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Gastroenterology:新研究揭示非酒精性脂肪肝炎的有效治疗靶标和血清诊断标志物

2021-03-30 生物探索 生物探索

非酒精性脂肪肝病新疗法

在物质条件充盈的当下,暴饮暴食和懒于运动的生活方式虽然深受人们喜爱,但也导致了我国非酒精性脂肪肝病(NAFLD)的发病率骤升。NAFLD是由单纯性肝脏脂肪变性、非酒精性脂肪肝炎(NASH),最终进展到肝纤维化、肝硬化和肝细胞癌(HCC)的慢性进展性疾病,而肥胖、糖尿病和代谢综合征引起的肝脏代谢失调是NASH发病的关键驱动力。因此,靶向脂质代谢途径抑制NAFLD进展或促进NASH的分解是被寄予期望的治疗干预手段。

近日,来自我国香港中文大学的研究人员在《Gastroenterology》上发表了题为Squalene epoxidase induces nonalcoholic steatohepatitis via binding to carbonic anhydrase 3 and is a therapeutic target的研究成果,其发现角鲨烯环氧化酶(SQLE)通过诱导胆固醇生物合成和SQLE / CA3(碳酸酐酶3)轴介导的脂肪生成来驱动NASH的进展,而SQLE和CA3的联合靶向抑制可为NAFLD / NASH带来显着治疗益处。同时血清SQLE和CA3也可作为NASH患者非侵入性诊断的新型生物标志物。

已有研究发现胆固醇是NASH发展的主要脂毒性分子,角鲨烯环氧酶(SQLE)是胆固醇生物合成途径中的限速酶,也是NAFLD-HCC的病因。基于SQLE促进胆固醇和胆固醇酯在肝细胞中的蓄积,研究人员认为SQLE可能在NASH的发展中起着重要作用。

研究思路模式

为了评估SQLE是否参与NAFLD,研究人员检测了NAFLD和NASH模型小鼠中SQLE的表达,发现无论是转录水平还是蛋白水平,SQLE的表达都被显着上调了。之后,研究人员生成了肝脏特异性SQLE过表达小鼠,并对其分别进行HFHC(高脂肪高碳水化合物)和MCD(蛋氨酸及胆碱缺乏)饮食以诱导NASH,检测其肝脏重量、质量、脂质含量、肝脂肪变性程度、促炎介质等水平后,发现SQLE过表达可以触发与NAFLD临床表现相一致的表型,并在肝脏中诱导了促炎性信号传导。同时肝细胞特异的SQLE过表达加速了HFHC和MCD饮食诱导的NASH进展和程度,在促进脂肪性肝炎的发展中起着关键作用。

小鼠肝脏SQLE过表达引发自发性NAFLD

基于这个结果,同时为探究SQLE在NASH发病机理中的作用,研究人员对两种小鼠的肝脏进行了转录组和代谢组联合分析,结果发现肝细胞特异的SQLE过表达激活了肝脏中胆固醇的生物合成和肝脏新生脂肪的形成,进而介导了SQLE诱导的NASH。例如SQLE过表达小鼠肝脏中脂肪和甘油三酸酯生物合成基因和炎症相关的基因表达被显着上调,非必需脂肪酸及羊毛甾醇、24-脱氢胆固醇、酵母甾醇等类固醇生物合成途径中的代谢产物也明显增加了。

SQLE过表达诱导肝脏中的胆固醇生物合成和新生脂肪形成

为了深入阐明SQLE在NASH中发挥作用的分子基础,研究人员通过免疫共沉淀和质谱分析,从中鉴定到SQLE过表达小鼠中碳酸酐酶3(CA3)是SQLE的互作蛋白,进一步分析发现了SQLE / CA3轴以胆固醇非依赖性的方式激活脂肪生成和NF-κB促炎途径,从而促进了NAFLD和NASH的发展。

特比萘芬(Terbinafine)是经FDA批准的SQLE抑制剂,通常用于治疗真菌感染,乙酰唑胺是另一种已被批准使用的CA3抑制剂。研究人员认为或许SQLE和CA3可以作为NAFLD / NASH的潜在治疗靶点,因此其对HFHC喂养的SQLE过表达小鼠进行特比萘芬联合乙酰唑胺靶向治疗,结果发现,该治疗手段显着降低了肝脏重量、消除了HFHC饮食引起的肝脏和血清甘油三酸酯的蓄积,减轻了脂肪性肝炎,脂质蓄积和肝纤维化,降低了对肝的损伤,在HFHC饮食诱导的NAFLD / NASH中具有卓越的治疗益处。

除此之外,研究人员还通过检测NASH患者及健康人体的血清,评估认证了SQLE和CA3可以作为NASH患者潜在的非侵入性诊断标志物用于筛查。

SQLE和CA3的药理抑制作用协同改善了NASH的发展

简而言之,该研究发现并证明了SQLE / CA3可以作为非酒精性脂肪肝病治疗的新型有效靶点,其联合靶向治疗可为NASH带来显着的益处,同时这两种蛋白也可以作为血清标志物筛查辅助诊断NASH!

原始出处:

Dabin Liu, et al. Squalene Epoxidase Induces Nonalcoholic Steatohepatitis Via Binding to Carbonic Anhydrase 3 and is a Therapeutic Target. Gastroenterology, 2021. DOI:https://doi.org/10.1053/j.gastro.2021.02.051.

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  7. 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  8. 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topicName=非酒精性)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=d18c27357544, createdName=Tommy1958, createdTime=Sun Jun 20 11:44:24 CST 2021, time=2021-06-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1909469, encodeId=26bc1909469a7, content=<a href='/topic/show?id=be1864e205a' target=_blank style='color:#2F92EE;'>#治疗靶标#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=104, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=64720, encryptionId=be1864e205a, topicName=治疗靶标)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=a885259, createdName=yourmama, createdTime=Mon Mar 07 14:44:24 CST 2022, time=2022-03-07, status=1, ipAttribution=)]
    2022-01-02 许安
  9. 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