PT  - JOURNAL ARTICLE
AU  - Eunji Oh
AU  - Jae Lee
AU  - Sungji Cho
AU  - Sung Wook Kim
AU  - Kyung Won
AU  - Won Sik Shin
AU  - Seung Hee Gwak
AU  - Joohun Ha
AU  - So Yeon Jeon
AU  - Jin-Hyang Park
AU  - Im-Sook Song
AU  - Themis Thoudam
AU  - In-Kyu Lee
AU  - Seonyong Kim
AU  - Se-Young Choi
AU  - Kyong-Tai Kim
TI  - Gossypetin Prevents the Progression of Nonalcoholic Steatohepatitis by Regulating Oxidative Stress and AMP-Activated Protein Kinase
AID  - 10.1124/molpharm.123.000675
DP  - 2023 Nov 01
TA  - Molecular Pharmacology
PG  - 214--229
VI  - 104
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/104/5/214.short
4100  - http://molpharm.aspetjournals.org/content/104/5/214.full
SO  - Mol Pharmacol2023 Nov 01; 104
AB  - Nonalcoholic steatohepatitis (NASH) is a severe liver metabolic disorder, however, there are still no effective and safe drugs for its treatment. Previous clinical trials used various therapeutic approaches to target individual pathologic mechanisms, but these approaches were unsuccessful because of the complex pathologic causes of NASH. Combinatory therapy in which two or more drugs are administered simultaneously to patients with NASH, however, carries the risk of side effects associated with each individual drug. To solve this problem, we identified gossypetin as an effective dual-targeting agent that activates AMP-activated protein kinase (AMPK) and decreases oxidative stress. Administration of gossypetin decreased hepatic steatosis, lobular inflammation and liver fibrosis in the liver tissue of mice with choline-deficient high-fat diet and methionine-choline deficient diet (MCD) diet-induced NASH. Gossypetin functioned directly as an antioxidant agent, decreasing hydrogen peroxide and palmitate-induced oxidative stress in the AML12 cells and liver tissue of MCD diet-fed mice without regulating the antioxidant response factors. In addition, gossypetin acted as a novel AMPK activator by binding to the allosteric drug and metabolite site, which stabilizes the activated structure of AMPK. Our findings demonstrate that gossypetin has the potential to serve as a novel therapeutic agent for nonalcoholic fatty liver disease /NASH.SIGNIFICANCE STATEMENT This study demonstrates that gossypetin has preventive effect to progression of nonalcoholic steatohepatitis (NASH) as a novel AMP-activated protein kinase (AMPK) activator and antioxidants. Our findings indicate that simultaneous activation of AMPK and oxidative stress using gossypetin has the potential to serve as a novel therapeutic approach for nonalcoholic fatty liver disease /NASH patients.