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Insulin activates intracellular transport of lipid droplets to release triglycerides from the liver

Triglyceride-rich lipid droplets (LDs) are catabolized with high efficiency in hepatocytes to supply fatty acids for producing lipoprotein particles. Fasting causes a massive influx of adipose-derived fatty acids into the liver. The liver in the fasted state is therefore bloated with LDs but, remark...

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Autores principales: Kumar, Mukesh, Ojha, Srikant, Rai, Priyanka, Joshi, Alaumy, Kamat, Siddhesh S., Mallik, Roop
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829650/
https://www.ncbi.nlm.nih.gov/pubmed/31604801
http://dx.doi.org/10.1083/jcb.201903102
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author Kumar, Mukesh
Ojha, Srikant
Rai, Priyanka
Joshi, Alaumy
Kamat, Siddhesh S.
Mallik, Roop
author_facet Kumar, Mukesh
Ojha, Srikant
Rai, Priyanka
Joshi, Alaumy
Kamat, Siddhesh S.
Mallik, Roop
author_sort Kumar, Mukesh
collection PubMed
description Triglyceride-rich lipid droplets (LDs) are catabolized with high efficiency in hepatocytes to supply fatty acids for producing lipoprotein particles. Fasting causes a massive influx of adipose-derived fatty acids into the liver. The liver in the fasted state is therefore bloated with LDs but, remarkably, still continues to secrete triglycerides at a constant rate. Here we show that insulin signaling elevates phosphatidic acid (PA) dramatically on LDs in the fed state. PA then signals to recruit kinesin-1 motors, which transport LDs to the peripherally located smooth ER inside hepatocytes, where LDs are catabolized to produce lipoproteins. This pathway is down-regulated homeostatically when fasting causes insulin levels to drop, thus preventing dangerous elevation of triglycerides in the blood. Further, we show that a specific peptide against kinesin-1 blocks triglyceride secretion without any apparent deleterious effects on cells. Our work therefore reveals fundamental mechanisms that maintain lipid homeostasis across metabolic states and leverages this knowledge to propose a molecular target against hyperlipidemia.
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spelling pubmed-68296502020-05-04 Insulin activates intracellular transport of lipid droplets to release triglycerides from the liver Kumar, Mukesh Ojha, Srikant Rai, Priyanka Joshi, Alaumy Kamat, Siddhesh S. Mallik, Roop J Cell Biol Research Articles Triglyceride-rich lipid droplets (LDs) are catabolized with high efficiency in hepatocytes to supply fatty acids for producing lipoprotein particles. Fasting causes a massive influx of adipose-derived fatty acids into the liver. The liver in the fasted state is therefore bloated with LDs but, remarkably, still continues to secrete triglycerides at a constant rate. Here we show that insulin signaling elevates phosphatidic acid (PA) dramatically on LDs in the fed state. PA then signals to recruit kinesin-1 motors, which transport LDs to the peripherally located smooth ER inside hepatocytes, where LDs are catabolized to produce lipoproteins. This pathway is down-regulated homeostatically when fasting causes insulin levels to drop, thus preventing dangerous elevation of triglycerides in the blood. Further, we show that a specific peptide against kinesin-1 blocks triglyceride secretion without any apparent deleterious effects on cells. Our work therefore reveals fundamental mechanisms that maintain lipid homeostasis across metabolic states and leverages this knowledge to propose a molecular target against hyperlipidemia. Rockefeller University Press 2019-11-04 2019-10-11 /pmc/articles/PMC6829650/ /pubmed/31604801 http://dx.doi.org/10.1083/jcb.201903102 Text en © 2019 Kumar et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Kumar, Mukesh
Ojha, Srikant
Rai, Priyanka
Joshi, Alaumy
Kamat, Siddhesh S.
Mallik, Roop
Insulin activates intracellular transport of lipid droplets to release triglycerides from the liver
title Insulin activates intracellular transport of lipid droplets to release triglycerides from the liver
title_full Insulin activates intracellular transport of lipid droplets to release triglycerides from the liver
title_fullStr Insulin activates intracellular transport of lipid droplets to release triglycerides from the liver
title_full_unstemmed Insulin activates intracellular transport of lipid droplets to release triglycerides from the liver
title_short Insulin activates intracellular transport of lipid droplets to release triglycerides from the liver
title_sort insulin activates intracellular transport of lipid droplets to release triglycerides from the liver
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829650/
https://www.ncbi.nlm.nih.gov/pubmed/31604801
http://dx.doi.org/10.1083/jcb.201903102
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