title: Autophagy regulates sphingolipid levels in the liver.
abstract: Sphingolipid levels are tightly regulated to maintain cellular homeostasis. During pathologic conditions such as in aging, inflammation, and metabolic and neurodegenerative diseases, levels of some sphingolipids, including the bioactive metabolite ceramide, are elevated. Sphingolipid metabolism has been linked to autophagy, a critical catabolic process in both normal cell function and disease; however, the in vivo relevance of the interaction is not well-understood. Here, we show that blocking autophagy in the liver by deletion of the Atg7 gene, which is essential for autophagosome formation, causes an increase in sphingolipid metabolites including ceramide. We also show that overexpression of serine palmitoyltransferase to elevate de novo sphingolipid biosynthesis induces autophagy in the liver. The results reveal autophagy as a process that limits excessive ceramide levels and that is induced by excessive elevation of de novo sphingolipid synthesis in the liver. Dysfunctional autophagy may be an underlying mechanism causing elevations in ceramide that may contribute to pathogenesis in diseases.
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Alexaki
authors.affiliation: Departments of Biochemistry Uniformed Services University of the Health Sciences, Bethesda, MD 20184.
authors.forename: Sita D
authors.initials: SD
authors.lastname: Gupta
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Saurav
authors.initials: S
authors.lastname: Majumder
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Mari
authors.initials: M
authors.lastname: Kono
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Galina
authors.initials: G
authors.lastname: Tuymetova
authors.affiliation: Molecular Biology and Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20184.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Harmon
authors.affiliation: Departments of Biochemistry Uniformed Services University of the Health Sciences, Bethesda, MD 20184.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Dunn
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Proia
mesh_terms: D000818:Animals; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D002518:Ceramides / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism / Q000648:ultrastructure; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D051102:Serine C-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism*; D013107:Sphingolipids / Q000378:metabolism*
chemical_list: C502661:Atg7 protein, mouse; D002518:Ceramides; D008869:Microtubule-Associated Proteins; D050505:Mutant Proteins; D011993:Recombinant Fusion Proteins; D013107:Sphingolipids; D049452:Green Fluorescent Proteins; D051102:Serine C-Palmitoyltransferase; C495088:Sptlc1 protein, mouse; C495090:Sptlc2 protein, mouse; D000071193:Autophagy-Related Protein 7
keywords: ceramide; endoplasmic reticulum; lipids; lipophagy; triglycerides