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Cited by 23Lipid metabolism and biosynthesisLiver Disease Diagnosis and TreatmentLipid metabolism and disorders

Lipid droplet membrane proteome remodeling parallels ethanol-induced hepatic steatosis and its resolution

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Casey, Carol A., Donohue, Terrence M., Kubik, Jacy L., Kumar, Vikas, Naldrett, Michael J., Woods, Nicholas T., Frisbie, Cole P., McNiven, Mark A. +1 more·2021·Journal of Lipid Research
DOI 10.1016/j.jlr.2021.100049PMC PMC8010705
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Abstract

Lipid droplets (LDs) are composed of neutral lipids enclosed in a phospholipid monolayer, which harbors membrane-associated proteins that regulate LD functions. Despite the crucial role of LDs in lipid metabolism, remodeling of LD protein composition in disease contexts, such as steatosis, remains poorly understood. We hypothesized that chronic ethanol consumption, subsequent abstinence from ethanol, or fasting differentially affects the LD membrane proteome content and that these changes influence how LDs interact with other intracellular organelles. Here, male Wistar rats were pair-fed liquid control or ethanol diets for 6 weeks, and then, randomly chosen animals from both groups were either refed a control diet for 7 days or fasted for 48 h before euthanizing. From all groups, LD membrane proteins from purified liver LDs were analyzed immunochemically and by MS proteomics. Liver LD numbers and sizes were greater in ethanol-fed rats than in pair-fed control, 7-day refed, or fasted rats. Compared with control rats, ethanol feeding markedly altered the LD membrane proteome, enriching LD structural perilipins and proteins involved in lipid biosynthesis, while lowering LD lipase levels. Ethanol feeding also lowered LD-associated mitochondrial and lysosomal proteins. In 7-day refed (i.e., ethanol-abstained) or fasted-ethanol-fed rats, we detected distinct remodeling of the LD proteome, as judged by lower levels of lipid biosynthetic proteins, and enhanced LD interaction with mitochondria and lysosomes. Our study reveals evidence of significant remodeling of the LD membrane proteome that regulates ethanol-induced steatosis, its resolution after withdrawal and abstinence, and changes in LD interactions with other intracellular organelles.

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  • Both cell type and cellular environment modulate the lipid droplet proteome and lipidome.

    “Importantly, both cell type and cellular environment modulate the lipid droplet proteome and lipidome3–9.”

    From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [5]

    The Discussion reports that ethanol feeding altered 338 lipid-droplet membrane-associated proteins, supporting an effect of cellular environment on the proteome. The study examines liver lipid droplets; our copy does not establish that cell type modulates their composition or that either factor modulates the lipid-droplet lipidome. (LLM, conf=0.85)

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Research works printed but not linked: 36

