BAR502, a dual FXR and GPBAR1 agonist, promotes browning of white adipose tissue and reverses liver steatosis and fibrosis.
BAR502, a dual FXR and GPBAR1 agonist, promotes browning of white adipose tissue and reverses liver steatosis and fibrosis.
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DOI：
10.1038/srep42801
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发表时间：
2017-02-16
影响因子：
4.6
通讯作者：
Fiorucci S
中科院分区：
文献类型：
--
作者：
Carino A;Cipriani S;Marchianò S;Biagioli M;Santorelli C;Donini A;Zampella A;Monti MC;Fiorucci S
非酒精性脂肪性肝炎（NASH）是一种高度流行的慢性肝脏疾病。在此，我们研究了BAR502（一种针对法尼醇X受体（FXR）和G蛋白偶联胆汁酸受体1（GPBAR1）的非胆汁酸类固醇双重配体）是否能逆转高脂肪饮食（HFD）和果糖喂养小鼠的脂肪性肝炎。9周后，高脂肪饮食喂养的小鼠体重增加了约30%（与正常组相比，P < 0.01），并且出现胰岛素抵抗。这些超重且有胰岛素抵抗的小鼠被随机分为继续高脂肪饮食组或高脂肪饮食联合BAR502组。18周后，高脂肪饮食组小鼠出现类似NASH的特征，包括严重的脂肪性肝炎和纤维化，肝脏中三酰甘油和胆固醇含量增加，以及固醇调节元件结合蛋白1c（SREPB1c）、脂肪酸合成酶（FAS）、载脂蛋白C2（ApoC2）、过氧化物酶体增殖物激活受体α和γ（PPARα和γ）、α -平滑肌肌动蛋白（α -SMA）、α1胶原蛋白和单核细胞趋化蛋白1（MCP1）mRNA的表达增加。BAR502治疗使体重降低了约10%，提高了胰岛素敏感性和高密度脂蛋白（HDL）的循环水平，同时降低了脂肪变性、炎症和纤维化评分，以及肝脏中SREPB1c、FAS、PPARγ、CD36和细胞色素P450 7A1（CYP7A1）mRNA的表达。BAR502增加了肝脏中小异二聚体伴侣蛋白（SHP）和三磷酸腺苷结合盒转运体G5（ABCG5）以及肠道中SHP、成纤维细胞生长因子15（FGF15）和胰高血糖素样肽 - 1（GLP1）的表达。BAR502促进了附睾白色脂肪组织（epWAT）的褐变，并减轻了四氯化碳（CCl4）诱导的肝纤维化。总之，BAR502作为一种FXR和GPBAR1双重激动剂，通过促进脂肪组织的褐变来预防高脂肪饮食引起的肝脏损伤。
Non-alcoholic steatohepatitis (NASH) is a highly prevalent chronic liver disease. Here, we have investigated whether BAR502, a non-bile acid, steroidal dual ligand for FXR and GPBAR1, reverses steato-hepatitis in mice fed a high fat diet (HFD) and fructose. After 9 week, mice on HFD gained ≈30% of b.w (P < 0.01 versus naïve) and were insulin resistant. These overweighting and insulin resistant mice were randomized to receive HFD or HFD in combination with BAR502. After 18 weeks, HFD mice developed NASH like features with severe steato-hepatitis and fibrosis, increased hepatic content of triacylglycerol and cholesterol and expression of SREPB1c, FAS, ApoC2, PPARα and γ, α-SMA, α1 collagen and MCP1 mRNAs. Treatment with BAR502 caused a ≈10% reduction of b.w., increased insulin sensitivity and circulating levels of HDL, while reduced steatosis, inflammatory and fibrosis scores and liver expression of SREPB1c, FAS, PPARγ, CD36 and CYP7A1 mRNA. BAR502 increased the expression of SHP and ABCG5 in the liver and SHP, FGF15 and GLP1 in intestine. BAR502 promoted the browning of epWAT and reduced liver fibrosis induced by CCl4. In summary, BAR502, a dual FXR and GPBAR1 agonist, protects against liver damage caused by HFD by promoting the browning of adipose tissue.