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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,4,30]]},"abstract":"<jats:p>\n                    Nonalcoholic fatty liver disease, recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is a progressive metabolic disorder that begins with aberrant triglyceride accumulation in the liver and can lead to cirrhosis and cancer. A common variant in the gene\n                    <jats:italic>PNPLA3<\/jats:italic>\n                    , encoding the protein PNPLA3-I148M, is the strongest known genetic risk factor for MASLD. Despite its discovery 20 y ago, the function of PNPLA3, and now the role of PNPLA3-I148M, remain unclear. In this study, we sought to dissect the biogenesis of PNPLA3 and PNPLA3-I148M and characterize changes induced by endogenous expression of the disease-causing variant. Contrary to bioinformatic predictions and prior studies with overexpressed proteins, we demonstrate here that PNPLA3 and PNPLA3-I148M are not endoplasmic reticulum-resident transmembrane proteins. To identify their intracellular associations, we generated a paired set of isogenic human hepatoma cells expressing PNPLA3 and PNPLA3-I148M at endogenous levels. Both proteins were enriched in lipid droplet, Golgi, and endosomal fractions. Purified PNPLA3 and PNPLA3-I148M proteins associated with phosphoinositides commonly found in these compartments. Despite a similar fractionation pattern as the wild-type variant, PNPLA3-I148M induced morphological changes in the Golgi apparatus, including increased lipid droplet\u2013Golgi contact sites, which were also observed in I148M-expressing primary human patient hepatocytes. In addition to lipid droplet accumulation, PNPLA3-I148M expression caused significant proteomic and transcriptomic changes that resembled all stages of liver disease. Cumulatively, we validate an endogenous human cellular system for investigating PNPLA3-I148M biology and identify the Golgi apparatus as a central hub of PNPLA3-I148M-driven cellular change.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2318619121","type":"journal-article","created":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T13:52:43Z","timestamp":1713966763000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":32,"title":["The fatty liver disease\u2013causing protein PNPLA3-I148M alters lipid droplet\u2013Golgi dynamics"],"prefix":"10.1073","volume":"121","author":[{"given":"David J.","family":"Sherman","sequence":"first","affiliation":[{"name":"Amgen Research, Thousand Oaks, CA 91320"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Liu","sequence":"additional","affiliation":[{"name":"Amgen Research, South San Francisco, CA 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Institute of Technology, Pasadena, CA 91125"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rati","family":"Verma","sequence":"additional","affiliation":[{"name":"Amgen Research, Thousand Oaks, CA 91320"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid C.","family":"Rulifson","sequence":"additional","affiliation":[{"name":"Amgen Research, South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3671-9354","authenticated-orcid":false,"given":"Raymond J.","family":"Deshaies","sequence":"additional","affiliation":[{"name":"Amgen Research, Thousand Oaks, CA 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