Lipid metabolites can both potentiate and treat alcoholic hepatitis

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 许多人（<25%的酗酒者）发展这种更晚期的肝脏疾病。因此，必须 修饰因素，防止或促进疾病活动/进展。膳食脂肪代表了一个关键的 AH的大量营养素疾病修饰剂。美国人的饮食中欧米茄6的含量急剧增加， 多不饱和脂肪酸（PUFA）的含量，并具有非常不平衡的ω-6：ω-3比例。在临床前啮齿类动物中 模型中，富含亚油酸（LA）的膳食PUFA促进酒精诱导的肝损伤。小鼠喂食 酒精+高PUFA（LA）饮食也产生有毒的亚油酸代谢氧化产物（OXLAMs 作为高反应性和毒性的醛脂质过氧化产物，（即，丙烯醛），其引起ER应激， 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生态失调，并降低体内PUFA的水平。 关键的短链脂肪酸，丁酸。我们假设患有AH的人类受试者将（i）增加 脂质过氧化产物丙烯醛（有毒醛）的水平，（ii）OXLAM的水平增加，和 (iii)肠道植物群改变，粪便中丁酸盐和丁酸盐产生菌的水平降低， 这与肝损伤的严重程度相关。我们还假设某些脂质产物（消退素， 丁酸盐）将在AH中具有治疗性。我们解决这个假设有三个具体的目标，使用独特的人类 通过NIAAA资助的AH中的U 01联盟生成的样本。 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 在AH中升高，并将这些水平与肠道通透性、肝细胞死亡/损伤和 疾病严重程度。 具体目标#2：确定人AH中OXLAMS的血清水平是否升高，并与 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。确定是否 在AH中消退素的血清水平降低， 减少促炎细胞因子。 具体目标#3：确定AH患者的短链脂肪酸（重点是丁酸盐）粪便水平， 并测定急性AH患者和恢复后的丁酸盐产生菌的丰度， 禁欲我们还将确定不同剂量的丁酸盐对体外细胞因子产生的影响， AH患者。 !

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. !