title: De NovoSphingolipid Biosynthesis Is Required for Adipocyte Survival and Metabolic Homeostasis.
abstract: Sphingolipids are a diverse class of essential cellular lipids that function as structural membrane components and as signaling molecules. Cells acquire sphingolipids by bothde novobiosynthesis and recycling of exogenous sphingolipids. The individual importance of these pathways for the generation of essential sphingolipids in differentiated cells is not well understood. To investigate the requirement forde novosphingolipid biosynthesis in adipocytes, a cell type with highly regulated lipid metabolism, we generated mice with an adipocyte-specific deletion ofSptlc1Sptlc1 is an obligate subunit of serine palmitoyltransferase, the enzyme responsible for the first and rate-limiting step ofde novosphingolipid biosynthesis. These mice, which initially developed adipose tissue, exhibited a striking age-dependent loss of adipose tissue accompanied by evidence of adipocyte death, increased macrophage infiltration, and tissue fibrosis. Adipocyte differentiation was not affected by theSptlc1deletion. The mice also had elevated fasting blood glucose, fatty liver, and insulin resistance. Collectively, these data indicate thatde novosphingolipid biosynthesis is required for adipocyte cell viability and normal metabolic function and that reducedde novosphingolipid biosynthesis within adipocytes is associated with adipocyte death, adipose tissue remodeling, and metabolic dysfunction.
authors.affiliation: From the Genetics of Development and Disease Branch and.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Alexaki
authors.affiliation: From the Genetics of Development and Disease Branch and.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Clarke
authors.affiliation: Mouse Metabolism Core Laboratory, NIDDK, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.affiliation: Mouse Metabolism Core Laboratory, NIDDK, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: From the Genetics of Development and Disease Branch and.
authors.forename: Hongling
authors.initials: H
authors.lastname: Zhu
authors.affiliation: From the Genetics of Development and Disease Branch and.
authors.forename: Xinran
authors.initials: X
authors.lastname: Ma
authors.affiliation: From the Genetics of Development and Disease Branch and.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Xu
authors.affiliation: From the Genetics of Development and Disease Branch and.
authors.forename: Galina
authors.initials: G
authors.lastname: Tuymetova
authors.affiliation: From the Genetics of Development and Disease Branch and.
authors.forename: Bridget C
authors.initials: BC
authors.lastname: Larman
authors.affiliation: From the Genetics of Development and Disease Branch and.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Allende
authors.affiliation: the Department of Biochemistry, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20184.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Dunn
authors.affiliation: From the Genetics of Development and Disease Branch and proia@nih.gov.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Proia
mesh_terms: D017667:Adipocytes / Q000166:cytology*; D050154:Adiposity; D000818:Animals; D002454:Cell Differentiation; D002470:Cell Survival; D017353:Gene Deletion; D006706:Homeostasis; D007249:Inflammation; D007333:Insulin Resistance; D050356:Lipid Metabolism; D050155:Lipogenesis; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051102:Serine C-Palmitoyltransferase / Q000235:genetics* / Q000378:metabolism; D013107:Sphingolipids / Q000096:biosynthesis*
chemical_list: D013107:Sphingolipids; D051102:Serine C-Palmitoyltransferase; C495088:Sptlc1 protein, mouse
keywords: adipocyte; inflammation; lipodystrophy; serine palmitoyltransferase; sphingolipid