{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T21:06:27Z","timestamp":1788296787142,"version":"build-2803163510"},"reference-count":25,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,27]],"date-time":"2025-04-27T00:00:00Z","timestamp":1745712000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"U.S. Department of Veterans Affairs:\u00a0Veterans Administration Merit Review Award","award":["I01 BX005895-01A2"],"award-info":[{"award-number":["I01 BX005895-01A2"]}]},{"name":"U.S. Department of Veterans Affairs:\u00a0Veterans Administration Merit Review Award","award":["411456"],"award-info":[{"award-number":["411456"]}]},{"name":"U.S. Department of Veterans Affairs:\u00a0Veterans Administration Merit Review Award","award":["411864"],"award-info":[{"award-number":["411864"]}]},{"name":"Virginia Commonwealth University VETAR Award","award":["I01 BX005895-01A2"],"award-info":[{"award-number":["I01 BX005895-01A2"]}]},{"name":"Virginia Commonwealth University VETAR Award","award":["411456"],"award-info":[{"award-number":["411456"]}]},{"name":"Virginia Commonwealth University VETAR Award","award":["411864"],"award-info":[{"award-number":["411864"]}]},{"name":"Virginia Commonwealth University Department of Internal Medicine Pilot Project Fund","award":["I01 BX005895-01A2"],"award-info":[{"award-number":["I01 BX005895-01A2"]}]},{"name":"Virginia Commonwealth University Department of Internal Medicine Pilot Project Fund","award":["411456"],"award-info":[{"award-number":["411456"]}]},{"name":"Virginia Commonwealth University Department of Internal Medicine Pilot Project Fund","award":["411864"],"award-info":[{"award-number":["411864"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The unfolded protein response (UPR) is a highly orchestrated survival response initiated in cells under endoplasmic reticulum (ER) stress. Steroidogenic acute regulatory-related lipid transfer domain 5 (StarD5) is an ER stress-responsive, cholesterol-binding protein under the regulation of IRE1. Based upon in vitro findings, StarD5 delivers a protective response by translocating ER cholesterol to the plasma membrane (PM) and accompanying protective changes in PM fluidity. The study aimed to determine if StarD5\u2032s ability to provide in vitro hepatocyte protective responses is translatable to in vivo conditions. ER stress in mouse livers was induced by intraperitoneal injection of tunicamycin (Tm). Adenovirus was used to restore the expression of StarD5 in the livers of StarD5\u2212\/\u2212 mice. Immunoblotting, histological analysis, and lipid measurements were performed. Induction of ER stress led to increased expression of StarD5 and steatosis in the livers of wild-type (WT) mice, while in StarD5\u2212\/\u2212 mice, steatosis and apoptosis were more acute compared to WT mice, as evidenced by increased lipid accumulation and cleavage of PARP, respectively. Selectively restoring StarD5 expression to ER-stressed StarD5\u2212\/\u2212 mice blunted the effects of tunicamycin. StarD5 appears to play a critical role in the ER stress survival response through its ability to regulate intracellular cholesterol homeostasis.<\/jats:p>","DOI":"10.3390\/ijms26094157","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T11:48:33Z","timestamp":1745840913000},"page":"4157","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["StarD5 Plays a Critical Role in the Hepatocyte ER Stress Survival Response"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6288-6484","authenticated-orcid":false,"given":"William M.","family":"Pandak","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Central Virginia VA Healthcare System, Richmond, VA 23248, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0366-6903","authenticated-orcid":false,"given":"Genta","family":"Kakiyama","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Central Virginia VA Healthcare System, Richmond, VA 23248, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5521-6314","authenticated-orcid":false,"given":"Daniel","family":"Rodriguez-Agudo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Central Virginia VA Healthcare System, Richmond, VA 23248, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.molmed.2011.07.010","article-title":"Endoplasmic reticulum stress, obesity and diabetes","volume":"18","author":"Cnop","year":"2012","journal-title":"Trends Mol. 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