title: Sortilin deficiency improves the metabolic phenotype and reduces hepatic steatosis of mice subjected to diet-induced obesity.
abstract: OBJECTIVE
  Sortilin traffics newly synthesized molecules from the trans-Golgi apparatus along secretory pathways to endosomes, lysosomes or to the cell surface. Sortilin trafficking of acid sphingomyelinase (aSMase) may regulate ceramide levels, a major modulator of insulin signalling. We therefore tested whether sortilin deficiency reduces hepatic and adipose tissue aSMase activity, improving insulin sensitivity in diet-induced obesity (DIO).
  
  
  METHODS
  DIO in C57BL/6 (WT) and sortilin(-/-) mice was induced by high-fat diet feeding for 10 weeks.
  
  
  RESULTS
  Sortilin(-/-) mice gained less body weight and less visceral fat, despite similar food intake compared to WT type mice and had enhanced glucose uptake in insulin tolerance tests, which was further corroborated by enhanced hepatic pAkt expression. Sortilin deficiency led to attenuated hepatic steatosis, reduced expression of genes involved in lipogenesis, ceramide synthesis and inflammatory cytokine production and reduced activity of ceramide synthase 5/6 (CerS5/6). Sortilin(-/-) mice had reduced hepatic aSMase activity under both steady-state and DIO. Likewise, sortilin(-/-) hepatocytes displayed hypersensitivity to insulin, due to enhanced insulin receptor downstream signalling. In adipose tissue, sortilin(-/-) mice exhibited lower expression of inflammatory cytokines and lower expression and activity of CerS5/6. As in liver, adipose tissue displayed increased insulin signalling, accompanied by attenuated aSMase activity.
  
  
  CONCLUSIONS
  Sortilin deficiency induces a beneficial metabolic phenotype in liver and adipose tissue upon DIO, mediated in part by reduced aSMase activity.
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Liane
authors.initials: L
authors.lastname: Rabinowich
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Sigal
authors.initials: S
authors.lastname: Fishman
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Einav
authors.initials: E
authors.lastname: Hubel
authors.affiliation: Internal Medicine D, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Thurm
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel; Department of Biochemistry, School of Medicine, Gachon University, Incheon 406-799, Republic of Korea.
authors.forename: Woo-Jae
authors.initials: WJ
authors.lastname: Park
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Pewzner-Jung
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ashish
authors.initials: A
authors.lastname: Saroha
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Noam
authors.initials: N
authors.lastname: Erez
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Zamir
authors.initials: Z
authors.lastname: Halpern
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: isab@tlvmc.gov.il.
authors.forename: Isabel
authors.initials: I
authors.lastname: Zvibel
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D012313:RNA; D000099183:Sortilin
keywords: Acid sphingomyelinase; Ceramide synthesis; Hepatic steatosis; Insulin resistance; Sortilin