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Electron Tomography Revels that Milk Lipids Originate from Endoplasmic Reticulum Domains with Novel Structural Features

Ladinsky, Mark S. and Mardones, Gonzalo A. and Orlicky, David J. and Howell, Kathryn E. and McManaman, James L. (2019) Electron Tomography Revels that Milk Lipids Originate from Endoplasmic Reticulum Domains with Novel Structural Features. Journal of Mammary Gland Biology and Neoplasia, 24 (4). pp. 293-304. ISSN 1083-3021. https://resolver.caltech.edu/CaltechAUTHORS:20191118-075107769

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Abstract

Lipid droplets (LD) are dynamically-regulated organelles that originate from the endoplasmic reticulum (ER), and function in the storage, trafficking and metabolism of neutral lipids. In mammary epithelial cells (MEC) of lactating animals, intact LD are secreted intact into milk to form milk lipids by a novel apocrine mechanism. The secretion of intact LD and the relatively large amounts of lipid secreted by lactating MEC increase demands on the cellular processes responsible for lipid synthesis and LD formation. As yet these processes are poorly defined due to limited understanding of LD-ER interactions. To overcome these limitations, we used rapid-freezing and freeze-substitution methods in conjunction with 3D electron tomography and high resolution immunolocalization to define interactions between LD with ER in MEC of pregnant and lactating rats. Using these approaches, we identified distinct ER domains that contribute to lipid droplet formation and stabilization and which possess unique features previously unrecognized or not fully appreciated. Our results show nascent lipid droplets within the ER lumen and the association of both forming and mature droplets with structurally unique regions of ER cisternae, characterized by the presence of perilipin-2, a protein implicated in lipid droplet formation, and enzymes involved in lipid synthesis. These data demonstrate that milk lipids originate from LD-ER domains with novel structural features and suggest a mechanism for initial droplet formation in the ER lumen and subsequent maturation of the droplets in association with ER cisternae.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1007/s10911-019-09438-yDOIArticle
ORCID:
AuthorORCID
Ladinsky, Mark S.0000-0002-1036-3513
Mardones, Gonzalo A.0000-0001-9390-5893
Orlicky, David J.0000-0002-0417-1400
McManaman, James L.0000-0003-4735-6429
Additional Information:© 2019 Springer Science+Business Media, LLC, part of Springer Nature. Article First Online: 10 November 2019. We thank Dr. Robert Farese Jr., Harvard School of Public Health for the antibodies against Dgat1 and Dgat2 and Dr. T.Y. Chang of Dartmouth Medical School for the antibodies Acat1. This work was supported by NIH grants PO1GM61306 (KEH); 5PO1HD038129 (KEH); 2PO1HD038129 (JLM); and 2R01HD45965 and R01HD093729 (JLM).
Funders:
Funding AgencyGrant Number
NIHPO1GM61306
NIH5PO1HD038129
NIH2PO1HD038129
NIH2R01HD45965
NIHR01HD093729
Subject Keywords:Mammary gland; Lipid droplet; Endoplasmic reticulum domain; Electron microscopy; Tomography; Differentiation
Issue or Number:4
Record Number:CaltechAUTHORS:20191118-075107769
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20191118-075107769
Official Citation:Ladinsky, M.S., Mardones, G.A., Orlicky, D.J. et al. J Mammary Gland Biol Neoplasia (2019) 24: 293. https://doi.org/10.1007/s10911-019-09438-y
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:99885
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:18 Nov 2019 16:11
Last Modified:17 Dec 2019 15:56

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