  1. [1]You M. Arteel G.E. Effect of ethanol on lipid metabolism J. Hepatol. 70 2019 237 248 30658725 PMC6436537
  2. [2]Thomes P.G. Rasineni K. Yang L. Donohue T.M. Jr. Kubik J.L. McNiven M.A. Casey C.A. Ethanol withdrawal mitigates fatty liver by normalizing lipid catabolism Am. J. Physiol. Gastrointest. Liver Physiol. 316 2019 G509 G518 30714813 PMC6957361
  3. [3]Donohue T.M. Jr. Thomes P.G. Ethanol-induced oxidant stress modulates hepatic autophagy and proteasome activity Redox Biol. 3 2014 29 39 25462063 PMC4297932
  4. [4]Thomes P.G. Donohue T.M. Role of early growth response-1 in the development of alcohol-induced steatosis Curr. Mol. Pharmacol. 10 2017 179 185 26278386
  5. [5]Walther T.C. Chung J. Farese R.V. Jr. Lipid droplet biogenesis Annu. Rev. Cell Dev. Biol 33 2017 491 510 28793795 PMC6986389
  6. [6]Olzmann J.A. Carvalho P. Dynamics and functions of lipid droplets Nat. Rev. Mol. Cell Biol 20 2019 137 155 30523332 PMC6746329
  7. [7]Khan S.A. Wollaston-Hayden E.E. Markowski T.W. Higgins L. Mashek D.G. Quantitative analysis of the murine lipid droplet-associated proteome during diet-induced hepatic steatosis J. Lipid Res. 56 2015 2260 2272 26416795 PMC4655982
  8. [8]Krahmer N. Najafi B. Schueder F. Quagliarini F. Steger M. Seitz S. Kasper R. Salinas F. Cox J. Uhlenhaut N.H. Walther T.C. Jungmann R. Zeigerer A. Borner G.H.H. Mann M. Organellar proteomics and phospho-proteomics reveal subcellular reorganization in diet-induced hepatic steatosis Dev. Cell 47 2018 205 221 e207 30352176
  9. [9]Wang Z. Yao T. Song Z. Chronic alcohol consumption disrupted cholesterol homeostasis in rats: down-regulation of low-density lipoprotein receptor and enhancement of cholesterol biosynthesis pathway in the liver Alcohol Clin. Exp. Res. 34 2010 471 478 20028367 PMC3260025
  10. [10]Schulze R.J. Rasineni K. Weller S.G. Schott M.B. Schroeder B. Casey C.A. McNiven M.A. Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7 Hepatol. Commun. 1 2017 140 152 29404450 PMC5721426
  11. [11]Rasineni K. Donohue T.M. Jr. Thomes P.G. Yang Li. Tuma D.L. McNiven M.A. Casey C.A. Ethanol-induced steatosis involves impairment of lipophagy, associated with reduced dynamin2 activity Hepatol. Commun. 1 2017 501 512 29152606 PMC5678901
  12. [12]Zhang H. Wang Y. Li J. Yu J. Pu J. Li L. Zhang H. Zhang S. Peng G. Yang F. Liu P. Proteome of skeletal muscle lipid droplet reveals association with mitochondria and apolipoprotein a-I J. Proteome Res. 10 2011 4757 4768 21870882
  13. [13]Ding Y. Zhang S. Yang L. Na H. Zhang P. Zhang H. Wang Y. Chen Y. Yu J. Huo C. Xu S. Garaiova M. Cong Y. Liu P. Isolating lipid droplets from multiple species Nat. Protoc. 8 2013 43 51 23222457
  14. [14]Rasineni K. McVicker B.L. Tuma D.J. McNiven M.A. Casey C.A. Rab GTPases associate with isolated lipid droplets (LDs) and show altered content after ethanol administration: potential role in alcohol-impaired LD metabolism Alcohol. Clin. Exp. Res. 38 2014 327 335 24117505 PMC3946799
  15. [15]Bouchoux J. Beilstein F. Pauquai T. Guerrera I.C. Chateau D. Ly N. Alqub M. Klein C. Chambaz J. Rousset M. Lacorte J.M. Morel E. Demignot S. The proteome of cytosolic lipid droplets isolated from differentiated Caco-2/TC7 enterocytes reveals cell-specific characteristics Biol. Cell 103 2011 499 517 21787361 PMC3181828
  16. [16]Brasaemle D.L. Wolins N.E. Isolation of lipid droplets from cells by density gradient centrifugation Curr. Protoc. Cell Biol 72 2016 3 15 11 13 15 13 27580706 PMC5064949
  17. [17]Edens N.K. Leibel R.L. Hirsch J. Mechanism of free fatty acid re-esterification in human adipocytes in vitro J. Lipid Res. 31 1990 1423 1431 2280183
  18. [18]Bersuker K. Olzmann J.A. Establishing the lipid droplet proteome: mechanisms of lipid droplet protein targeting and degradation Biochim. Biophys. Acta Mol. Cell Biol Lipids 1862 2017 1166 1177 28627435 PMC5595636
  19. [19]Su W. Wang Y. Jia X. Wu W. Li L. Tian X. Li S. Wang C. Xu H. Cao J. Han Q. Xu S. Chen Y. Zhong Y. Zhang X. Comparative proteomic study reveals 17beta-HSD13 as a pathogenic protein in nonalcoholic fatty liver disease Proc. Natl. Acad. Sci. U.S.A. 111 2014 11437 11442 25028495 PMC4128098
  20. [20]Ma Y. Belyaeva O.V. Brown P.M. Fujita K. Valles K. Karki S. de Boer Y.S. Koh C. Chen Y. Du X. Handelman S.K. Chen V. Speliotes E.K. Nestlerode C. Thomas E. 17-Beta hydroxysteroid dehydrogenase 13 is a hepatic retinol dehydrogenase associated with histological features of nonalcoholic fatty liver disease Hepatology 69 2019 1504 1519 30415504 PMC6438737
  21. [21]Liu Y. Xu S. Zhang C. Zhu X. Hammad M.A. Zhang X. Christian M. Zhang H. Liu P. Hydroxysteroid dehydrogenase family proteins on lipid droplets through bacteria, C. elegans, and mammals Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1863 2018 881 894 29702244
  22. [22]Thomes P.G. Trambly C.S. Fox H.S. Tuma D.J. Donohue T.M. Jr. Acute and chronic ethanol administration differentially modulate hepatic autophagy and transcription factor EB Alcohol Clin. Exp. Res. 39 2015 2354 2363 26556759
  23. [23]Kaushik S. Cuervo A.M. Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis Nat. Cel. Biol. 17 2015 759 770 PMC4449813 25961502
  24. [24]Bersuker K. Peterson C.W.H. To M. Sahl S.J. Savikhin V. Grossman E.A. Nomura D.K. Olzmann J.A. a proximity labeling strategy provides insights into the composition and dynamics of lipid droplet proteomes Dev. Cell 44 2018 97 112 e117 29275994 PMC5764092
  25. [25]Crunk A.E. Monks J. Murakami A. Jackman M. Maclean P.S. Ladinsky M. Bales E.S. Cain S. Orlicky D.J. McManaman J.L. Dynamic regulation of hepatic lipid droplet properties by diet PLoS One 8 2013 e67631 PMC3708958 23874434
  26. [26]Rondini E.A. Duniec-Dmuchowski Z. Cukovic D. Dombkowski A.A. Kocarek T.A. Differential regulation of gene expression by cholesterol biosynthesis inhibitors that reduce (pravastatin) or enhance (squalestatin 1) nonsterol isoprenoid levels in primary cultured mouse and rat hepatocytes J. Pharmacol. Exp. Ther. 358 2016 216 229 27225895 PMC4959097
  27. [27]Gordaliza-Alaguero I. Canto C. Zorzano A. Metabolic implications of organelle-mitochondria communication EMBO Rep. 20 2019 e47928 PMC6726909 31418169
  28. [28]Cui L. Mirza A.H. Zhang S. Liang B. Liu P. Lipid droplets and mitochondria are anchored during brown adipocyte differentiation Protein Cell 10 2019 921 926 31667701 PMC6881423
  29. [29]Jagerstrom S. Polesie S. Wickstrom Y. Johansson B.R. Schroder H.D. Hojlund K. Bostrom P. Lipid droplets interact with mitochondria using SNAP23 Cell Biol Int. 33 2009 934 940 19524684
  30. [30]Settembre C. Di Malta C. Polito V.A. Garcia Arencibia M. Vetrini F. Erdin S. Erdin S.U. Huynh T. Medina D. Colella P. Sardiello M. Rubinsztein D.C. Ballabio A. TFEB links autophagy to lysosomal biogenesis Science 332 2011 1429 1433 21617040 PMC3638014
  31. [31]Greenberg A.S. Coleman R.A. Kraemer F.B. McManaman J.L. Obin M.S. Puri V. Yan Q.W. Miyoshi H. Mashek D.G. The role of lipid droplets in metabolic disease in rodents and humans J. Clin. Invest 121 2011 2102 2110 21633178 PMC3104768
  32. [32]Szkudelski T. Lisiecka M. Nowicka E. Kowalewska A. Nogowski L. Szkudelska K. Short-term fasting and lipolytic activity in rat adipocytes Horm. Metab. Res. 36 2004 667 673 15523590
  33. [33]Schott M.B. Weller S.G. Schulze R.J. Krueger E.W. Drizyte-Miller K. Casey C.A. McNiven M.A. Lipid droplet size directs lipolysis and lipophagy catabolism in hepatocytes J. Cell Biol. 218 2019 3320 3335 31391210 PMC6781454
  34. [34]Farese R.V. Jr. Walther T.C. Lipid droplets finally get a little R-E-S-P-E-C-T Cell 139 2009 855 860 19945371 PMC3097139
  35. [35]Donohue T.M. Jr. McVicker D.L. Kharbanda K.K. Chaisson M.L. Zetterman R.K. Ethanol administration alters the proteolytic activity of hepatic lysosomes Alcohol. Clin. Exp. Res. 18 1994 536 541 7943651
  36. [36]Kharbanda K.K. McVicker D.L. Zetterman R.K. Donohue T.M. Jr. Ethanol consumption reduces the proteolytic capacity and protease activities of hepatic lysosomes Biochim. Biophys. Acta 1245 1995 421 429 8541322

