Mechanisms of obesity-induced hepatocarcinogenesis

描述(由申请者提供)：肥胖是一个主要的公共健康问题，影响着近三分之一的美国人口。流行病学研究的证据表明，肥胖与多种癌症的发生有关，其中与肝癌的关系尤为密切。在美国，肥胖与非酒精性脂肪性肝病(NAFLD)和肝癌的高发病率有关。肥胖人群患肝癌风险增加的机制尚不完全清楚。由于脂肪组织会释放促进炎症的激素，因此人们认为肥胖人群中常见的脂肪肝的慢性炎症才是罪魁祸首。在这个双PI项目中，我们将集中讨论脂质过氧化(LPO)引起的DNA损伤及其对DNA修复和突变的影响，以及它们在肝细胞癌(HCC)发生中的作用。我们认为，在NAFLD中，由于慢性炎症而由脂肪酸氧化产生的醛形成的内源性环状DNA加合物增加，包括丙烷ACR-DG和HNE-DG，da和DG的乙烯基，以及最近发现的DHH-乙烯基DA和DHH-乙烯基DG；同时，这些醛也可以抑制DNA修复机制。我们认为，这些效应可以通过非酒精性脂肪性肝炎(NASH)(NAFLD的一种进行性形式)诱导驱动基因突变，促进肝癌的发生。我们建议以遗传易感性肥胖的C57BL/6(B-6)小鼠作为NAFLD和肝细胞癌的易感模型，并与培养的小鼠和人肝细胞平行，通过以下目的来验证这一假说：1)确定高脂饮食喂养的B-6小鼠在肝细胞癌形成过程中肝脏中环状DNA加合物的形成；2)测定b6小鼠在非酒精性脂肪肝和肝细胞癌阶段的肝脏和经低密度脂蛋白处理的培养肝细胞中大体积环状dna加合物和氧化-dna损伤(ODD)基因p53和�-catenin(Ctnnb1)的突变谱和分布；3)确定低密度脂蛋白醛对dna修复能力和突变敏感性的影响；4)检测硫辛基化合物潜在的化学预防活性。 酸和多酚E对肥胖B-6小鼠肝细胞癌形成的影响。

DESCRIPTION (provided by applicant): Obesity is a major public health problem that impacts nearly a third of the US population. Evidence from epidemiological studies indicates that obesity is associated with the development of many types of cancer and its connection with liver cancer is particularly strong. In the US, obesity is associated with a high incidence of non-alcoholic-induced fatty liver disease (NAFLD) and liver cancer. The mechanisms underlying the increased risk of liver cancer in obese population are not fully understood. Because fatty tissues release hormones that promote inflammation, it is believed that chronic inflammation in fatty liver disease commonly seen in obese people is the culprit. In this two-PI project, we will focus on lipid peroxidation (LPO)-induced DNA damage and its effects on DNA repair and mutagenesis, and their roles in hepatocellular carcinoma (HCC) development. We propose that the formation of endogenous cyclic DNA adducts, including the propano Acr-dG and HNE-dG, the etheno of dA and dG, and the recently discovered DHH-etheno dA and DHH-etheno dG, from aldehydes generated by fatty acid oxidation as a result of chronic inflammation is increased in NAFLD; concomitantly, these aldehydes can also inhibit DNA repair mechanisms. We believe that these effects can induce mutations at driver genes for the promotion of hepatocarcinogenesis through non-alcoholic-induced steatohepatitis (NASH), a progressive form of NAFLD. We propose to use the genetically predisposed obese C57BL/6 (B-6) mice as a model, which are prone to develop NAFLD and HCC, in parallel with cultured mouse and human hepatocytes, to examine the hypothesis by carrying out the following aims: 1) to determine the formation of cyclic DNA adducts in livers of B-6 mice fed high fat diet during the course of HCC development; 2) to determine the mutational spectrum and map the distribution of bulky cyclic DNA adducts and oxidative-DNA damage (ODD) in two liver cancer driver genes, p53 and �-catenin (CTNNB1), in livers of B-6 mice during the NAFLD and HCC stages and in cultured hepatocytes treated with LPO aldehyde byproducts; 3) to determine the effects of LPO aldehydes on DNA repair capacity and mutational susceptibility; and 4) to examine the potential chemopreventive activities of lipoic acid and Polyphenon E for HCC development in obese B-6 mice.