首页|Herpetrione,a New Type of PPARα Ligand as a Therapeutic Strategy Against Nonalcoholic Steatohepatitis

Herpetrione,a New Type of PPARα Ligand as a Therapeutic Strategy Against Nonalcoholic Steatohepatitis

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Non-alcoholic fatty liver disease,especially nonalcoholic steatohepatitis(NASH),is a leading cause of cirrhosis and liver cancer worldwide;nevertheless,there are no Food and Drug Administration-approved drugs for treating NASH until now.Peroxisome proliferator-activated receptor alpha(PPARα)is an interesting therapeutic target for treating metabolic disorders in the clinic,including NASH.Herpetrione,a natural lignan compound isolated from Tibetan medicine Herpetospermum caudigerum,exerts various hepatoprotective effects,but its efficacy and molecular mechanism in treating NASH have not yet been elucidated.Here,we discovered that herpetrione lessened lipid accumulation and inflammation in hepatocytes stimulated with oleic acid and lipopolysaccharide,and effectively alleviated NASH caused by a high-fat diet or methionine-choline-deficient diet by regulating glucolipid metabolism,insulin resistance,and inflammation.Mechanistically,RNA-sequencing analyses further showed that herpetrione activated PPAR signaling,which was validated by protein expression.Furthermore,the analysis of molecular interactions illustrated that herpetrione bound directly to the PPARα protein,with binding sites extending to the Arm Ⅲ domain.PPARαdeficiency also abrogated the protective effects of herpetrione against NASH,suggesting that herpetrione protects against hepatic steatosis and inflammation by activation of PPARα signaling,thereby alleviating NASH.Our findings shed light on the efficacy of a natural product for treating NASH,as well as the broader prospects for NASH treatment by targeting PPARα.

Lang Linghu、Wei Zong、Yixuan Liao、Qianyu Chen、Fancheng Meng、Guowei Wang、Zhihua Liao、Xiaozhong Lan、Min Chen

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Key Laboratory of Luminescence Analysis and Molecular Sensing(Southwest University),Ministry of Education,College of Pharmaceutical Sciences,Southwest University,Chongqing 400715,China

School of Pharmacy,Zunyi Medical University,Zunyi 563000,China

School of Life Sciences,Integrative Science Center of Germplasm Creation in Western China(CHONGQING)Science City and Southwest University,TAAHC SWU Medicinal Plant Joint R&D Centre,Southwest University,Chongqing 400715,China

TAAHC-SWU Medicinal Plant R&D Center,Tibet Agricultural and Animal Husbandry University,Nyingchi,Tibet 860000,China

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2024

10.34133/research.0276

研究(英文)

研究(英文)

CSTPCD
ISSN：
年,卷(期)：2024.2024(3)