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Effects of combined PPAR-γ and PPAR-α agonist therapy on fructose induced NASH in rats: Modulation of gene expression.
Eur J Pharmacol. 2016 Feb 15; 773:59-70.EJ

Abstract

Peroxisome proliferator-activated receptors (PPARs) gamma and alpha have been shown to play key roles in maintaining glucose and lipid homeostasis by acting as insulin sensitizers and lipid-lowering agents respectively, which would make them potential candidates for the treatment of non-alcoholic steatohepatitis (NASH) characterized by insulin resistance, hyperglycemia, and hypertriglyceridemia. The effects of pioglitazone, a PPAR-γ agonist, and fenofibrate, a PPAR-α agonist, as monotherapy and in combination on the expressions of key genes linked to the development of NASH were studied in rats with fructose-induced NASH. Fructose-enriched diet was given to rats for 12 weeks. Fenofibrate (100mg/kg), pioglitazone (4 mg/kg) and combined treatment with both in half doses were given. Body weight, liver index, insulin resistance indices, triglycerides, oxidative stress markers, AST/ALT ratio and TNF-α were measured. Additionally, hepatic genes expressions of SOCS-3, sterol regulatory element binding protein-1c, fatty acid synthase, malonyl CoA decarboxylase, TGF-β1, and adipose tissue genes expressions of leptin and adiponectin were investigated. The combination of both drugs, in half doses, improved NASH-related disturbances similar to, or even better than, a full dose of fenofibrate alone possibly due to attenuating effects of pioglitazone on expression of genes responsible for insulin resistance, fatty acid synthesis and fibrosis in addition to correcting the balance between leptin and adiponectin. Histopathology confirmed the ability of this combination to decrease steatosis area and to normalize hepatic tissue structure. In Conclusion, dual activation of PPAR-γ and PPAR-α has remarkable effect in ameliorating NASH by modulation of some hepatic and adipose tissue genes expressions.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: enas.ahmed@pharma.cu.edu.eg.Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26825546

Citation

Abd El-Haleim, Enas A., et al. "Effects of Combined PPAR-γ and PPAR-α Agonist Therapy On Fructose Induced NASH in Rats: Modulation of Gene Expression." European Journal of Pharmacology, vol. 773, 2016, pp. 59-70.
Abd El-Haleim EA, Bahgat AK, Saleh S. Effects of combined PPAR-γ and PPAR-α agonist therapy on fructose induced NASH in rats: Modulation of gene expression. Eur J Pharmacol. 2016;773:59-70.
Abd El-Haleim, E. A., Bahgat, A. K., & Saleh, S. (2016). Effects of combined PPAR-γ and PPAR-α agonist therapy on fructose induced NASH in rats: Modulation of gene expression. European Journal of Pharmacology, 773, 59-70. https://doi.org/10.1016/j.ejphar.2016.01.011
Abd El-Haleim EA, Bahgat AK, Saleh S. Effects of Combined PPAR-γ and PPAR-α Agonist Therapy On Fructose Induced NASH in Rats: Modulation of Gene Expression. Eur J Pharmacol. 2016 Feb 15;773:59-70. PubMed PMID: 26825546.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of combined PPAR-γ and PPAR-α agonist therapy on fructose induced NASH in rats: Modulation of gene expression. AU - Abd El-Haleim,Enas A, AU - Bahgat,Ashraf K, AU - Saleh,Samira, Y1 - 2016/01/26/ PY - 2015/06/28/received PY - 2016/01/21/revised PY - 2016/01/25/accepted PY - 2016/1/31/entrez PY - 2016/1/31/pubmed PY - 2016/11/1/medline KW - Adiponectin KW - Leptin KW - NASH KW - PPAR KW - SOCS-3 KW - SREBP-1c SP - 59 EP - 70 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 773 N2 - Peroxisome proliferator-activated receptors (PPARs) gamma and alpha have been shown to play key roles in maintaining glucose and lipid homeostasis by acting as insulin sensitizers and lipid-lowering agents respectively, which would make them potential candidates for the treatment of non-alcoholic steatohepatitis (NASH) characterized by insulin resistance, hyperglycemia, and hypertriglyceridemia. The effects of pioglitazone, a PPAR-γ agonist, and fenofibrate, a PPAR-α agonist, as monotherapy and in combination on the expressions of key genes linked to the development of NASH were studied in rats with fructose-induced NASH. Fructose-enriched diet was given to rats for 12 weeks. Fenofibrate (100mg/kg), pioglitazone (4 mg/kg) and combined treatment with both in half doses were given. Body weight, liver index, insulin resistance indices, triglycerides, oxidative stress markers, AST/ALT ratio and TNF-α were measured. Additionally, hepatic genes expressions of SOCS-3, sterol regulatory element binding protein-1c, fatty acid synthase, malonyl CoA decarboxylase, TGF-β1, and adipose tissue genes expressions of leptin and adiponectin were investigated. The combination of both drugs, in half doses, improved NASH-related disturbances similar to, or even better than, a full dose of fenofibrate alone possibly due to attenuating effects of pioglitazone on expression of genes responsible for insulin resistance, fatty acid synthesis and fibrosis in addition to correcting the balance between leptin and adiponectin. Histopathology confirmed the ability of this combination to decrease steatosis area and to normalize hepatic tissue structure. In Conclusion, dual activation of PPAR-γ and PPAR-α has remarkable effect in ameliorating NASH by modulation of some hepatic and adipose tissue genes expressions. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/26825546/Effects_of_combined_PPAR_γ_and_PPAR_α_agonist_therapy_on_fructose_induced_NASH_in_rats:_Modulation_of_gene_expression_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(16)30011-5 DB - PRIME DP - Unbound Medicine ER -