title: PPARα/γ antagonists reverse the ameliorative effects of osthole on hepatic lipid metabolism and inflammatory response in steatohepatitic rats.
abstract: Our previous studies have indicated that osthole may ameliorate the hepatic lipid metabolism and inflammatory response in nonalcoholic steatohepatitic rats, but the underlying mechanisms remain unclear. This study aimed to determine whether the effects of osthole were mediated by the activation of hepatic peroxisome proliferator-activated receptor α/γ (PPARα/γ). A rat model with steatohepatitis was induced by orally feeding high-fat and high-sucrose emulsion for 6 weeks. These experimental rats were then treated with osthole (20 mg/kg), PPARα antagonist MK886 (1 mg/kg) plus osthole (20 mg/kg), PPARγ antagonist GW9662 (1 mg/kg) plus osthole (20 mg/kg) and MK886 (1 mg/kg) plus GW9662 (1 mg/kg) plus osthole (20 mg/kg) for 4 weeks. The results showed that after osthole treatment, the hepatic triglycerides, free fatty acids, tumor necrosis factor-α, monocyte chemotactic protein-1, interleukin-6 (IL-6), IL-8 and liver index decreased by 52.3, 31.0, 32.4, 28.9, 36.3, 29.3 and 29.9%, respectively, and the score of steatohepatitis also decreased by 70.0%, indicating that osthole improved the hepatic steatosis and inflammation. However, these effects of osthole were reduced or abrogated after simultaneous addition of the specific PPARα antagonist MK886 or/and the PPARγ antagonist GW9662, especially in the co-PPARα/γ antagonists-treated group. Importantly, the osthole-induced hepatic expressions of PPARα/γ proteins were decreased, and the osthole-regulated hepatic expressions of lipogenic and inflammatory gene proteins were also reversed by PPARα/γ antagonist treatment. These findings demonstrated that the ameliorative effect of osthole on nonalcoholic steatohepatitis was mediated by PPARα/γ activation, and osthole might be a natural dual PPARα/γ activator.
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, China.|Department of Pharmaceutical Laboratory, School of Pharmacy, Nantong University, Nantong, 226001, Jiangsu Province, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhao
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, China.
authors.forename: Feng
authors.initials: F
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, China.
authors.forename: Ruijun
authors.initials: R
authors.lastname: Zhou
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, China.|Department of Pharmacy, The Affiliated Children's Hospital of Soochow University, Suzhou, 215003, Jiangsu Province, China.
authors.forename: Zengyan
authors.initials: Z
authors.lastname: Zhu
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, China. xiemeilin@suda.edu.cn.
authors.forename: Meilin
authors.initials: M
authors.lastname: Xie
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D003374:Coumarins / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005234:Fatty Liver; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects*; D008297:Male; D047493:PPAR alpha / Q000037:antagonists & inhibitors*; D047495:PPAR gamma / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000378:metabolism; D002722:Chlorobenzenes
chemical_list: D000813:Anilides; D003374:Coumarins; D005230:Fatty Acids, Nonesterified; D007211:Indoles; D047493:PPAR alpha; D047495:PPAR gamma; D014280:Triglycerides; C457499:2-chloro-5-nitrobenzanilide; C060893:MK-886; D002722:Chlorobenzenes; C046627:osthol
keywords: Inflammatory response; Lipid metabolism; Nonalcoholic steatohepatitis; Osthole; Peroxisome proliferator-activated receptor α/γ