Peroxisome proliferator-activated receptor-α agonist, Wy 14,643, improves metabolic indices, steatosis and ballooning in diabetic mice with non-alcoholic steatohepatitis

J Gastroenterol Hepatol. 2012 Feb;27(2):341-50. doi: 10.1111/j.1440-1746.2011.06939.x.


Background and aims: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Animals
  • Blotting, Western
  • Chemokine CCL2 / metabolism
  • Diabetes Mellitus / drug therapy*
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / pathology
  • Disease Models, Animal
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Enzyme Activation
  • Enzyme-Linked Immunosorbent Assay
  • Fatty Liver / drug therapy*
  • Fatty Liver / genetics
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Female
  • Gene Expression Regulation / drug effects
  • Inflammation Mediators / metabolism
  • Insulin Resistance
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lipid Metabolism / drug effects
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Metabolic Syndrome / drug therapy*
  • Metabolic Syndrome / genetics
  • Metabolic Syndrome / metabolism
  • Metabolic Syndrome / pathology
  • Mice
  • Mice, Inbred NOD
  • NF-kappa B / pharmacology
  • Non-alcoholic Fatty Liver Disease
  • Oxidative Stress / drug effects
  • PPAR alpha / agonists*
  • PPAR alpha / metabolism
  • Pyrimidines / pharmacology*
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Time Factors


  • Ccl2 protein, rat
  • Chemokine CCL2
  • Inflammation Mediators
  • NF-kappa B
  • PPAR alpha
  • Pyrimidines
  • pirinixic acid
  • JNK Mitogen-Activated Protein Kinases