Selective Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 Attenuates High-Fat Diet-Induced Hepatic Steatosis in Mice.
Selective Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 Attenuates High-Fat Diet-Induced Hepatic Steatosis in Mice.
复制标题
选择性抑制 11β-羟基类固醇脱氢酶 1 型可减轻高脂饮食引起的小鼠肝脂肪变性
DOI：
10.2147/dddt.s285828
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Zha J
中科院分区：
文献类型：
--
作者：
Li H;Sheng J;Wang J;Gao H;Yu J;Ding G;Ding N;He W;Zha J
抑制11β-羟基类固醇脱氢酶1（11β-HSD 1）对肝脂肪变性的影响尚不完全清楚。在这里，我们的目的是确定BVT. 2733，一种选择性11β-HSD 1抑制剂，对肝脂肪变性的治疗作用。将C57 B/6 J小鼠随机分为低脂饮食（LFD）喂养组和高脂饮食（HFD）喂养组。用HFD喂养小鼠28周，诱导肥胖和严重的肝脂肪变性。将两组进一步分为以下四组：LFD、LFD + BVT. 2733、HFD和HFD + BVT. 2733。LFD+BVT和HFD+BVT组中的小鼠每天腹膜内注射BVT. 2733，持续30天。评估BVT. 2733对小鼠体重、血清脂质谱、血清游离脂肪酸（FFA）、糖皮质激素水平、脂肪和肝组织中的基因表达的影响。注射低剂量BVT. 2733（50 mg/kg/天）可减轻体重和高脂血症，但不能改善饮食诱导的肥胖小鼠的葡萄糖耐量和胰岛素抵抗。低剂量的BVT. 2733减轻了饮食诱导的肥胖小鼠的肝脂肪变性、肝损伤和肝脂肪分解基因表达。此外，低剂量的BVT. 2733降低了饮食诱导的肥胖小鼠的内脏脂肪组织、肝脏FFA和血清皮质酮水平中的脂肪量和脂解。我们的研究表明，BVT. 2733对11β-HSD 1的中度抑制减少了脂肪组织中的FFA和皮质酮合成，从而减弱了皮质酮和FFA向肝脏的递送。总的来说，这可以预防高脂饮食诱导的肝脂肪变性。
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. 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. 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. 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.