title: Phospholipase D1 deficiency in mice causes nonalcoholic fatty liver disease via an autophagy defect.
abstract: Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides (TG) as lipid droplets in the liver. 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 Pld1-/-hepatocytes, with decreased β-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 Pld1-/-hepatocytes, confirming that lysosomal PA produced by PLD1 regulates autophagy. Notably, PLD1 expression in Pld1-/-liver significantly reduced hepatic lipid accumulation, compared with Pld1-/-liver. Thus, PLD1 plays an important role in hepatic steatosis via the regulation of autophagy.
authors.affiliation: Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406-840, Korea.|Korea Mouse Metabolic Phenotyping Center (KMMPC), Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406-840, Korea.
authors.forename: Jang Ho
authors.initials: JH
authors.lastname: Hur
authors.affiliation: Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406-840, Korea.|Korea Mouse Metabolic Phenotyping Center (KMMPC), Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406-840, Korea.
authors.forename: Shi-Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, United States of America.
authors.forename: Claudia
authors.initials: C
authors.lastname: Dall'Armi
authors.affiliation: Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406-840, Korea.|Korea Mouse Metabolic Phenotyping Center (KMMPC), Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406-840, Korea.
authors.forename: Jae Sung
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, United States of America.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Di Paolo
authors.affiliation: Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406-840, Korea.|Korea Mouse Metabolic Phenotyping Center (KMMPC), Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406-840, Korea.
authors.forename: Hui-Young
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406-840, Korea.|Korea Mouse Metabolic Phenotyping Center (KMMPC), Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406-840, Korea.
authors.forename: Mee-Sup
authors.initials: MS
authors.lastname: Yoon
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 609-735, Korea.
authors.forename: Do Sik
authors.initials: DS
authors.lastname: Min
authors.affiliation: Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406-840, Korea.|Korea Mouse Metabolic Phenotyping Center (KMMPC), Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406-840, Korea.|Endocrinology, Internal Medicine, Gachon University Gil Medical Center, Incheon 405-760, Korea.
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D059305:Diet, High-Fat; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism / Q000473:pathology; D010101:Oxygen Consumption / Q000187:drug effects; D010712:Phosphatidic Acids / Q000032:analysis / Q000494:pharmacology; D010739:Phospholipase D / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D053719:Tandem Mass Spectrometry; D014280:Triglycerides / Q000097:blood
chemical_list: D001562:Benzimidazoles; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; C585271:N-(1-(4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo(d)imidazol-1-yl)piperidin-1-yl)propan-2-yl)-2-naphthamide; D010712:Phosphatidic Acids; D010880:Piperidines; D014280:Triglycerides; D010739:Phospholipase D; C106801:phospholipase D1