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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.JG

Abstract

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.

Authors+Show Affiliations

Liver Research Group, ANU Medical School at The Canberra Hospital, Garran, Australian Capital Territory, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21929649

Citation

Larter, Claire Z., et al. "Peroxisome Proliferator-activated Receptor-α Agonist, Wy 14,643, Improves Metabolic Indices, Steatosis and Ballooning in Diabetic Mice With Non-alcoholic Steatohepatitis." Journal of Gastroenterology and Hepatology, vol. 27, no. 2, 2012, pp. 341-50.
Larter CZ, Yeh MM, Van Rooyen DM, et al. 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;27(2):341-50.
Larter, C. Z., Yeh, M. M., Van Rooyen, D. M., Brooling, J., Ghatora, K., & Farrell, G. C. (2012). Peroxisome proliferator-activated receptor-α agonist, Wy 14,643, improves metabolic indices, steatosis and ballooning in diabetic mice with non-alcoholic steatohepatitis. Journal of Gastroenterology and Hepatology, 27(2), 341-50. https://doi.org/10.1111/j.1440-1746.2011.06939.x
Larter CZ, et al. 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;27(2):341-50. PubMed PMID: 21929649.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Peroxisome proliferator-activated receptor-α agonist, Wy 14,643, improves metabolic indices, steatosis and ballooning in diabetic mice with non-alcoholic steatohepatitis. AU - Larter,Claire Z, AU - Yeh,Matthew M, AU - Van Rooyen,Derrick M, AU - Brooling,John, AU - Ghatora,Kamaljit, AU - Farrell,Geoffrey C, PY - 2011/9/21/entrez PY - 2011/9/21/pubmed PY - 2012/5/16/medline SP - 341 EP - 50 JF - Journal of gastroenterology and hepatology JO - J. Gastroenterol. Hepatol. VL - 27 IS - 2 N2 - 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. SN - 1440-1746 UR - https://www.unboundmedicine.com/medline/citation/21929649/Peroxisome_proliferator_activated_receptor_α_agonist_Wy_14643_improves_metabolic_indices_steatosis_and_ballooning_in_diabetic_mice_with_non_alcoholic_steatohepatitis_ L2 - https://doi.org/10.1111/j.1440-1746.2011.06939.x DB - PRIME DP - Unbound Medicine ER -