{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:40:29Z","timestamp":1792521629085,"version":"4.5.0"},"reference-count":0,"publisher":"American Diabetes Association","license":[{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"name":"Merck Sharp & Dohme LLC"},{"name":"Merck & Co., Inc., Rahway, NJ USA"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>People with an I148M mutation in the PNPLA3 protein are at high risk of developing hepatic steatosis and progressive liver disease. The PNPLA3-I148M mutant protein accumulates on the membrane of lipid droplets (LDs) where it can interfere with the function of adipose tissue triglyceride lipase (ATGL) by depleting their shared cofactor \u03b1\/\u03b2-hydrolase domain-containing protein 5 (ABHD5). We hypothesized that restoring ABHD5 supply to ATGL by either ABHD5 overexpression or interruption of the protein-protein interaction (PPI) between ABHD5 and PNPLA3-I148M would recover lipolysis and ameliorate steatosis. In PNPLA3-I148M\u2013expressing HuH7 cells and primary human hepatocytes homozygous for the PNPLA3-I148M mutation, overexpression of ABHD5 stimulated lipolysis and reduced LD accumulation. In PNPLA3-I148M knockin mice, adeno-associated virus\u2013mediated overexpression of ABHD5 improved diet-induced hepatic steatosis. The amino acids (AAs) essential for the PPI between ABHD5 and PNPLA3 were identified using AlphaFold structural predictions, and AA substitutions (F17A\/R120A) were verified to disrupt the PPI via competitive binding assay. Disruption of the PNPLA3-ABHD5 PPI reduced LD accumulation in HuH7 cells and improved hepatic steatosis in PNPLA3-I148M knockin mice. Together, our data support the hypothesis that PNPLA3-I148M causes hepatic steatosis via sequestration of ABHD5 from ATGL and that disruption of the PPI between ABHD5 and PNPLA3-I148M can resolve hepatic dysfunction.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>We evaluate the importance of the protein-protein interaction (PPI) between PNPLA3-I148M and its cofactor \u03b1\/\u03b2-hydrolase domain-containing protein 5 (ABHD5) in PNPLA3-I148M\u2013mediated hepatic steatosis. We demonstrate that disrupting the PNPLA3-ABHD5 PPI improves I148M-associated steatosis and markers of liver injury. This work supports the development of therapies targeting the PNPLA3-ABHD5 PPI for the treatment of PNPLA3-I148M\u2013associated metabolic dysfunction\u2013associated steatotic liver disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db26-0108","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:17:38Z","timestamp":1792520258000},"update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":0,"title":["Disrupting the PNPLA3-ABHD5 Interaction Stimulates Lipolysis and Improves PNPLA3-I148M\u2013Associated Hepatic Steatosis"],"prefix":"10.2337","author":[{"given":"Simon Steinbring","family":"Hoffman","sequence":"first","affiliation":[{"name":"1Merck & Co., Inc., South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily Tso","family":"Newman","sequence":"additional","affiliation":[{"name":"1Merck & Co., Inc., South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Lin","sequence":"additional","affiliation":[{"name":"1Merck & Co., Inc., South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Chen","sequence":"additional","affiliation":[{"name":"1Merck & Co., Inc., South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Yang","sequence":"additional","affiliation":[{"name":"1Merck & Co., Inc., South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Cheng","sequence":"additional","affiliation":[{"name":"1Merck & Co., Inc., South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas W.","family":"Rosahl","sequence":"additional","affiliation":[{"name":"2Merck & Co., Inc., Rahway, NJ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather H.","family":"Zhou","sequence":"additional","affiliation":[{"name":"2Merck & Co., Inc., Rahway, NJ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saswata","family":"Talukdar","sequence":"additional","affiliation":[{"name":"1Merck & Co., Inc., South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8910-0272","authenticated-orcid":false,"given":"Yingjiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"1Merck & Co., Inc., South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2026,10,20]]},"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/doi\/10.2337\/db26-0108\/899405\/db260108.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/doi\/10.2337\/db26-0108\/899405\/db260108.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:17:38Z","timestamp":1792520258000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/doi\/10.2337\/db26-0108\/172861\/Disrupting-the-PNPLA3-ABHD5-Interaction-Stimulates"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,20]]},"references-count":0,"URL":"https:\/\/doi.org\/10.2337\/db26-0108","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,20]]},"article-number":"db260108"}}