Lipid metabolites can both potentiate and treat alcoholic hepatitis

脂质代谢物可以增强和治疗酒精性肝炎

基本信息

批准号：
10202388
负责人：
Swati Joshi-Barve
金额：
$ 23.69万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-22 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202388
关键词：
Abstinence Acrolein Acute Alcoholic Hepatitis Address Alcoholic Hepatitis Alcoholic liver damage Alcohols Aldehydes American diet Arachidonate 15-Lipoxygenase Attenuated Bacteria Biological Markers Blood Butyrates Cell Death Cell membrane Cessation of life Data Development Diet Diet and Nutrition Dietary Fats Disease Dose Endotoxemia Fatty acid glycerol esters Free Radicals Funding Genetic Health Care Costs Heavy Drinking Hepatocyte Human Injury Institution Intake Intervention Intestinal permeability Investigation Laboratories Linoleic Acids Lipid Peroxidation Lipids Liver Liver diseases Macronutrients Nutrition Mediating Membrane Lipids Metabolism Morbidity - disease rate Mus National Institute on Alcohol Abuse and Alcoholism Nutritional Omega-3 Fatty Acids Omega-6 Fatty Acids Oxidative Stress Oxides Patient Care Patients Play Polyunsaturated Fatty Acids Production Receptor Activation Recovery Research Risk Rodent Rodent Model Role Sampling Serum Severities Severity of illness Smoking Testing Therapeutic Tissues Toll-like receptors United States Universities Urine Volatile Fatty Acids adduct alcohol research cytokine dysbiosis endoplasmic reticulum stress gut bacteria gut dysbiosis gut microbiota human subject improved inflammatory disease of the intestine liver injury mortality mouse model nutrition organ injury oxidation polyunsaturated fat pre-clinical prevent response tributyrin

项目摘要

Alcoholic Hepatitis (AH) is an important cause of morbidity, mortality, and health care costs. Only a limited number (<25% of those who drink heavily) develop this more advanced liver disease. Thus, there must be modifying factors that either prevent or facilitate disease activity/progression. Dietary fat represents a critical macronutrient disease modifier for AH. The American diet has increased dramatically in omega 6- polyunsaturated fat (PUFA) content and has a very imbalanced omega-6:omega-3 ratio. In pre-clinical rodent models, dietary PUFA enriched in linoleic acid (LA), promotes alcohol-induced liver damage. Mice fed an alcohol + high PUFA (LA) diet generate toxic oxidized products of linoleic acid metabolism (OXLAMs) as well as a highly reactive and toxic aldehyde lipid peroxidation product, (i.e., acrolein), which causes ER stress and liver injury. This high PUFA diet plus alcohol in rodents also causes gut dysbiosis and decreases levels of the critical short chain fatty acid, butyrate. We postulate that human subjects with AH will have (i) increased levels of the lipid peroxidation product, acrolein (toxic aldehyde), (ii) increased levels of OXLAMs, and (iii) altered gut flora with decreased fecal levels of butyrate and butyrate producing bacteria, all of which correlate with severity of liver injury. We also postulate that certain lipid products (resolvins, butyrate) will be therapeutic in AH. We address this hypothesis with three specific aims using unique human samples generated through the NIAAA-funded U01-consortium in AH. Specific Aim #1: Determine whether levels of acrolein metabolites and adducts in serum/urine/tissue are elevated in AH, and correlate these levels with biomarkers of gut permeability, hepatic cell death/injury and disease severity. Specific Aim #2: Determine whether serum levels of OXLAMS are elevated in human AH, and correlate those levels with biomarkers of severity of AH, hepatocyte death, and gut permeability. Determine whether serum levels of resolvins are decreased in AH and whether resolvin administration to AH blood ex vivo decreases proinflammatory cytokines. Specific Aim #3: Determine fecal levels of short-chain fatty acids (focusing on butyrate) in patients with AH, and determine abundance of butyrate-producing bacteria in patients with acute AH and after recovery with abstinence. We will also determine the effects of different doses of butyrate on ex-vivo cytokine production in AH patients. !

酒精性肝炎 (AH) 是发病率、死亡率和医疗费用的重要原因。只有有限的许多人（重度饮酒者中 <25%）患有这种更严重的肝病。因此，必须有改变预防或促进疾病活动/进展的因素。膳食脂肪是一个关键因素 AH 的宏量营养素疾病修饰剂。美国人的饮食中欧米伽 6 含量急剧增加- 多不饱和脂肪 (PUFA) 含量高，并且 omega-6:omega-3 比例非常不平衡。在临床前啮齿动物中在模型中，富含亚油酸 (LA) 的膳食 PUFA 会促进酒精引起的肝损伤。老鼠喂了一个酒精 + 高 PUFA (LA) 饮食也会产生有毒的亚油酸代谢氧化产物 (OXLAM) 作为一种高反应性和毒性的醛类脂质过氧化产物（即丙烯醛），会导致 ER 应激和肝损伤。啮齿类动物的这种高 PUFA 饮食加上酒精也会导致肠道菌群失调，并降低关键短链脂肪酸，丁酸盐。我们假设患有 AH 的人类受试者 (i) 增加脂质过氧化产物丙烯醛（有毒醛）的水平，(ii) OXLAM 水平增加，以及 (iii) 肠道菌群改变，粪便中丁酸盐和产生丁酸盐的细菌水平降低，所有这些与肝损伤的严重程度相关。我们还假设某些脂质产品（溶解素、丁酸盐）对 AH 有治疗作用。我们利用独特的人类技术通过三个具体目标来解决这个假设样本是通过 NIAAA 资助的 U01 联盟在 AH 生成的。具体目标#1：确定血清/尿液/组织中丙烯醛代谢物和加合物的水平是否 AH 升高，并将这些水平与肠道通透性、肝细胞死亡/损伤和疾病的严重程度。具体目标 #2：确定人 AH 中 OXLAMS 的血清水平是否升高，并关联这些水平与 AH 严重程度、肝细胞死亡和肠道通透性的生物标志物有关。判断是否 AH 中 resolvins 的血清水平降低以及是否离体向 AH 血液施用 resolvin 减少促炎细胞因子。具体目标#3：确定 AH 患者粪便中的短链脂肪酸（重点是丁酸盐）水平，并测定急性 AH 患者及其康复后产生丁酸的细菌的丰度节制。我们还将确定不同剂量的丁酸盐对离体细胞因子产生的影响啊病人。！