title: Involvement of microsomal triglyceride transfer protein in nonalcoholic steatohepatitis in novel spontaneous mouse model.
abstract: OBJECTIVE
  Nonalcoholic fatty liver disease (NAFLD) is currently recognized as a global health issue and encompasses a wide spectrum of entities, ranging from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). The lack of a spontaneous animal model of NASH, however, has hampered basic research in this field.
  
  
  METHODS
  We examined the hepatic lesions in the inbred Fatty Liver Shionogi (FLS) mouse, which exhibits type 2 diabetes, and investigated the molecular mechanism leading to NAFLD/NASH. Using vector-mediated hepatic expression of microsomal triglyceride transfer protein (MTP), a key molecule for very low density lipoprotein (VLDL) assembly and export, its contribution to the hepatic lesions as well as to glucose intolerance was examined.
  
  
  RESULTS
  The FLS mouse, maintained on normal chow, exhibited excessive hepatic triglyceride (TG) accumulation due to impaired VLDL secretion, and subsequently hepatic lesions comparable to NASH, with increased expression of inflammatory molecules as well as insulin resistance. Gene expression and Western blot analyses demonstrated reduced hepatic expression of MTP in the FLS mouse. Hepatic induction of MTP resulted in a reduction in hepatic TG accumulation, improvement of VLDL export, and amelioration of NASH-like lesions, as well as glucose intolerance.
  
  
  CONCLUSIONS
  These data suggest that the FLS mouse could serve as a spontaneous model of NASH with insulin resistance, and that reduced MTP is involved in the development of NASH, pointing towards MTP as a critical target for the prevention and treatment of NASH.
authors.affiliation: Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Nobuyasu
authors.initials: N
authors.lastname: Shindo
authors.forename: Tomomi
authors.initials: T
authors.lastname: Fujisawa
authors.forename: Ken
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Koji
authors.initials: K
authors.lastname: Nojima
authors.forename: Aya
authors.initials: A
authors.lastname: Oze-Fukai
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yoshikawa
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Osamu
authors.initials: O
authors.lastname: Yasuda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ikegami
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015243:Cholesterol, VLDL / Q000097:blood; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015870:Gene Expression / Q000502:physiology; D018149:Glucose Intolerance / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008862:Microsomes, Liver / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D002352:Carrier Proteins; D015243:Cholesterol, VLDL; D007328:Insulin; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein