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

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、死亡率和卫生保健费用的重要原因。只有有限的