{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:43:24Z","timestamp":1791999804415,"version":"4.4.0"},"reference-count":24,"publisher":"Rockefeller University Press","issue":"8","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/rupress.org\/pages\/terms102024"}],"funder":[{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["AA020735"],"award-info":[{"award-number":["AA020735"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK044650"],"award-info":[{"award-number":["DK044650"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,8,4]]},"abstract":"<jats:p>The liver stores substantial numbers of neutral lipid organelles termed lipid droplets (LDs) that accumulate within hepatocytes in response to chronic ethanol (EtOH) consumption leading to hepatic steatosis. Mass spectrometry analysis of LDs isolated from EtOH-damaged rat livers revealed a substantial reduction in the valosin-containing protein ATPase (VCP\/p97) that acts to remove targeted proteins from cellular membranes for degradation. Experimental disruption of VCP function resulted in an increase in LD content in hepatocytes and mouse livers along with a marked increase in LD-associated hydroxysteroid dehydrogenase (HSD17\u03b213) known to contribute to hepatic steatosis. Surprisingly, treatment of hepatocytes with the proteasome inhibitor MG132 had no effect on HSD17\u03b213 levels, while a disruption of lysosome function and chaperone-mediated autophagy increased cellular HSD17\u03b213 levels substantially. These findings provide new insights into the cellular mechanisms by which the liver regulates its lipid stores and how this is disrupted by chronic EtOH exposure.<\/jats:p>","DOI":"10.1083\/jcb.202408205","type":"journal-article","created":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T02:21:07Z","timestamp":1748658067000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["An ethanol-induced loss of the lipid droplet\u2013associated segregase VCP\/p97 leads to hepatic steatosis"],"prefix":"10.1083","volume":"224","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5191-4134","authenticated-orcid":true,"given":"Sandhya","family":"Sen","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02qp3tb03","id-type":"ROR","asserted-by":"publisher"}],"name":"Mayo Clinic College of Medicine 1 The GI Center for Digestive Diseases, The Department of Biochemistry and Molecular Biology, , Rochester, MN,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2239-6165","authenticated-orcid":true,"given":"Shaun","family":"Weller","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02qp3tb03","id-type":"ROR","asserted-by":"publisher"}],"name":"Mayo Clinic College of Medicine 1 The GI Center for Digestive Diseases, The Department of Biochemistry and Molecular Biology, , Rochester, MN,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6427-9301","authenticated-orcid":true,"given":"Ryan J.","family":"Schulze","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02qp3tb03","id-type":"ROR","asserted-by":"publisher"}],"name":"Mayo Clinic College of Medicine 1 The GI Center for Digestive Diseases, The Department of Biochemistry and Molecular Biology, , Rochester, MN,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2339-7349","authenticated-orcid":true,"given":"Donglin","family":"Ding","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02qp3tb03","id-type":"ROR","asserted-by":"publisher"}],"name":"Mayo Clinic College of Medicine 1 The GI Center for Digestive Diseases, The Department of Biochemistry and Molecular Biology, , Rochester, MN,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7501-0495","authenticated-orcid":true,"given":"Carol A.","family":"Casey","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00thqtb16","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Nebraska Medical Center 2 The Department of Internal Medicine, , Omaha, NE,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3816-6124","authenticated-orcid":true,"given":"Conrad","family":"Weihl","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine 3 Department of Neurology, , St. Louis, MO,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9830-1885","authenticated-orcid":true,"given":"Mark A.","family":"McNiven","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02qp3tb03","id-type":"ROR","asserted-by":"publisher"}],"name":"Mayo Clinic College of Medicine 1 The GI Center for Digestive Diseases, The Department of Biochemistry and Molecular Biology, , Rochester, MN,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2025,7,29]]},"reference":[{"key":"2025072909335997700_bib1","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1056\/NEJMoa1712191","article-title":"A protein-truncating HSD17B13 variant and protection from chronic liver disease","volume":"378","author":"Abul-Husn","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"2025072909335997700_bib2","doi-asserted-by":"publisher","first-page":"46","DOI":"10.3389\/fnbeh.2016.00046","article-title":"Label-free proteomic analysis of protein changes in the striatum during chronic ethanol use and early withdrawal","volume":"10","author":"Ayers-Ringler","year":"2016","journal-title":"Front. Behav. Neurosci."},{"key":"2025072909335997700_bib3","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.devcel.2017.11.020","article-title":"A proximity labeling strategy provides insights into the composition and dynamics of lipid droplet proteomes","volume":"44","author":"Bersuker","year":"2018","journal-title":"Dev. Cell"},{"key":"2025072909335997700_bib4","doi-asserted-by":"publisher","first-page":"105182","DOI":"10.1016\/j.jbc.2023.105182","article-title":"Structural insights of the p97\/VCP AAA+ ATPase: How adapter interactions coordinate diverse cellular functionality","volume":"299","author":"Braxton","year":"2023","journal-title":"J. Biol. Chem."},{"key":"2025072909335997700_bib5","doi-asserted-by":"publisher","first-page":"2578","DOI":"10.1016\/j.febslet.2015.08.028","article-title":"Control of p97 function by cofactor binding","volume":"589","author":"Buchberger","year":"2015","journal-title":"FEBS Lett."},{"key":"2025072909335997700_bib6","doi-asserted-by":"publisher","first-page":"100049","DOI":"10.1016\/j.jlr.2021.100049","article-title":"Lipid droplet membrane proteome remodeling parallels ethanol-induced hepatic steatosis and its resolution","volume":"62","author":"Casey","year":"2021","journal-title":"J. Lipid Res."