5-Bis-(2,6-difluoro-benzylidene) Cyclopentanone Acts as a Selective 11β-Hydroxysteroid Dehydrogenase one Inhibitor to Treat Diet-Induced Nonalcoholic Fatty Liver Disease in Mice

Hongguo Guan,Huitao Li,Xiaoheng Li,Qiqi Zhu,Yiyan Wang,Guang Liang,Ren-Shan Ge

doi:10.3389/fphar.2021.594437

Abstract

Background: 11β-Hydroxysteroid dehydrogenase one is responsible for activating inert glucocorticoid cortisone into biologically active cortisol in humans and may be a novel target for the treatment of nonalcoholic fatty liver disease. Methods: A series of benzylidene cyclopentanone derivatives were synthesized, and the selective inhibitory effects on rat, mouse and human 11β-hydroxysteroid dehydrogenase one and two were screened. The most potent compound [5-bis-(2,6-difluoro-benzylidene)-cyclopentanone] (WZS08), was used to treat nonalcoholic fatty liver disease in mice fed a high-fat-diet for 100 days. Results: WZS08 was the most potent inhibitor of rat, mouse, and human 11β-hydroxysteroid dehydrogenase 1, with half maximum inhibitory concentrations of 378.0, 244.1, and 621.1 nM, respectively, and it did not affect 11β-hydroxysteroid dehydrogenase two at 100 μM. When mice were fed WZS08 (1, 2, and 4 mg/kg) for 100 days, WZS08 significantly lowered the serum insulin levels and insulin index at 4 mg/kg. WZS08 significantly reduced the levels of serum triglycerides, cholesterol, low-density lipoprotein, and hepatic fat ratio at low concentration of 1 mg/kg. It down-regulated Plin2 expression and up-regulated Fabp4 expression at low concentration of 1 mg/kg. It significantly improved the morphology of the non-alcoholic fatty liver. Conclusion: WZS08 selectively inhibits rat, mouse, and human 11β-hydroxysteroid dehydrogenase 1, and can treat non-alcoholic fatty liver disease in a mouse model.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is a common disease in humans and a liver manifestation of metabolic syndrome (Nakajima and Naito, 2015)
Recent studies have shown that PLIN2 and PLIN3 are involved in the formation of lipid droplets and in the pathophysiological process of NAFLD, which is characterized by excessive accumulation of lipids in hepatocytes (Carr and Ahima, 2016; Graffmann et al, 2016; Sahini and Borlak, 2016)
We have proved that 5-bis-(2,6-difluorobenzylidene)-cyclopentanone (WZS08) is one of the most potent analogues that inhibit 11β-HSD1 without affecting 11βHSD2, and can effectively treat high-fat diet (HFD)-induced NAFLD in mice

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a common disease in humans and a liver manifestation of metabolic syndrome (Nakajima and Naito, 2015). Excessive consumption of HFD can lead to the accumulation of lipids in the liver, and is considered to be one of the main risks leading to NAFLD and a series of complications (Tsuchida et al, 2012; Softic et al, 2016), because of impaired liver lipid and glucose metabolism. Some lipid-binding proteins may be associated with the progression of NAFLD. One family of these proteins is perilipins (PLINs). Recent studies have shown that PLIN2 (encoded by Plin2) and PLIN3 (encoded by Plin3) are involved in the formation of lipid droplets and in the pathophysiological process of NAFLD, which is characterized by excessive accumulation of lipids in hepatocytes (Carr and Ahima, 2016; Graffmann et al, 2016; Sahini and Borlak, 2016)

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