{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T19:42:45Z","timestamp":1792438965015,"version":"4.5.0"},"reference-count":65,"publisher":"National Academy of Sciences","issue":"6","license":[{"start":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T00:00:00Z","timestamp":1706659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017618","name":"HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases","doi-asserted-by":"publisher","award":["RO1-DK 090066"],"award-info":[{"award-number":["RO1-DK 090066"]}],"id":[{"id":"10.13039\/100017618","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["PO1 HL160487"],"award-info":[{"award-number":["PO1 HL160487"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","award":["30996"],"award-info":[{"award-number":["30996"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,2,6]]},"abstract":"<jats:p>\n                    A missense variant in patatin-like phospholipase domain-containing protein 3 [PNPLA3(I148M)] is the most impactful genetic risk factor for fatty liver disease (FLD). We previously showed that PNPLA3 is ubiquitylated and subsequently degraded by proteasomes and autophagosomes and that the PNPLA3(148M) variant interferes with this process. To define the machinery responsible for PNPLA3 turnover, we used small interfering (si)RNAs to inactivate components of the ubiquitin proteasome system. Inactivation of bifunctional apoptosis regulator (BFAR), a membrane-bound E3 ubiquitin ligase, reproducibly increased PNPLA3 levels in two lines of cultured hepatocytes. Conversely, overexpression of BFAR decreased levels of endogenous PNPLA3 in HuH7 cells. BFAR and PNPLA3 co-immunoprecipitated when co-expressed in cells. BFAR promoted ubiquitylation of PNPLA3 in vitro in a reconstitution assay using purified, epitope-tagged recombinant proteins. To confirm that BFAR targets PNPLA3, we inactivated\n                    <jats:italic>Bfar<\/jats:italic>\n                    in mice. Levels of PNPLA3 protein were increased twofold in hepatic lipid droplets of\n                    <jats:italic>\n                      Bfar\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice with no associated increase in PNPLA3 mRNA levels. Taken together these data are consistent with a model in which BFAR plays a role in the post-translational degradation of PNPLA3. The identification of BFAR provides a potential target to enhance PNPLA3 turnover and prevent FLD.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2312291121","type":"journal-article","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T12:45:30Z","timestamp":1706705130000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":19,"title":["The ubiquitin E3 ligase BFAR promotes degradation of PNPLA3"],"prefix":"10.1073","volume":"121","author":[{"given":"Avash","family":"Das","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haili","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3041-2615","authenticated-orcid":false,"given":"Lisa N.","family":"Kinch","sequence":"additional","affiliation":[{"name":"HHMI, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guosheng","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8700-9897","authenticated-orcid":false,"given":"Helen H.","family":"Hobbs","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390"},{"name":"HHMI, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0984-2864","authenticated-orcid":false,"given":"Jonathan C.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390"},{"name":"Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,1,31]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/S0025-6196(24)00530-5","article-title":"Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease","volume":"55","author":"Ludwig J.","year":"1980","unstructured":"J. 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