title: Peroxisome proliferator-activated receptor-α agonist, Wy 14,643, improves metabolic indices, steatosis and ballooning in diabetic mice with non-alcoholic steatohepatitis.
abstract: OBJECTIVE
  Lipid accumulation precedes hepatocellular injury and liver inflammation in non-alcoholic steatohepatitis (NASH). The peroxisome proliferator-activated receptor (PPAR)α regulates hepatic lipid disposal. We studied whether pharmacological stimulation of PPARα reverses NASH associated with metabolic syndrome in high-fat (HF)-fed foz/foz obese/diabetic mice.
  
  
  METHODS
  Female foz/foz mice and wildtype (WT) littermates were fed HF diet for 16 weeks to initiate NASH then treated with Wy 14,643 (Wy) for 10 days or 20 days. Liver disease was assessed by histology, serum alanine aminotransferase, genes (real-time polymerase chain reaction) and proteins (Western blot, enzyme-linked immunosorbent assay) of interest and pro-inflammatory signaling pathways were determined.
  
  
  RESULTS
  In diabetic foz/foz mice, NASH was associated with elevated serum MCP1 and hepatic activation of nuclear factor (NF)-κB and c-Jun N-terminal kinase, but not oxidative or endoplasmic reticulum stress. Wy treatment decreased steatosis and injury, although induction of PPARα-responsive fatty acid oxidation genes was proportionally less than in WT. The PPARα agonist lowered serum insulin, corrected hyperglycemia, and suppressed the carbohydrate-dependent lipogenic transcription factor, carbohydrate response element binding protein. Steatosis resolution was associated with suppression of NF-κB and JNK activation and decreased hepatic macrophages and neutrophils. Despite this, histology inflammation score remained high, associated with serum monocyte chemoattractant protein (MCP)1 elevation, a pro-inflammatory chemokine related to higher adipose, not liver MCP1 mRNA expression.
  
  
  CONCLUSIONS
  Pharmacological activation of PPARα improves metabolic milieu, steatosis, ballooning, and combats NF-κB and JNK activation, neutrophil and F4/80 macrophage recruitment in diabetes-related NASH. However, persistent liver inflammation with high serum MCP1 due to unsuppressed adipose inflammation may limit PPARα agonists' efficacy as therapy for NASH.
authors.affiliation: Liver Research Group, ANU Medical School at The Canberra Hospital, Garran, Australian Capital Territory, Australia.
authors.forename: Claire Z
authors.initials: CZ
authors.lastname: Larter
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.forename: Derrick M
authors.initials: DM
authors.lastname: Van Rooyen
authors.forename: John
authors.initials: J
authors.lastname: Brooling
authors.forename: Kamaljit
authors.initials: K
authors.lastname: Ghatora
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Farrell
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000378:metabolism; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005234:Fatty Liver / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016328:NF-kappa B / Q000494:pharmacology; D065626:Non-alcoholic Fatty Liver Disease; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D016328:NF-kappa B; D047493:PPAR alpha; D011743:Pyrimidines; C006253:pirinixic acid; D048031:JNK Mitogen-Activated Protein Kinases