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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2019
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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. |
format | Online Article Text |
id | pubmed-6829650 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
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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