Role of 11β-hydroxysteroid dehydrogenase type 1 inhibition in the antiobesity effect of J2H-1702 on adipocytes and a high-fat diet-induced NASH model

Dahae Lee; Kiwon Jung; Jaemin Lee; Hyo Jin Kang; Ju Young Lee; Jason Kim; Dayeon Ham; Jaejin Cho; Dae-Woon Eom; Ki Sung Kang

doi:10.1016/j.ejphar.2025.177272

Role of 11β-hydroxysteroid dehydrogenase type 1 inhibition in the antiobesity effect of J2H-1702 on adipocytes and a high-fat diet-induced NASH model

Eur J Pharmacol. 2025 Jan 12:177272. doi: 10.1016/j.ejphar.2025.177272. Online ahead of print.

Authors

Dahae Lee¹, Kiwon Jung², Jaemin Lee¹, Hyo Jin Kang³, Ju Young Lee³, Jason Kim³, Dayeon Ham⁴, Jaejin Cho⁵, Dae-Woon Eom⁶, Ki Sung Kang⁷

Affiliations

¹ College of Korean Medicine, Gachon University, Seongnam 13120, Korea.
² College of Pharmacy, Seoul National University, Seoul 08826, Korea.
³ J2H Biotech, B-210ho,142-10, Saneop-ro 156, Gwonseon-gu, Suwon-si, Gyeonggi-do, Korea.
⁴ College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI, United States.
⁵ Department of Dental Regenerative Biotechnology, School of Dentistry, Seoul National University, Seoul, Korea; Dental Research Institute, Seoul National University, Seoul, Korea.
⁶ Department of Pathology, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung 210-711, Korea. Electronic address: edwjyh@gnah.co.kr.
⁷ College of Korean Medicine, Gachon University, Seongnam 13120, Korea. Electronic address: kkang@gachon.ac.kr.

PMID: 39809350
DOI: 10.1016/j.ejphar.2025.177272

Abstract

Obesity due to excessive body fat accumulation remains a global problem. Patients with obesity have high cortisol levels, and its dysregulation is caused by increased 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) levels. The effects and mechanism of J2H-1702, an 11β-HSD1 inhibitor, on nonalcoholic steatohepatitis (NASH) were explored. This study compared the antiadipogenic effects of J2H-1702, elafibranor (PPARα/δ agonist), and BVT14225 (selective 11β-HSD1 inhibitor) using mouse 3T3-L1 pre-adipocytes. J2H-1702, elafibranor, and BVT14225 inhibited adipocyte differentiation and intracellular lipid accumulation in 3T3-L1 cells by downregulating phospho-extracellular signal-regulated kinase, extracellular signal-regulated kinase, phospho-c-Jun-N-terminal Kinase, c-Jun-N-terminal Kinase, phospho-P38 (P-P38), P38, CCAAT/enhancer-binding proteins alpha and β, peroxisome proliferator-activated receptor γ, and glucocorticoid receptor. Additionally, J2H-1702, elafibranor, and BVT14225 treatments effectively inhibited 11β-HSD1 activity, as revealed by cortisol concentrations, and inhibited cortisone-induced adipocyte differentiation and intracellular lipid accumulation in 3T3-L1 cells. These effects were associated with 11β-HSD1 protein inhibition. Furthermore, J2H-1702 and BVT14225 increased the expression of Akt and phosphoinositide 3-kinase involved in insulin resistance in 3T3L-1 adipocytes. In the LX-2 human hepatic stellate cell line, the relative expression of N-cadherin, 11β-HSD1, collagen1α (COLA1), α-actin of smooth muscle (α-SMA) genes in LX-2 activated with TGF-β increased significantly, and after treatment with J2H-1702, it was significantly reduced. The expression of E-cadherin is decreased in TGF-β-treated LX-2 cells and increased after treatment with J2H-1702. We tested the potential of J2H-1702 as a therapeutic agent for NASH using a high-fat diet-induced NASH model, with obeticholic acid, an FXR agonist, and elafibranor as reference drugs. All drugs significantly decreased the elevated triglyceride levels in the livers of high-fat, high-carbohydrate (HFHC-fed mice. The results may add to the benefits of targeting 11β-HSD1 inhibitors with antiadipogenic activity in developing a therapeutic agent for obesity treatment.

Keywords: 11β-HSD1; Obesity; PPARγ.