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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,5,19]]},"abstract":"<jats:p>The liver controls plasma lipids by secreting lipid-rich very low density lipoproteins (VLDL) into blood. Inside hepatocytes in the liver, Lipid Droplets (LDs) are transported to the Smooth Endoplasmic Reticulum by kinesin-1 motors, where they are catabolized to supply lipids for VLDL assembly. Here we find that kinesin-1 uses its tail domain to bind the monolayer phospholipid membrane of LDs, but alternative mechanisms to bind cellular organelles with bilayer membranes. A peptide corresponding to the tail domain of kinesin-1 therefore competes with and removes kinesin-1 selectively from LDs with minimal effect on other organelles. Delivery of lipids for VLDL assembly is consequently reduced, causing a remarkable reduction of ~50% of secreted lipids (triglycerides and cholesterol) in cell culture. Strikingly, the peptide causes no unwanted accumulation of lipids inside cells because it redistributes LDs across the cell, enhancing LD-to-mitochondria lipid trafficking for mitochondrial lipid utilization. Further, we show that egg-liposomes can be used to orally deliver the kinesin tail domain peptide to zebrafish. The peptide accumulates in the zebrafish liver, and reverses diet-induced hyperlipidemia to bring zebrafish back to a normolipidemic state. Reflecting its effects in cell culture, the peptide causes no unwanted hepatic accumulation of lipids, no toxicity, and no developmental or behavioral defects in zebrafish. Using a peptide to displace proteins (e.g., kinesin) selectively from LDs provides a radically different approach against lipid disorders. This monolayer-vs.-bilayer strategy can potentially be extended to target other LD-bound proteins that function as key regulators of Lipid metabolism.<\/jats:p>","DOI":"10.1073\/pnas.2528332123","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T17:59:20Z","timestamp":1778608760000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Selective targeting of kinesin on lipid droplets in the liver reduces plasma lipids"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2798-1622","authenticated-orcid":false,"given":"Subham Kumar","family":"Tripathy","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02qyf5152","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay","place":["Mumbai, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Archisman","family":"Mahapatra","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02qyf5152","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay","place":["Mumbai, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ojal","family":"Saharan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/028qa3n13","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, Indian Institute of Science Education and Research","place":["Pune, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hindol","family":"Chatterjee","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00djv2c17","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata","place":["Mohanpur, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neelanjana","family":"Sengupta","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00djv2c17","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata","place":["Mohanpur, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6132-7574","authenticated-orcid":false,"given":"Siddhesh","family":"Kamat","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/028qa3n13","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, Indian Institute of Science Education and Research","place":["Pune, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7309-339X","authenticated-orcid":false,"given":"Sreelaja","family":"Nair","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02qyf5152","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay","place":["Mumbai, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6820-6556","authenticated-orcid":false,"given":"Roop","family":"Mallik","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02qyf5152","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay","place":["Mumbai, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"e_1_3_4_1_2","first-page":"373","article-title":"Lipid droplets: A unified view of a dynamic organelle","volume":"7","author":"Martin S.","year":"2006","unstructured":"S. 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