title: Vagus nerve contributes to the development of steatohepatitis and obesity in phosphatidylethanolamine N-methyltransferase deficient mice.
abstract: OBJECTIVE
  Phosphatidylethanolamine N-methyltransferase (PEMT), a liver enriched enzyme, is responsible for approximately one third of hepatic phosphatidylcholine biosynthesis. When fed a high-fat diet (HFD), Pemt(-/-) mice are protected from HF-induced obesity; however, they develop steatohepatitis. The vagus nerve relays signals between liver and brain that regulate peripheral adiposity and pancreas function. Here we explore a possible role of the hepatic branch of the vagus nerve in the development of diet induced obesity and steatohepatitis in Pemt(-/-) mice.
  
  
  METHODS
  8-week old Pemt(-/-) and Pemt(+/+) mice were subjected to hepatic vagotomy (HV) or capsaicin treatment, which selectively disrupts afferent nerves, and were compared to sham-operated or vehicle-treatment, respectively. After surgery, mice were fed a HFD for 10 weeks.
  
  
  RESULTS
  HV abolished the protection against the HFD-induced obesity and glucose intolerance in Pemt(-/-) mice. HV normalized phospholipid content and prevented steatohepatitis in Pemt(-/-) mice. Moreover, HV increased the hepatic anti-inflammatory cytokine interleukin-10, reduced chemokine monocyte chemotactic protein-1 and the ER stress marker C/EBP homologous protein. Furthermore, HV normalized the expression of mitochondrial electron transport chain proteins and of proteins involved in fatty acid synthesis, acetyl-CoA carboxylase and fatty acid synthase in Pemt(-/-) mice. However, disruption of the hepatic afferent vagus nerve by capsaicin failed to reverse either the protection against the HFD-induced obesity or the development of HF-induced steatohepatitis in Pemt(-/-) mice.
  
  
  CONCLUSIONS
  Neuronal signals via the hepatic vagus nerve contribute to the development of steatohepatitis and protection against obesity in HFD fed Pemt(-/-) mice.
authors.affiliation: Group on the Molecular and Cell Biology of Lipids, and Department of Biochemistry, University of Alberta, Edmonton, Canada.
authors.forename: Xia
authors.initials: X
authors.lastname: Gao
authors.affiliation: Group on the Molecular and Cell Biology of Lipids, and Department of Biochemistry, University of Alberta, Edmonton, Canada.
authors.forename: Jelske N
authors.initials: JN
authors.lastname: van der Veen
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, AB, Canada.
authors.forename: Linfu
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Todd
authors.initials: T
authors.lastname: Chaba
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Bilbao, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ordoñez
authors.affiliation: Group on the Molecular and Cell Biology of Lipids, and Department of Biochemistry, University of Alberta, Edmonton, Canada.
authors.forename: Susanne
authors.initials: S
authors.lastname: Lingrell
authors.affiliation: Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Debby P Y
authors.initials: DP
authors.lastname: Koonen
authors.affiliation: Cardiovascular Research Centre and Department of Pediatrics, University of Alberta, Edmonton, Canada.
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Bilbao, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gomez-Muñoz
authors.affiliation: Group on the Molecular and Cell Biology of Lipids, and Department of Biochemistry, University of Alberta, Edmonton, Canada.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Vance
authors.affiliation: Group on the Molecular and Cell Biology of Lipids, and Department of Agricultural, Food & Nutritional Science, University of Alberta, Edmonton, Canada. Electronic address: rjacobs@ualberta.ca.
authors.forename: René L
authors.initials: RL
authors.lastname: Jacobs
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects / Q000379:methods; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016753:Interleukin-10 / Q000378:metabolism; D008099:Liver / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009765:Obesity; D010713:Phosphatidylcholines / Q000096:biosynthesis*; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000378:metabolism*; D011184:Postoperative Period; D051742:Transcription Factor CHOP / Q000378:metabolism; D014628:Vagotomy / Q000009:adverse effects / Q000379:methods; D014630:Vagus Nerve / Q000503:physiopathology
chemical_list: D018932:Chemokine CCL2; D010713:Phosphatidylcholines; D016753:Interleukin-10; D051742:Transcription Factor CHOP; C559160:PEMT protein, mouse; D050918:Phosphatidylethanolamine N-Methyltransferase
keywords: Capsaicin; Hepatic vagotomy; Obesity; PEMT; Steatohepatitis