RGD Reference Report - The PPAR-alpha agonist, Wy 14,643, improves metabolic indices, steatosis and ballooning in diabetic mice with NASH. - Rat Genome Database

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The PPAR-alpha agonist, Wy 14,643, improves metabolic indices, steatosis and ballooning in diabetic mice with NASH.

Authors: Larter, CZ  Yeh, MM  Van Rooyen, DM  Brooling, J  Ghatora, K  Farrell, GC 
Citation: Larter CZ, etal., J Gastroenterol Hepatol. 2011 Sep 19. doi: 10.1111/j.1440-1746.2011.06939.x.
RGD ID: 5509939
Pubmed: PMID:21929649   (View Abstract at PubMed)
DOI: DOI:10.1111/j.1440-1746.2011.06939.x   (Journal Full-text)

Background and Aims: Lipid accumulation precedes hepatocellular injury and liver inflammation in non-alcoholic steatohepatitis (NASH). The peroxisome proliferator-activated receptor (PPAR)alpha regulates hepatic lipid disposal. We studied whether pharmacological stimulation of PPARalpha 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 16wks to initiate NASH then treated with Wy 14,643 (Wy) for 10d or 20d. Liver disease was assessed by histology, serum ALT, genes (real-time PCR) and proteins (western blot, ELISA) of interest and pro-inflammatory signalling pathways determined. Results: In diabetic foz/foz mice, NASH was associated with elevated serum MCP1 and hepatic activation of NF-kappaB and JNK, but not oxidative or ER stress. Wy treatment decreased steatosis and injury, although induction of PPARalpha-responsive fatty acid oxidation genes was proportionally less than in WT. The PPARalpha agonist lowered serum insulin, corrected hyperglycemia, and suppressed the carbohydrate-dependent lipogenic transcription factor, ChREBP. Steatosis resolution was associated with suppression of NF-kappaB and JNK activation and decreased hepatic macrophages and neutrophils. Despite this, histology inflammation score remained high, associated with serum MCP1 elevation, a pro-inflammatory chemokine related to higher adipose, not liver MCP1 mRNA expression. Conclusions: Pharmacological activation of PPARalpha improves metabolic milieu, steatosis, ballooning, and combats NF-kappaB 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 PPARalpha agonists efficacy as therapy for NASH.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
PPARAHumansteatotic liver disease  ISOPpara (Mus musculus)associated with Diabetes Mellitus (CTD:0000249) and in high fat-fed foz/foz obese/diabetic miceRGD 
PparaRatsteatotic liver disease  ISOPpara (Mus musculus)associated with Diabetes Mellitus (CTD:0000249) and in high fat-fed foz/foz obese/diabetic miceRGD 
PparaMousesteatotic liver disease  IDA associated with Diabetes Mellitus (CTD:0000249) and in high fat-fed foz/foz obese/diabetic miceRGD 

Objects Annotated

Genes (Rattus norvegicus)
Ppara  (peroxisome proliferator activated receptor alpha)

Genes (Mus musculus)
Ppara  (peroxisome proliferator activated receptor alpha)

Genes (Homo sapiens)
PPARA  (peroxisome proliferator activated receptor alpha)