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Authors
Casey, C. A., Donohue, T. M., Kubik, J. L., Kumar, V., Naldrett, M. J., Woods, N. T., Frisbie, C. P., McNiven, M. A., & Thomes, P. G.
Affiliations
  • VA Nebraska Western Iowa Health Care System (US)
  • Omaha VA Medical Center (US)
  • University of Nebraska Medical Center (US)
  • University of Nebraska–Lincoln (US)
  • Mayo Clinic (US)
Corresponding author
Thomes, Paul G.
ORCID
Venue
Journal of Lipid Research
Publisher
Elsevier BV
Published
2021
Volume
62
Pages
100049
ISSN
0022-2275 (ISSN-L)
DOI
10.1016/j.jlr.2021.100049
PMC
PMC8010705
OpenAlex
W3130382345
Cited by
23
References
0
Citations by year
2026: 6 · 2025: 6 · 2024: 5 · 2023: 3 · 2022: 3
FWCI
1.13
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Lipid Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DigitalCommons@UNMC (submittedVersion, cc-by)
  • Lincoln (University of Nebraska) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
lipid droplets, alcoholic liver disease, ethanol withdrawal, fasting, perilipin, lipogenesis, lipase, mitochondrial association, organelle interactions, liver
MeSH terms
Ethanol, Animals, Fatty Liver, Liver, Male, Rats, Wistar, Proteome, Lipid Metabolism, Rats, Lipid Droplets

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