title: Dietary modification dampens liver inflammation and fibrosis in obesity-related fatty liver disease.
abstract: BACKGROUND
  Alms1 mutant (foz/foz) mice develop hyperphagic obesity, diabetes, metabolic syndrome, and fatty liver (steatosis). High-fat (HF) feeding converts pathology from bland steatosis to nonalcoholic steatohepatitis (NASH) with fibrosis, which leads to cirrhosis in humans.
  
  
  OBJECTIVE
  We sought to establish how dietary composition contributes to NASH pathogenesis.
  
  
  METHODS
  foz/foz mice were fed HF diet or chow 24 weeks, or switched HF to chow after 12 weeks. Serum ALT, NAFLD activity score (NAS), fibrosis severity, neutrophil, macrophage and apoptosis immunohistochemistry, uncoupling protein (UCP)2, ATP, NF-κB activation/expression of chemokines/adhesion molecules/fibrogenic pathways were determined.
  
  
  RESULTS
  HF intake upregulated liver fatty acid and cholesterol transporter, CD36. Dietary switch expanded adipose tissue and decreased hepatomegaly by lowering triglyceride, cholesterol ester, free cholesterol and diacylglyceride content of liver. There was no change in lipogenesis or fatty acid oxidation pathways; instead, CD36 was suppressed. These diet-induced changes in hepatic lipids improved NAS, reduced neutrophil infiltration, normalized UCP2 and increased ATP; this facilitated apoptosis with a change in macrophage phenotype favoring M2 cells. Dietary switch also abrogated NF-κB activation and chemokine/adhesion molecule expression, and arrested fibrosis by dampening stellate cell activation.
  
  
  CONCLUSIONS
  Reversion to a physiological dietary composition after HF feeding in foz/foz mice alters body weight distribution but not obesity. This attenuates NASH severity and fibrotic progression by suppressing NF-κB activation and reducing neutrophil and macrophage activation. However, adipose inflammation persists and is associated with continuing apoptosis in the residual fatty liver disease. Taken together, these findings indicate that other measures, such as weight reduction, may be required to fully reverse obesity-related NASH.
authors.affiliation: Liver Research Group, ANU Medical School at the Canberra Hospital, Garran, ACT, Australia.
authors.forename: Claire Z
authors.initials: CZ
authors.lastname: Larter
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.forename: W Geoffrey
authors.initials: WG
authors.lastname: Haigh
authors.forename: Derrick M
authors.initials: DM
authors.lastname: Van Rooyen
authors.forename: John
authors.initials: J
authors.lastname: Brooling
authors.forename: Deborah
authors.initials: D
authors.lastname: Heydet
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Nolan
authors.forename: Narci C
authors.initials: NC
authors.lastname: Teoh
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Farrell
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004032:Diet; D059305:Diet, High-Fat / Q000009:adverse effects; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000150:complications / Q000178:diet therapy*; D055166:Hepatic Stellate Cells / Q000378:metabolism; D007249:Inflammation / Q000178:diet therapy / Q000473:pathology; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D050155:Lipogenesis / Q000502:physiology; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000178:diet therapy* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000150:complications / Q000178:diet therapy* / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D000071246:Uncoupling Protein 2; D015854:Up-Regulation
chemical_list: D018955:CD36 Antigens; D004041:Dietary Fats; D007473:Ion Channels; D024101:Mitochondrial Proteins; D016328:NF-kappa B; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D014280:Triglycerides; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D019716:Tissue Inhibitor of Metalloproteinase-2; D002784:Cholesterol; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse