Rai, Priyanka and Kumar, Mukesh and Sharma, Geetika and Barak, Pradeep and Das, Saumitra and Kamat, Siddhesh S and Mallik, Roop (2017) Kinesin-dependent mechanism for controlling triglyceride secretion from the liver. In: Proceedings of the National Academy of Sciences, 114 (49). pp. 12958-12963. ISSN 0027-8424
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Abstract
Despite massive fluctuations in its internal triglyceride content, the liver secretes triglyceride under tight homeostatic control. This buffering function is most visible after fasting, when liver triglyceride increases manyfold but circulating serum triglyceride barely fluctuates. How the liver controls triglyceride secretion is unknown, but is fundamentally important for lipid and energy homeostasis in animals. Here we find an unexpected cellular and molecular mechanism behind such control. We show that kinesin motors are recruited to triglyceride-rich lipid droplets (LDs) in the liver by the GTPase ARF1, which is a key activator of lipolysis. This recruitment is activated by an insulin-dependent pathway and therefore responds to fed/fasted states of the animal. In fed state, ARF1 and kinesin appear on LDs, consequently transporting LDs to the periphery of hepatocytes where the smooth endoplasmic reticulum (sER) is present. Because the lipases that catabolize LDs in hepatocytes reside on the sER, LDs can now be catabolized efficiently to provide triglyceride for lipoprotein assembly and secretion from the sER. Upon fasting, insulin is lowered to remove ARF1 and kinesin from LDs, thus down-regulating LD transport and sER–LD contacts. This tempers triglyceride availabiity for very low density lipoprotein assembly and allows homeostatic control of serum triglyceride in a fasted state. We further show that kinesin knockdown inhibits hepatitis-C virus replication in hepatocytes, likely because translated viral proteins are unable to transfer from the ER to LDs.
| Item Type: | Journal Article |
|---|---|
| Publication: | Proceedings of the National Academy of Sciences |
| Publisher: | National Academy of Sciences |
| Additional Information: | The copyright for this article belongs to the Authors. |
| Keywords: | ARF1; Hepatitis C; Kinesin; Lipid droplet; VLDL secretion |
| Department/Centre: | Division of Biological Sciences > Microbiology & Cell Biology |
| Date Deposited: | 02 Jun 2022 05:13 |
| Last Modified: | 02 Jun 2022 05:13 |
| URI: | https://eprints.iisc.ac.in/id/eprint/73022 |
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