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The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking

Lipoprotein lipase (LPL) is a rate-limiting enzyme for hydrolysing circulating triglycerides (TG) into free fatty acids that are taken up by peripheral tissues. Postprandial LPL activity rises in white adipose tissue (WAT), but declines in the heart and skeletal muscle, thereby directing circulating...

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Detalles Bibliográficos
Autor principal: Zhang, Ren
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852456/
https://www.ncbi.nlm.nih.gov/pubmed/27053679
http://dx.doi.org/10.1098/rsob.150272
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author Zhang, Ren
author_facet Zhang, Ren
author_sort Zhang, Ren
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description Lipoprotein lipase (LPL) is a rate-limiting enzyme for hydrolysing circulating triglycerides (TG) into free fatty acids that are taken up by peripheral tissues. Postprandial LPL activity rises in white adipose tissue (WAT), but declines in the heart and skeletal muscle, thereby directing circulating TG to WAT for storage; the reverse is true during fasting. However, the mechanism for the tissue-specific regulation of LPL activity during the fed–fast cycle has been elusive. Recent identification of lipasin/angiopoietin-like 8 (Angptl8), a feeding-induced hepatokine, together with Angptl3 and Angptl4, provides intriguing, yet puzzling, insights, because all the three Angptl members are LPL inhibitors, and the deficiency (overexpression) of any one causes hypotriglyceridaemia (hypertriglyceridaemia). Then, why does nature need all of the three? Our recent data that Angptl8 negatively regulates LPL activity specifically in cardiac and skeletal muscles suggest an Angptl3-4-8 model: feeding induces Angptl8, activating the Angptl8–Angptl3 pathway, which inhibits LPL in cardiac and skeletal muscles, thereby making circulating TG available for uptake by WAT, in which LPL activity is elevated owing to diminished Angptl4; the reverse is true during fasting, which suppresses Angptl8 but induces Angptl4, thereby directing TG to muscles. The model suggests a general framework for how TG trafficking is regulated.
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spelling pubmed-48524562016-05-05 The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking Zhang, Ren Open Biol Review Lipoprotein lipase (LPL) is a rate-limiting enzyme for hydrolysing circulating triglycerides (TG) into free fatty acids that are taken up by peripheral tissues. Postprandial LPL activity rises in white adipose tissue (WAT), but declines in the heart and skeletal muscle, thereby directing circulating TG to WAT for storage; the reverse is true during fasting. However, the mechanism for the tissue-specific regulation of LPL activity during the fed–fast cycle has been elusive. Recent identification of lipasin/angiopoietin-like 8 (Angptl8), a feeding-induced hepatokine, together with Angptl3 and Angptl4, provides intriguing, yet puzzling, insights, because all the three Angptl members are LPL inhibitors, and the deficiency (overexpression) of any one causes hypotriglyceridaemia (hypertriglyceridaemia). Then, why does nature need all of the three? Our recent data that Angptl8 negatively regulates LPL activity specifically in cardiac and skeletal muscles suggest an Angptl3-4-8 model: feeding induces Angptl8, activating the Angptl8–Angptl3 pathway, which inhibits LPL in cardiac and skeletal muscles, thereby making circulating TG available for uptake by WAT, in which LPL activity is elevated owing to diminished Angptl4; the reverse is true during fasting, which suppresses Angptl8 but induces Angptl4, thereby directing TG to muscles. The model suggests a general framework for how TG trafficking is regulated. The Royal Society 2016-04-06 /pmc/articles/PMC4852456/ /pubmed/27053679 http://dx.doi.org/10.1098/rsob.150272 Text en © 2016 The Authors. http://creativecommons.org/licenses/by/4.0/ Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.
spellingShingle Review
Zhang, Ren
The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking
title The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking
title_full The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking
title_fullStr The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking
title_full_unstemmed The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking
title_short The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking
title_sort angptl3-4-8 model, a molecular mechanism for triglyceride trafficking
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852456/
https://www.ncbi.nlm.nih.gov/pubmed/27053679
http://dx.doi.org/10.1098/rsob.150272
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