Iso-alpha acids from hops (Humulus lupulus) inhibit hepatic steatosis, inflammation, and fibrosis
Iso-alpha acids from hops (Humulus lupulus) inhibit hepatic steatosis, inflammation, and fibrosis
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DOI：
10.1038/s41374-018-0112-x
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发表时间：
2018-12-01
影响因子：
5
通讯作者：
Hellerbrand, Claus
中科院分区：
文献类型：
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作者：
Mahli, Abdo;Koch, Andreas;Hellerbrand, Claus
非酒精性脂肪性肝病（NAFLD）被认为是代谢综合征的肝脏表现。异α酸（IAAs），啤酒中啤酒花衍生的苦味化合物，已被证明有益于影响代谢综合征的不同组分，如胰岛素抵抗和血脂异常。然而，IAAs尚未在慢性肝病的背景下进行研究。本文分析了IAA在NAFLD发病中的作用。有一次，我们将IAA与诱导NAFLD的西式饮食（WTD）组合应用于小鼠，并观察到IAA显著抑制WTD诱导的体重增加、葡萄糖耐受不良和肝脂肪变性。与此相适应，IAA剂量依赖性地抑制体外原代人肝细胞（PHH）中的细胞脂质积累。PPAR-gamma和脂质合成关键酶的表达减少以及PPAR-alpha表达增加（指示脂质燃烧增加）被确定为体外和体内肝细胞脂肪变性减少的潜在机制。对肝脏HMOX 1表达的分析表明，IAA治疗小鼠的氧化应激减少，这是由于JNK通路和促炎基因表达的活化减少以及免疫细胞浸润减少。此外，IAA减少肝星状细胞（HSC）的激活和促纤维化基因的表达。同样，IAA也剂量依赖性地降低脂肪变性PHH中的氧化应激和JNK活化，抑制HSC活化，并降低体外已活化HSC中的增殖和促纤维化基因表达。总之，IAAs抑制NAFLD疾病进展的不同病理生理步骤。与先前的研究一起，这些研究证明了即使长期应用IAA在人类中的安全性，我们的数据表明IAA是预防和治疗（非）酒精性（脂肪）肝病的有前途的治疗剂。
Non-alcoholic fatty liver disease (NAFLD) is considered to be the hepatic manifestation of the metabolic syndrome. Isoalpha acids (IAAs), hop-derived bitter compounds in beer, have been shown to beneficially affect different components of the metabolic syndrome such as insulin resistance and dyslipidemia. However, IAAs have not yet been studied in the context of chronic liver disease. Here we analyzed the effect of IAA on the pathogenesis of NAFLD. Once, we applied IAA to mice in combination with a NAFLD-inducing Western-type diet (WTD), and observed that IAA significantly inhibited WTD-induced body weight gain, glucose intolerance, and hepatic steatosis. Fitting to this, IAA dose-dependently inhibited cellular lipid accumulation in primary human hepatocytes (PHH) in vitro. Reduced expression of PPAR-gamma and key enzymes of lipid synthesis as well as increased expression of PPAR-alpha, indicative for increased lipid combustion, were identified as underlying mechanisms of reduced hepatocellular steatosis in vitro and in vivo. Analysis of hepatic HMOX1 expression indicated reduced oxidative stress in IAA-treated mice, which was paralleled by reduced activation of the JNK pathway and pro-inflammatory gene expression and immune cell infiltration. Furthermore, IAA reduced hepatic stellate cell (HSC) activation and pro-fibrogenic gene expression. Similarly, IAA also dose-dependently reduced oxidative stress and JNK activation in steatotic PHH, inhibited HSC activation, and reduced proliferation and pro-fibrogenic gene expression in already activated HSC in vitro. In conclusion, IAAs inhibit different pathophysiological steps of disease progression in NAFLD. Together with previous studies, which demonstrated the safety of even long-term application of IAA in humans, our data suggest IAA as promising therapeutic agent for the prevention and treatment of (non) alcoholic (fatty) liver disease.