Kumar, Mukesh ; Ojha, Srikant ; Rai, Priyanka ; Joshi, Alaumy ; Kamat, Siddhesh S. ; Mallik, Roop (2019) Insulin activates intracellular transport of lipid droplets to release triglycerides from the liver Journal of Cell Biology, 218 (11). pp. 3697-3713. ISSN 0021-9525
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Official URL: http://doi.org/10.1083/jcb.201903102
Related URL: http://dx.doi.org/10.1083/jcb.201903102
Abstract
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.
Item Type: | Article |
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Source: | Copyright of this article belongs to The Rockefeller University Press. |
ID Code: | 124024 |
Deposited On: | 30 Oct 2021 09:53 |
Last Modified: | 30 Oct 2021 09:53 |
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