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

• 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
• 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; 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

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，死亡率和医疗保健费用的重要原因。只有有限 数量（<25％的人喝大量的人）发展了这种更晚期的肝病。因此，必须有 修改因素，以预防或促进疾病活动/进展。饮食脂肪代表着关键 AH的大量营养素疾病修饰剂。在欧米茄6-中，美国饮食急剧增加 多不饱和脂肪（PUFA）含量，并且具有非常不平衡的omega-6：omega-3比。在临床前啮齿动物中 富含亚油酸（LA）的饮食PUFA模型可促进酒精引起的肝脏损害。喂养的小鼠 酒精 +高PUFA（LA）饮食还产生了亚油酸代谢（Oxlams）的有毒氧化产物 作为一种高反应性和有毒的醛脂质过氧化产物（即丙烯醛），会导致ER应激和 肝损伤。这种高的PUFA饮食加啮齿动物中的酒精也会引起肠道营养不良，并降低 关键的短链脂肪酸，丁酸酯。我们假设AH的人类受试者会增加（i） 脂质过氧化产物的水平，丙烯醛（毒性醛），（ii）Oxlams的水平升高和 （iii）随着粪便水平降低的丁酸酯和丁酸酯产生细菌的含量降低，肠道菌群改变了所有 与肝损伤严重程度相关。我们还假设某些脂质产品（Resolvins， 丁酸）将在AH中具有治疗性。我们使用独特的人来解决这一假设 通过AH中的NIAAA资助的U01-Constortium生成的样品。 特定目的＃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是 AH的升高，并将这些水平与肠道渗透性，肝细胞死亡/损伤和 疾病的严重程度。 特定目的＃2：确定人类AH中的Oxlam的血清水平是否升高，并相关 这些水平具有AH严重性，肝细胞死亡和肠道渗透性的生物标志物。确定是否 AH中的血清溶质水平降低，以及溶质对AH血液的施用是否降低 降低促炎细胞因子。 特定目的＃3：确定AH，AH， 并确定急性AH患者的丁酸酯细菌的丰度，并在 节制。我们还将确定不同剂量的丁酸酯对前体细胞因子产生的影响 啊患者。 呢