title: Targeted Induction of Ceramide Degradation Leads to Improved Systemic Metabolism and Reduced Hepatic Steatosis.
abstract: Sphingolipids have garnered attention for their role in insulin resistance and lipotoxic cell death. We have developed transgenic mice inducibly expressing acid ceramidase that display a reduction in ceramides in adult mouse tissues. Hepatic overexpression of acid ceramidase prevents hepatic steatosis and prompts improvements in insulin action in liver and adipose tissue upon exposure to high-fat diet. Conversely, overexpression of acid ceramidase within adipose tissue also prevents hepatic steatosis and systemic insulin resistance. Induction of ceramidase activity in either tissue promotes a lowering of hepatic ceramides and reduced activation of the ceramide-activated protein kinase C isoform PKCζ, though the induction of ceramidase activity in the adipocyte prompts more rapid resolution of hepatic steatosis than overexpression of the enzyme directly in the liver. Collectively, our observations suggest the existence of a rapidly acting "cross-talk" between liver and adipose tissue sphingolipids, critically regulating glucose metabolism and hepatic lipid uptake.
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8549.
authors.forename: Jonathan Y
authors.initials: JY
authors.lastname: Xia
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8549.
authors.forename: William L
authors.initials: WL
authors.lastname: Holland
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8549.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Kusminski
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8549.
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8549.
authors.forename: Ankit X
authors.initials: AX
authors.lastname: Sharma
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8549.
authors.forename: Mackenzie J
authors.initials: MJ
authors.lastname: Pearson
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8549.
authors.forename: Angelika J
authors.initials: AJ
authors.lastname: Sifuentes
authors.affiliation: Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8549.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: McDonald
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8549.
authors.forename: Ruth
authors.initials: R
authors.lastname: Gordillo
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8549.|Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8549.
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
mesh_terms: D055573:Acid Ceramidase / Q000096:biosynthesis* / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002518:Ceramides / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism
chemical_list: D002518:Ceramides; C497256:Prkce protein, mouse; D051744:Protein Kinase C-epsilon; D055573:Acid Ceramidase; C526734:Asah1 protein, mouse