Pathogenesis and Novel Therapeutic Targets of Fatty Liver Disease and Cancer

脂肪肝疾病和癌症的发病机制和新的治疗靶点

• 批准号: 10004417
• 负责人: bin gao
• 金额: $ 111.62万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10004417
• 关键词: Acetaldehyde; Affect; Aging; Alcohol consumption; Alcohol-Related Hepatocellular Carcinoma; Alcoholic Liver Diseases; Alcohols; Anti-inflammatory; Asians; BCL2 gene; CXCL10 gene; Carbon Tetrachloride; Chronic; Cirrhosis; DNA; Development; Disease; Disease Progression; Enzymes; Ethanol; Ethanol Metabolism; Fatty Liver; Fibrosis; Genes; Genetic; Genetic Polymorphism; Goals; Heavy Drinking; Hepatic; Hepatitis B; Hepatocyte; High Fat Diet; Human; Immunologics; In Vitro; Inflammation; Inflammatory; Knock-in; Knockout Mice; Laboratories; Liver; Liver Fibrosis; Liver diseases; MAPK8 gene; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Messenger RNA; MicroRNAs; Microarray Analysis; Mitochondrial DNA; Modeling; Mus; Mutant Strains Mice; Oncogenic; Oxides; Pathogenesis; Pathway interactions; Patients; Play; Population; Primary carcinoma of the liver cells; Resistance; Risk; STAT3 gene; Sampling; Transcriptional Coactivator with PDZ-Binding Motif; Wild Type Mouse; acetaldehyde dehydrogenase; alcohol exposure; alcohol risk; aldehyde dehydrogenases; chemokine; clinically relevant; experimental study; extracellular vesicles; in vivo; liver injury; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; overexpression; therapeutic target

Our laboratory has been actively studying the pathogenesis of alcoholic liver disease, focusing on how acetaldehyde dehydrogenase 2 (ALDH2)and miRNA-223 on fatty liver disease and its associated liver cancer. First, we have demonstrated that ALDH2 deficiency promotes alcohol-associated liver cancer by activating oncogenic pathways via oxidized DNA enriched extracellular vesicles. Abstracts: BACKGROUND & AIMS: Excessive alcohol drinking is one of the major causes of hepatocellular carcinoma (HCC). Approximately 30-40% Asian population are deficient for aldehyde dehydrogenase 2 (ALDH2), a key enzyme to detoxify the ethanol metabolite acetaldehyde. However, how ALDH2 deficiency affects alcohol-related HCC remains obscure. METHODS: ALDH2 polymorphism in 646 patients with viral hepatitis B (HBV) infection with or without alcohol drinking was studied. A new model of HCC induced by chronic carbon tetrachloride (CCl4) and alcohol administration was developed and studied in three lines of Aldh2-deficient mice: including Aldh2 global knockout (KO) mice, Aldh2*1/*2 knock-in mutant mice, and liver-specific Aldh2 KO mice. RESULTS: We demonstrated that ALDH2 deficiency was not associated with liver disease progression but was associated with an increased risk of HCC development in cirrhotic HBV patients with excessive alcohol consumption. The mechanisms underlying HCC development associated with cirrhosis and alcohol consumption were studied in Aldh2-deficient mice. We found that all three lines of Aldh2-deficient mice were more susceptible to CCl4 plus alcohol-associated liver fibrosis and HCC development. Furthermore, our results from in vivo and in vitro mechanistic studies revealed that after CCl4 plus ethanol exposure, Aldh2-deficient hepatocytes produced a large amount of harmful oxidized mtDNA via extracellular vesicles (EVs), which were then transferred into neighboring HCC cells and together with acetaldehyde activated multiple oncogenic pathways (JNK, STAT3, BCL-2, and TAZ), thereby promoting HCC. CONCLUSIONS: ALDH2 deficiency is associated with an increased risk of alcohol related-HCC development from fibrosis in patients and in mice. Mechanistic studies reveal a novel mechanism that Aldh2-deficient hepatocytes promote alcohol-associated HCC by transferring harmful oxidized mtDNA-enriched EVs into HCC and subsequently activating multiple oncogenic pathways in HCC. Second, we have demonstrated that microRNA-223 ameliorates nonalcoholic steatohepatitis and cancer by targeting multiple inflammatory and oncogenic genes in hepatocytes. Abstract: Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases ranging from simple steatosis to more severe forms of liver injury including nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC). In humans, only 20%-40% of patients with fatty liver progress to NASH, and mice fed a high-fat diet (HFD) develop fatty liver but are resistant to NASH development. To understand how simple steatosis progresses to NASH, we examined hepatic expression of anti-inflammatory microRNA-223 (miR-223) and found that this miRNA was highly elevated in hepatocytes in HFD-fed mice and in human NASH samples. Genetic deletion of miR-223 induced a full spectrum of NAFLD in long-term HFD-fed mice including steatosis, inflammation, fibrosis, and HCC. Furthermore, microarray analyses revealed that, compared to wild-type mice, HFD-fed miR-223 knockout (miR-223KO) mice had greater hepatic expression of many inflammatory genes and cancer-related genes, including (C-X-C motif) chemokine 10 (Cxcl10) and transcriptional coactivator with PDZ-binding motif (Taz), two well-known factors that promote NASH development. In vitro experiments demonstrated that Cxcl10 and Taz are two downstream targets of miR-223 and that overexpression of miR-223 reduced their expression in cultured hepatocytes. Hepatic levels of miR-223, CXCL10, and TAZ mRNA were elevated in human NASH samples, which positively correlated with hepatic levels of several miR-223 targeted genes as well as several proinflammatory, cancer-related, and fibrogenic genes. Conclusion: HFD-fed miR-223KO mice develop a full spectrum of NAFLD, representing a clinically relevant mouse NAFLD model; miR-223 plays a key role in controlling steatosis-to-NASH progression by inhibiting hepatic Cxcl10 and Taz expression and may be a therapeutic target for the treatment of NASH.

