Hepatic Steatosis and the Lipid Metabolome

描述(申请人提供)：肝脏脂肪变性(脂肪肝)是酒精性肝病(ALD)和非酒精性脂肪性肝病(NAFLD)的早期和可逆阶段，这两种疾病都是与肝脏相关的疾病和死亡的主要原因。然而，未加控制的肝脏脂肪变性可进展为不可逆转的脂肪性肝炎、纤维化、肝硬变，最终发展为肝细胞癌。我们的目标是阐明导致脂肪肝的机制，开发脂肪肝的生物标志物以帮助早期诊断，并确定在这一早期和可逆的肝病阶段进行干预的分子靶点。我们的初步研究表明，S-腺苷甲硫氨酸(SAM)介导的细胞分子甲基化减弱是脂肪肝的原因，因为给予SAM前体缺乏的饮食的大鼠表现出肝脏脂肪变性和脂质的低甲基化。我们假设细胞甲基化减少会导致脂肪肝，脂肪肝的特征是脂类代谢组的改变，特别是甲基化脂质的减少，作为脂肪变性的生物标记物。代谢组学将用于在SAM前体缺乏饮食(目标1)损害生物分子甲基化的大鼠身上测试这一假说，这种情况因饮酒(目标2)而加剧，并可通过膳食补充剂(甜菜碱)(目标3)逆转。代谢组和蛋白质组的脂质相关变化(生物合成、降解和转运)将在血浆和肝脏中相互关联，因此血浆变化可以作为肝脏脂肪变性的生物标志物。该项目将由一个经验丰富的多学科团队进行，其中包括脂类化学家/生物化学家、肝病学家、病理学家和生物信息学家。我们的结果应该确定SAM缺乏是肝脏脂肪变性的核心，并因酗酒而加剧。通过使用转组学技术(代谢组学、蛋白质组学和基因组学)，我们将识别一种新的肝脏脂肪变性的生物标志物(甲基化脂肪)，该标记最终可用于脂肪变性的诊断。此外，通过这些基因组技术识别脂肪肝的一系列事件应该识别早期干预的分子靶点。健康相关性：脂肪肝是一个早期和可逆的阶段，导致酒精性肝病(ALD)和非酒精性脂肪性肝病(NAFLD)，这两种疾病是肝脏相关死亡的主要原因。该项目将识别脂肪肝的生物标志物以进行早期诊断，并为开发预防ALD和NAFLD的新药提供潜在的靶点。

DESCRIPTION (provided by applicant): Hepatic steatosis (fatty liver) is an early and reversible stage of both alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), which are major causes of liver-associated illness and death. However, unchecked hepatic steatosis can advance to irreversible steatohepatitis, fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. Our objective is to elucidate the mechanisms leading to fatty liver, develop a biomarker signature of fatty liver to aid early diagnosis, and identify molecular targets for intervention at this early and reversible stage of liver diseases. Our preliminary studies suggest that diminished S-adenosylmethionine (SAM)-mediated methylation of cellular molecules is responsible for fatty liver because rats given a SAM precursor-deficient diet demonstrated hepatic steatosis and hypomethylation of lipids. We hypothesize that decreased cellular methylation leads to fatty liver, which can be characterized by an altered lipid metabolome (lipidome), especially decreased methylated lipids, to serve as a biomarker signature of steatosis. Metabolomics will be used to test this hypothesis in rats where methylation of biomolecules is compromised by a SAM precursor-deficient diet (aim 1), a situation exacerbated by alcohol consumption (aim 2), and which can be reversed by dietary supplement (betaine) (aim 3). Lipid-associated changes of the metabolome and proteome (in biosynthesis, degradation and transport) will be correlated in the plasma and liver so that plasma changes can serve as a biomarker signature of hepatic steatosis. This project will be conducted by an experienced multidisciplinary team including lipid chemists/biochemists, a hepatologist, a pathologist and bioinformatricians. Our results should establish that SAM deficiency is central to liver steatosis and exacerbated by alcohol abuse. By using trans-omic techniques (metabolomics, proteomics and genomics) we will identify a novel biomarker signature (methylated lipids) of hepatic steatosis which can ultimately be utilized for diagnosis of steatosis. Furthermore, the sequence of events leading to fatty liver identification by these trans-omic techniques should identify molecular targets for an early intervention. Health Relevance: Fatty liver is an early and reversible stage leading to both alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), major causes of liver-associated deaths. This project will identify biomarkers of fatty liver for an early diagnosis, and also potential targets for the development of new drugs to prevent ALD and perhaps NAFLD.