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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Bibliographic Details
Published in:The Journal of cell biology 2019-11, Vol.218 (11), p.3697-3713
Main Authors: Kumar, Mukesh, Ojha, Srikant, Rai, Priyanka, Joshi, Alaumy, Kamat, Siddhesh S, Mallik, Roop
Format: Article
Language:English
Subjects:
Animals
Biological Transport
Cells, Cultured
Droplets
Fasting
Fatty acids
Hepatocytes
Homeostasis
Hyperlipidemia
Insulin
Insulin - metabolism
Kinesin
Lipid Droplets - metabolism
Lipids
Lipoproteins
Liver
Liver - cytology
Liver - metabolism
Phosphatidic acid
Rats
Rats, Sprague-Dawley
Secretion
Transport
Triglycerides
Triglycerides - metabolism
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Summary: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.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.201903102