我们的实验室一直在积极研究酒精性肝病的发病机理，重点是乙醛脱氢酶2（ALDH2）和miRNA-223如何在脂肪肝病及其相关的肝癌上。 首先，我们已经证明ALDH2缺乏通过通过氧化的DNA富含细胞外囊泡激活致癌途径来促进与酒精相关的肝癌。摘要：背景和目的：过量饮酒是肝细胞癌（HCC）的主要原因之一。大约30-40％的亚洲人群缺乏醛脱氢酶2（ALDH2），这是一种对乙醇代谢物乙醛排毒的关键酶。但是，ALDH2缺乏影响与酒精相关的HCC的影响仍然晦涩。方法：研究或不饮用饮酒的646例病毒B（HBV）感染患者的ALDH2多态性。开发并研究了由慢性四氯化碳（CCL4）和酒精给药引起的新模型的新模型。结果：我们证明ALDH2缺乏症与肝病进展无关，但与饮酒过量过量的HBV患者的HCC发育风险增加有关。在ALDH2缺陷型小鼠中研究了与肝硬化和饮酒相关的HCC发育的基础机制。我们发现，所有三种缺陷型小鼠都更容易受到CCL4以及与酒精相关的肝纤维化和HCC发育的影响。 Furthermore, our results from in vivo and in vitro mechanistic studies revealed that after CCl4 plus ethanol exposure, Aldh2-deficient hepatocytes produced a large amount of harmful oxidized mtDNA via extracellular vesicles (EVs), which were then transferred into neighboring HCC cells and together with acetaldehyde activated multiple oncogenic pathways (JNK, STAT3, BCL-2,和taz），从而促进HCC。结论：ALDH2缺乏症与患者和小鼠中纤维化相关的HCC与HCC相关HCC的风险增加有关。机械研究揭示了一种新的机制，即通过将有害氧化的MTDNA富含电动汽车转移到HCC中，并随后激活HCC中的多个致癌途径，从而促进了与酒精相关的HCC促进酒精相关的HCC。 其次，我们已经证明MicroRNA-223通过靶向肝细胞中多种炎症和致癌基因来改善非酒精性脂肪性肝炎和癌症。摘要：非酒精性脂肪肝病（NAFLD）代表了一系列疾病，从简单的脂肪变性到更严重的肝损伤形式，包括非酒精性脂肪性肝炎（NASH），纤维化和肝细胞癌（HCC）。在人类中，只有20％-40％的脂肪肝脏患者纳什（NASH）进展，而喂养高脂饮食（HFD）的小鼠会发展出脂肪肝，但对NASH的发育有抵抗力。为了了解简单的脂肪变性如何发展为纳什，我们检查了抗炎microRNA-223（miR-223）的肝表达，发现该miRNA在HFD喂养的小鼠和人类NASH样品中的肝细胞中高度升高。 miR-223的遗传缺失诱导了长期的HFD喂养小鼠中的NAFLD，包括脂肪变性，炎症，纤维化和HCC。 Furthermore, microarray analyses revealed that, compared to wild-type mice, HFD-fed miR-223 knockout (miR-223KO) mice had greater hepatic expression of many inflammatory genes and cancer-related genes, including (C-X-C motif) chemokine 10 (Cxcl10) and transcriptional coactivator with PDZ-binding motif (Taz), two well-known factors that promote NASH 发展。体外实验表明，CXCL10和TAZ是miR-223的两个下游靶标，而miR-223的过表达降低了它们在培养的肝细胞中的表达。在人NASH样品中，miR-223，CXCL10和TAZ mRNA的肝水平升高，它们与几种miR-223靶向基因的肝水平以及几种促炎，与癌症相关和纤维化基因呈正相关。结论：HFD喂养的miR-223KO小鼠会形成全频谱，代表了临床上相关的小鼠NAFLD模型。 miR-223通过抑制肝CXCL10和TAZ表达在控制脂肪变性到核心进展中起关键作用，并且可能是治疗NASH治疗的治疗靶标。