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Although lipid-metabolizing enzymes are considered important in NAFLD, the involvement of phospholipase D1 (PLD1) has not yet been studied. Here, we show that the genetic ablation of PLD1 in mice induces NAFLD due to an autophagy defect. PLD1 expression was decreased in high-fat diet-induced NAFLD. Subsequently, PLD1 deficiency led to an increase in hepatic TGs and liver weight. Autophagic flux was blocked in <jats:italic>Pld1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> hepatocytes, with decreased \u03b2-oxidation rate, reduced oxidation-related gene expression, and swollen mitochondria. The dynamics of autophagy was restored by treatment with the PLD product, phosphatidic acid (PA) or adenoviral PLD1 expression in <jats:italic>Pld1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> hepatocytes, confirming that lysosomal PA produced by PLD1 regulates autophagy. Notably, PLD1 expression in <jats:italic>Pld1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> liver significantly reduced hepatic lipid accumulation, compared with <jats:italic>Pld1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> liver. Thus, PLD1 plays an important role in hepatic steatosis via the regulation of autophagy.<\/jats:p>","DOI":"10.1038\/srep39170","type":"journal-article","created":{"date-parts":[[2016,12,15]],"date-time":"2016-12-15T12:38:37Z","timestamp":1481805517000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Phospholipase D1 deficiency in mice causes nonalcoholic fatty liver disease via an autophagy defect"],"prefix":"10.1038","volume":"6","author":[{"given":"Jang Ho","family":"Hur","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-Young","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Dall\u2019Armi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Sung","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilbert","family":"Di Paolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Young","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mee-Sup","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Do Sik","family":"Min","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheol Soo","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,12,15]]},"reference":[{"key":"BFsrep39170_CR1","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1111\/j.1872-034X.2011.00824.x","volume":"41","author":"AJ Sanyal","year":"2011","unstructured":"Sanyal, A. 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