katherine Xie and Hyesoo Jung and Scheithauer, {Julia L.} and Anni Kumari and Gabriel Birrane and Russell, {Anna M.} and Deepa Balasubramaniam and Zhongping Liao and Siegel, {Robert W.} and Yuewei Qian and Michael Ploug and Young, {Stephen G.} and Konrad, {Robert J.}",
year = "2024",
doi = "10.1073/pnas.2322332121",
language = "English",
volume = "121",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "17",

}

RIS

TY - JOUR

T1 - Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity

AU - Chen, Yan Q.

AU - Yang, Ye

AU - Zhen, Eugene Y.

AU - Beyer, Thomas P.

AU - Li, Hongxia

AU - Wen, Yi

AU - Ehsani, Mariam

AU - Jackson, Nicholas

AU - Xie, Katherine

AU - Jung, Hyesoo

AU - Scheithauer, Julia L.

AU - Kumari, Anni

AU - Birrane, Gabriel

AU - Russell, Anna M.

AU - Balasubramaniam, Deepa

AU - Liao, Zhongping

AU - Siegel, Robert W.

AU - Qian, Yuewei

AU - Ploug, Michael

AU - Young, Stephen G.

AU - Konrad, Robert J.

PY - 2024

Y1 - 2024

N2 - 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 APOA5 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 amino acids ("APOA5Δ40"). Mouse WT-APOA5, but not APOA5Δ40, suppressed ANGPTL3/8's capacity to inhibit LPL catalytic activity and sharply reduced plasma TG levels in mice. WT-APOA5, but not APOA5Δ40, increased intracapillary LPL levels and reduced plasma TG levels in Apoa5-/- mice (where TG levels are high and intravascular LPL levels are low). Also, WT-APOA5, but not APOA5Δ40, blocked the ability of ANGPTL3/8 to detach LPL from cultured cells. Finally, an antibody against a synthetic peptide corresponding to the last 26 amino acids of mouse APOA5 reduced intracapillary LPL levels and increased plasma TG levels in WT mice. We conclude that C-terminal sequences in APOA5 are crucial for suppressing ANGPTL3/8 activity in vitro and for regulating intracapillary LPL levels and plasma TG levels in vivo.

AB - 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 APOA5 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 amino acids ("APOA5Δ40"). Mouse WT-APOA5, but not APOA5Δ40, suppressed ANGPTL3/8's capacity to inhibit LPL catalytic activity and sharply reduced plasma TG levels in mice. WT-APOA5, but not APOA5Δ40, increased intracapillary LPL levels and reduced plasma TG levels in Apoa5-/- mice (where TG levels are high and intravascular LPL levels are low). Also, WT-APOA5, but not APOA5Δ40, blocked the ability of ANGPTL3/8 to detach LPL from cultured cells. Finally, an antibody against a synthetic peptide corresponding to the last 26 amino acids of mouse APOA5 reduced intracapillary LPL levels and increased plasma TG levels in WT mice. We conclude that C-terminal sequences in APOA5 are crucial for suppressing ANGPTL3/8 activity in vitro and for regulating intracapillary LPL levels and plasma TG levels in vivo.

KW - ANGPTL3/8

KW - apolipoprotein AV

KW - lipoprotein lipase

KW - triglycerides

U2 - 10.1073/pnas.2322332121

DO - 10.1073/pnas.2322332121

M3 - Journal article

C2 - 38625948

AN - SCOPUS:85190903331

VL - 121

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 17

M1 - e2322332121

ER -

ID: 393504211