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.

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.