Selective Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 Attenuates High-Fat Diet-Induced Hepatic Steatosis in Mice

Abstract

Introduction

The effect of 11β-hydroxysteroid dehydrogenase type1 (11β-HSD1) inhibition on hepatic steatosis is incompletely understood. Here, we aimed to determine the therapeutic effect of BVT.2733, a selective 11β-HSD1 inhibitor, on hepatic steatosis.

Materials and Methods

C57B/6J mice were randomly divided into a low-fat diet (LFD) fed group and a high-fat diet (HFD) fed group. Mice were fed with HFD for 28 weeks which induced obesity and severe hepatic steatosis. The two groups were further divided into four groups as follows: LFD, LFD with BVT.2733, HFD, and HFD with BVT.2733. Mice in LFD+BVT and HFD+BVT groups were intraperitoneally injected with BVT.2733 daily for 30 days. Effects of BVT.2733 on mice body weight, serum lipid profile, serum free fatty acids (FFAs), glucocorticoid levels, gene expression in adipose and liver tissues were assessed.

Results

Injection of a low dose of BVT.2733 (50 mg/kg/day) reduced body weight and hyperlipidemia, but did not improve glucose tolerance and insulin resistance in diet-induced obese mice. The low dose of BVT.2733 attenuated hepatic steatosis, liver injury, and liver lipolytic gene expression in diet-induced obese mice. Besides, the low dose of BVT.2733 reduced fat mass and lipolysis in visceral adipose tissues, hepatic FFAs, and serum corticosterone levels in diet-induced obese mice.

Conclusion

Our study shows that moderate inhibition of 11β-HSD1 by BVT.2733 reduces FFAs and corticosterone synthesis in fatty tissues, thereby attenuates the delivery of corticosterone and FFAs to the liver. Collectively, this prevents high-fat diet-induced hepatic steatosis.

Keywords:

• 11β-HSD1
• hepatic steatosis
• inhibitor
• adipose tissue
• free fatty acids

Acknowledgment

Outstanding Youth Foundation of Jiangsu Province (BK20190043), The National Natural Science Foundation of China (31971062, 31900326, and 81200620), The Natural Science Foundation of Jiangsu Province (BK20180838), The Natural Science Foundation of the Jiangsu Higher Education Institutions of China (20KJA180003, 19KJB320003), The Livelihood and Technology Program of Suzhou City (SYS2020100, SYS2019030), The Open Fund of State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University (KF-GN-202004), and The Research Innovation Program for College Graduates of Jiangsu Province (KYCX19-1981). This work is also supported by the International Joint Research Center for Genomic Resources (2017B01012) and the Tang Scholar of Soochow University.

Abbreviations

11β-HSD1, 11β-hydroxysteroid dehydrogenase type1; Acc1, Acetyl-coa carboxylase 1; Acc2, Acetyl-coa carboxylase 2; ALP, Alkaline phosphatase; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; ATGL, Adipose triglyceride lipase; Atgl, Adipose triglyceride lipase; Dgat1, Acyl-coa: diacylglycerol acyltransferase 1; DNL, De novo lipogenesis; Elovl6, Elongation of very-long-chain fatty acids protein 6; ER, Endoplasmic reticulum; Fas, Fatty acid synthase; FFAs, Free fatty acids; GR, Glucocorticoid receptor; GTT, Glucose tolerance test; HDL, Lipoprotein; HFD, High-fat diet; HSL, Hormone-sensitive lipase; ITT, Insulin tolerance test; LDL, Low-density cholesterol; LFD, Low-fat diet; Lipe, Lipase E, hormone-sensitive type; Lxrα, Liver X receptor α; Lxrβ, Liver X receptor β; NAFLD, Nonalcoholic fatty liver disease; PBS, Phosphate-buffered saline; PFA, Paraformaldehyde; qRT-PCR, Quantitative Real-time PCR; Srebp1c, Sterol response element-binding protein-1c; TC, Total cholesterol; TG, Triglyceride.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

There are no conflicts of interest.