title: PPARα/γ agonists and antagonists differently affect hepatic lipid metabolism, oxidative stress and inflammatory cytokine production in steatohepatitic rats.
abstract: Peroxisome proliferator-activated receptor (PPAR) α/γ may control lipid metabolism and inflammatory response by regulating the downstream target genes, and play a crucial role in the process of non-alcoholic steatohepatitis (NASH) formation, but the difference and interaction between PPARα and PPARγ are poorly understood. The rat model with NASH was established by orally feeding high-fat and high-sucrose emulsion for 6weeks. The results shown that after the model rats were simultaneously treated with PPARα/γ agonists, the total cholesterol (TC), triglyceride (TG) and inflammatory cytokine levels in serum and hepatic tissue, the hepatic steatosis and inflammatory cellular infiltration were decreased, and were consistent with the results of hepatic lipogenic gene and nuclear factor (NF)-κB protein expressions. Conversely, these indexes were increased by PPARα/γ antagonist treatment. Compared with the model group, the serum free fatty acid (FFA) level was increased in the PPARα agonist-treated group, decreased in the PPARγ agonist-treated group, and unchanged in the PPARα/γ agonists-treated group. The hepatic FFA level was low in the PPARα/γ agonists-treated groups, but no significant variation in the PPARα/γ antagonists-treated groups. The increments of hepatic reduced glutathione (GSH) and superoxide dismutase (SOD) contents in the PPARα/γ agonists-treated groups were accompanied by decreased hepatic malondialdehyde (MDA) content. These findings demonstrated that PPARα/γ activation might decrease the hepatic lipid accumulation, oxidative stress and inflammatory cytokine production, and PPARγ could counterbalance the adverse effect of PPARα on circulating FFA. It was concluded that the integrative application of PPARα and PPARγ agonists might exert a synergic inhibitory effect on NASH formation through the modulation of PPARα/γ-mediated lipogenic and inflammatory gene expressions.
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu Province, PR China; Department of Gynecology and Obstetrics, Wuxi Maternal and Child Health Hospital, The Affiliated Hospital of Nanjing Medical University, Wuxi 214002, Jiangsu Province, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu Province, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu Province, PR China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu Province, PR China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Shang
authors.affiliation: Department of Pharmacy, Wuxi People's Hospital, Wuxi 214023, Jiangsu Province, PR China.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Qi
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu Province, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xue
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu Province, PR China; Department of Pharmaceutical Laboratory, Medical College of Nantong University, Nantong 226001, Jiangsu Province, PR China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Medical College of Soochow University, Suzhou 215123, Jiangsu Province, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Deng
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu Province, PR China. Electronic address: xiemeilin@suda.edu.cn.
authors.forename: Mei-Lin
authors.initials: ML
authors.lastname: Xie
mesh_terms: D000813:Anilides / Q000737:chemistry; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D011345:Fenofibrate / Q000737:chemistry; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D007211:Indoles / Q000737:chemistry; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000378:metabolism*; D018384:Oxidative Stress; D047493:PPAR alpha / Q000819:agonists* / Q000037:antagonists & inhibitors*; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D013482:Superoxide Dismutase / Q000378:metabolism; D045162:Thiazolidinediones / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D002722:Chlorobenzenes
chemical_list: D000813:Anilides; D018932:Chemokine CCL2; D016207:Cytokines; D005230:Fatty Acids, Nonesterified; D011345:Fenofibrate; D005978:Glutathione; D007211:Indoles; D015850:Interleukin-6; D016209:Interleukin-8; D008315:Malondialdehyde; D016328:NF-kappa B; D047493:PPAR alpha; D047495:PPAR gamma; D000077154:Rosiglitazone; D013482:Superoxide Dismutase; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; C457499:2-chloro-5-nitrobenzanilide; C491766:Ccl2 protein, rat; C060893:MK-886; D002722:Chlorobenzenes
keywords: Inflammatory cytokines; Lipid metabolism; Non-alcoholic steatohepatitis; Oxidative stress; Peroxisome proliferator-activated receptor alpha/gamma