},{"key":"2025072909335997700_bib7","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.yexcr.2014.08.025","article-title":"Should I stay or should I go: VCP\/p97-mediated chromatin extraction in the DNA damage response","volume":"329","author":"Dantuma","year":"2014","journal-title":"Exp. Cell Res."},{"key":"2025072909335997700_bib8","doi-asserted-by":"publisher","first-page":"1939","DOI":"10.3390\/ijms23041939","article-title":"Valosin containing protein (VCP): A multistep regulator of autophagy","volume":"23","author":"Ferrari","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"2025072909335997700_bib9","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1038\/s41580-018-0001-6","article-title":"The coming of age of chaperone-mediated autophagy","volume":"19","author":"Kaushik","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2025072909335997700_bib10","doi-asserted-by":"publisher","first-page":"5383","DOI":"10.1021\/ac025747h","article-title":"Empirical statistical model to estimate the accuracy of peptide identifications made by MS\/MS and database search","volume":"74","author":"Keller","year":"2002","journal-title":"Anal. Chem."},{"key":"2025072909335997700_bib11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000301","article-title":"Proteome-wide analysis of chaperone-mediated autophagy targeting motifs","volume":"17","author":"Kirchner","year":"2019","journal-title":"PLoS Biol."},{"key":"2025072909335997700_bib12","doi-asserted-by":"publisher","first-page":"1504","DOI":"10.1002\/hep.30350","article-title":"17-Beta hydroxysteroid dehydrogenase 13 is a hepatic retinol dehydrogenase associated with histological features of nonalcoholic fatty liver disease","volume":"69","author":"Ma","year":"2019","journal-title":"Hepatology"},{"key":"2025072909335997700_bib13","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.1002\/hep.31517","article-title":"17-Beta hydroxysteroid dehydrogenase 13 deficiency does not protect mice from obesogenic diet injury","volume":"73","author":"Ma","year":"2021","journal-title":"Hepatology"},{"key":"2025072909335997700_bib14","doi-asserted-by":"publisher","first-page":"4646","DOI":"10.1021\/ac0341261","article-title":"A statistical model for identifying proteins by tandem mass spectrometry","volume":"75","author":"Nesvizhskii","year":"2003","journal-title":"Anal. Chem."},{"key":"2025072909335997700_bib15","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1073\/pnas.1213738110","article-title":"Spatial regulation of UBXD8 and p97\/VCP controls ATGL-mediated lipid droplet turnover","volume":"110","author":"Olzmann","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025072909335997700_bib16","doi-asserted-by":"publisher","first-page":"4932","DOI":"10.1158\/0008-5472.CAN-20-1255","article-title":"KRAS controls pancreatic cancer cell lipid metabolism and invasive potential through the lipase HSL","volume":"80","author":"Rozeveld","year":"2020","journal-title":"Cancer Res."},{"key":"2025072909335997700_bib17","doi-asserted-by":"publisher","first-page":"3320","DOI":"10.1083\/jcb.201803153","article-title":"Lipid droplet size directs lipolysis and lipophagy catabolism in hepatocytes","volume":"218","author":"Schott","year":"2019","journal-title":"J. Cell Biol."},{"key":"2025072909335997700_bib18","doi-asserted-by":"publisher","first-page":"32443","DOI":"10.1073\/pnas.2011442117","article-title":"Direct lysosome-based autophagy of lipid droplets in hepatocytes","volume":"117","author":"Schulze","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025072909335997700_bib19","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1002\/hep4.1021","article-title":"Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7","volume":"1","author":"Schulze","year":"2017","journal-title":"Hepatol. Commun."},{"key":"2025072909335997700_bib20","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1038\/s41572-018-0014-7","article-title":"Alcoholic liver disease","volume":"4","author":"Seitz","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"2025072909335997700_bib21","doi-asserted-by":"publisher","first-page":"11437","DOI":"10.1073\/pnas.1410741111","article-title":"Comparative proteomic study reveals 17\u03b2-HSD13 as a pathogenic protein in nonalcoholic fatty liver disease","volume":"111","author":"Su","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025072909335997700_bib22","doi-asserted-by":"publisher","first-page":"6577","DOI":"10.1038\/s41467-022-34299-1","article-title":"Phosphorylation of 17\u03b2-hydroxysteroid dehydrogenase 13 at serine 33 attenuates nonalcoholic fatty liver disease in mice","volume":"13","author":"Su","year":"2022","journal-title":"Nat. Commun."},{"key":"2025072909335997700_bib23","doi-asserted-by":"publisher","first-page":"5544","DOI":"10.3390\/ijms23105544","article-title":"Down-regulating the high level of 17-Beta-Hydroxysteroid dehydrogenase 13 plays a therapeutic role for non-alcoholic fatty liver disease","volume":"23","author":"Wang","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"2025072909335997700_bib24","doi-asserted-by":"publisher","first-page":"109399","DOI":"10.1016\/j.celrep.2021.109399","article-title":"Neuronal VCP loss of function recapitulates FTLD-TDP pathology","volume":"36","author":"Wani","year":"2021","journal-title":"Cell Rep."}],"container-title":["Journal of Cell Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jcb\/article-pdf\/doi\/10.1083\/jcb.202408205\/1947923\/jcb_202408205.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jcb\/article-pdf\/doi\/10.1083\/jcb.202408205\/1947923\/jcb_202408205.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T13:34:07Z","timestamp":1753796047000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jcb\/article\/224\/8\/e202408205\/278160\/An-ethanol-induced-loss-of-the-lipid-droplet"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,29]]},"references-count":24,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,8,4]]}},"URL":"https:\/\/doi.org\/10.1083\/jcb.202408205","relation":{},"ISSN":["0021-9525","1540-8140"],"issn-type":[{"value":"0021-9525","type":"print"},{"value":"1540-8140","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,29]]},"article-number":"e202408205"}}