β3 肾上腺素能受体激动剂 BRL37344 对高脂肪饮食诱导的非酒精性脂肪性肝病（NAFLD）大鼠模型肝脂肪变性和炎症的保护作用。
The protective effects of the β3 adrenergic receptor agonist BRL37344 against liver steatosis and inflammation in a rat model of high-fat diet-induced nonalcoholic fatty liver disease (NAFLD).
机构信息
Gastroenterology Department, the First Affiliated Hospital of Harbin Medical University, #23 Postal Street, Harbin, 150001, Heilongjiang, China.
Gastroenterology Department, the Fourth Affiliated Hospital of Harbin Medical University, #37 Yiyuan Street, Harbin, 150001, Heilongjiang, China.
出版信息
Mol Med. 2020 Jun 5;26(1):54. doi: 10.1186/s10020-020-00164-4.
BACKGROUND
Our objective was to investigate the efficacy of the beta-3 adrenergic receptor (β3-AR) agonist BRL37344 for the prevention of liver steatosis and inflammation associated with nonalcoholic fatty liver disease (NAFLD).
METHODS
Four groups were established: a control group (given a standard diet), a high-fat diet (HFD) group, an HFD + β3-AR agonist (β3-AGO) group, and an HFD + β3-AR antagonist (β3-ANT) group. All rats were fed for 12 weeks. The β3-AR agonist BRL37344 and the antagonist L748337 were administered for the last 4 weeks with Alzet micro-osmotic pumps. The rat body weights (g) were measured at the end of the 4th, 8th, and 12th weeks. At the end of the 12th week, the liver weights were measured. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed with a Hitachi automatic analyzer. The lipid levels of the triglycerides (TGs), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) and the concentrations of free fatty acids (FFAs) were also measured. An oil red O kit was used to detect lipid droplet accumulation in hepatocytes. Steatosis, ballooning degeneration and inflammation were histopathologically determined. The protein and mRNA expression levels of β3-AR, peroxisome proliferator-activated receptor-alpha (PPAR-α), peroxisome proliferator-activated receptor-gamma (PPAR-γ), mitochondrial carnitine palmitoyltransferase-1 (mCPT-1), and fatty acid translocase (FAT)/CD36 were measured by western blot analysis and RT-qPCR, respectively.
RESULTS
After treatment with the β3-AR agonist BRL37344 for 4 weeks, the levels of ALT, AST, TGs, TC, LDL-C and FFAs were decreased in the NAFLD model group compared with the HFD group. Body and liver weights, liver index values and lipid droplet accumulation were lower in the HFD + β3-AGO group than in the HFD group. Decreased NAFLD activity scores (NASs) also showed that liver steatosis and inflammation were ameliorated after treatment with BRL37344. Moreover, the β3-AR antagonist L748337 reversed these effects. Additionally, the protein and gene expression levels of β3-AR, PPAR-α, and mCPT-1 were increased in the HFD + β3-AGO group, whereas those of PPAR-γ and FAT/CD36 were decreased.
CONCLUSION
The β3-AR agonist BRL37344 is beneficial for reducing liver fat accumulation and for ameliorating liver steatosis and inflammation in NAFLD. These effects may be associated with PPARs/mCPT-1 and FAT/CD36.
背景
我们的目的是研究β3 肾上腺素能受体（β3-AR）激动剂 BRL37344 预防非酒精性脂肪性肝病（NAFLD）相关肝脂肪变性和炎症的疗效。
方法
建立 4 组：对照组（给予标准饮食）、高脂肪饮食（HFD）组、HFD+β3-AR 激动剂（β3-AGO）组和 HFD+β3-AR 拮抗剂（β3-ANT）组。所有大鼠均喂养 12 周。最后 4 周用 Alzet 微渗透泵给予β3-AR 激动剂 BRL37344 和拮抗剂 L748337。在第 4、8 和 12 周末测量大鼠体重（g）。第 12 周末测量肝重。用日立自动分析仪分析血清丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）。还测量了甘油三酯（TGs）、总胆固醇（TC）和低密度脂蛋白胆固醇（LDL-C）的血脂水平以及游离脂肪酸（FFAs）的浓度。用油红 O 试剂盒检测肝细胞中脂质滴的积累。组织病理学确定脂肪变性、气球样变性和炎症。通过 Western blot 分析和 RT-qPCR 分别测量β3-AR、过氧化物酶体增殖物激活受体-α（PPAR-α）、过氧化物酶体增殖物激活受体-γ（PPAR-γ）、线粒体肉碱棕榈酰基转移酶-1（mCPT-1）和脂肪酸转位酶（FAT）/CD36 的蛋白和 mRNA 表达水平。
结果
用β3-AR 激动剂 BRL37344 治疗 4 周后，与 HFD 组相比，NAFLD 模型组的 ALT、AST、TGs、TC、LDL-C 和 FFAs 水平降低。HFD+β3-AGO 组的体重和肝重、肝指数值和脂质滴积累低于 HFD 组。降低的非酒精性脂肪性肝病活动评分（NASs）也表明 BRL37344 治疗后肝脂肪变性和炎症得到改善。此外，β3-AR 拮抗剂 L748337 逆转了这些作用。此外，HFD+β3-AGO 组β3-AR、PPAR-α 和 mCPT-1 的蛋白和基因表达水平增加，而 PPAR-γ 和 FAT/CD36 的表达水平降低。
结论
β3-AR 激动剂 BRL37344 有利于减少肝脏脂肪堆积，改善 NAFLD 中的肝脂肪变性和炎症。这些作用可能与 PPARs/mCPT-1 和 FAT/CD36 有关。
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