1. Blockade of 11β-hydroxysteroid dehydrogenase type 1 ameliorates metabolic dysfunction-associated steatotic liver disease and fibrosis
- Author
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Hwan Ma, Guo-Yan Sui, Jeong-Su Park, Feng Wang, Yuanqiang Ma, Dong-Su Shin, Nodir Rustamov, Jun Sung Jang, Soo Im Chang, Jin Lee, and Yoon Seok Roh
- Subjects
11β-HSD1 ,Cortisol ,Cortisone ,Lipid accumulation ,Liver fibrosis ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a key enzyme involved in the conversion of cortisone to active cortisol in the liver. Elevated cortisol levels can trigger oxidative stress, inflammation, and hepatocyte damage, highlighting the importance of 11β-HSD1 inhibition as a potential therapeutic approach. This study aimed to explore the effects of INU-101, an inhibitor of 11β-HSD1, on the development of metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis. Our findings demonstrated that INU-101 effectively mitigated cortisol-induced lipid accumulation, reactive oxygen species generation, and hepatocyte apoptosis. Furthermore, 11β-HSD1 inhibition suppressed hepatic stellate cell activation by modulating β-catenin and phosphorylated SMAD2/3. INU-101 administration significantly reduced hepatic lipid accumulation and liver fibrosis in mice fed fast-food diet. This study suggests that INU-101 holds promise as a clinical candidate for treating MASLD and fibrosis, offering potential therapeutic benefits by targeting the intricate processes involving 11β-HSD1 and cortisol regulation in the liver.
- Published
- 2024
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