Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease
Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease
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DOI：
10.1136/gutjnl-2014-306968
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发表时间：
2015-06-01
期刊：
影响因子：
24.5
通讯作者：
Hellerbrand, Claus
中科院分区：
文献类型：
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作者：
Arndt, Stephanie;Wacker, Eva;Hellerbrand, Claus
目的 骨形态发生蛋白 6 (BMP6) 已被确定为铁稳态的重要调节因子。然而，其在包括非酒精性脂肪肝病（NAFLD）及其晚期形式非酒精性脂肪性肝炎（NASH）在内的肝脏病理学中的进一步作用尚不清楚。本研究的目的是探讨BMP6在慢性肝病中的表达和功能。设计对慢性肝损伤小鼠模型和慢性肝病患者的肝样本中的BMP6进行分析。此外，还评估了包含 110 个具有不同程度的脂肪变性和炎症的人类肝脏组织的组织微阵列。在两种饮食 NASH 模型（即蛋氨酸胆碱缺乏（MCD）和高脂肪（HF）饮食）中比较 BMP6 缺陷（BMP6（-/-））和野生型小鼠。结果 BMP6 仅在 NAFLD 中上调，但在其他小鼠肝损伤模型或患病人类肝脏中没有上调。在 NAFLD 中，BMP6 表达与肝脂肪变性相关，但与炎症或肝细胞损伤无关。此外，体外原代人肝细胞中的细胞脂质积累诱导 BMP6 表达增加。与野生型小鼠相比，MCD 和 HF 饮食引起 BMP6(-/-) 小鼠更多的肝脏炎症和纤维化。然而，只有在 MCD 中而不是在 HF 饮食模型中，BMP6(-/-) 小鼠出现了明显的肝铁超载，这表明进一步的机制负责 BMP6 的保护作用。体外分析表明，重组BMP6抑制肝星状细胞(HSC)的激活，并减少已激活的HSC中促炎和促纤维化基因的表达。结论 NAFLD中脂肪变性诱导的BMP6上调具有保肝作用。 BMP6 信号传导的诱导可能是一种有前途的抗纤维化策略。
Objective Bone morphogenetic protein 6 (BMP6) has been identified as crucial regulator of iron homeostasis. However, its further role in liver pathology including non-alcoholic fatty liver disease (NAFLD) and its advanced form non-alcoholic steatohepatitis (NASH) is elusive. The aim of this study was to investigate the expression and function of BMP6 in chronic liver disease.Design BMP6 was analysed in hepatic samples from murine models of chronic liver injury and patients with chronic liver diseases. Furthermore, a tissue microarray comprising 110 human liver tissues with different degree of steatosis and inflammation was assessed. BMP6-deficient (BMP6(-/-)) and wild-type mice were compared in two dietary NASH-models, that is, methionine choline-deficient (MCD) and high-fat (HF) diets.Results BMP6 was solely upregulated in NAFLD but not in other murine liver injury models or diseased human livers. In NAFLD, BMP6 expression correlated with hepatic steatosis but not with inflammation or hepatocellular damage. Also, in vitro cellular lipid accumulation in primary human hepatocytes induced increased BMP6 expression. MCD and HF diets caused more hepatic inflammation and fibrosis in BMP6(-/-) compared with wild-type mice. However, only in the MCD and not in the HF diet model BMP6(-/-) mice developed marked hepatic iron overload, suggesting that further mechanisms are responsible for protective BMP6 effect. In vitro analysis revealed that recombinant BMP6 inhibited the activation of hepatic stellate cells (HSCs) and reduced proinflammatory and profibrogenic gene expression in already activated HSCs.Conclusions Steatosis-induced upregulation of BMP6 in NAFLD is hepatoprotective. Induction of BMP6-signalling may be a promising antifibrogenic strategy.