Lipid metabolites can both potentiate and treat alcoholic hepatitis

酒精性肝炎(AH)是发病率、死亡率和医疗费用的重要原因。只有有限的 很多人(25%的酗酒者)会患上这种更严重的肝病。因此，必须有 修改预防或促进疾病活动/进展的因素。膳食脂肪代表着一种关键的 常量营养素疾病改良剂，用于AH。美国人的饮食大幅增加了omega 6- 多不饱和脂肪(PUFA)含量高，omega-6：omega-3比例极不平衡。在临床前啮齿动物中 模型，饮食多不饱和脂肪酸富含亚油酸(LA)，促进酒精诱导的肝损伤。小鼠喂食安非他命 酒精+高多不饱和脂肪酸(LA)饮食也会产生有毒的亚油酸代谢氧化产物(OXLAM) 作为一种高活性和毒性的乙醛脂质过氧化产物(即丙烯醛)，导致内质网应激和 肝脏损伤。啮齿动物的这种高多不饱和脂肪酸饮食加上酒精也会导致肠道生态失调，并降低体内 丁酸盐关键短链脂肪酸。我们假设患有AH的人类受试者将有(I)增加 脂质过氧化产物丙烯醛(有毒醛)的水平，(Ii)OXLAMS水平的增加，以及 (Iii)肠道菌群改变，丁酸盐和丁酸盐产生菌的粪便水平下降，所有 它们与肝损伤的严重程度相关。我们还假设某些脂类产品(解毒剂， 丁酸盐)对急性胰腺炎有治疗作用。我们用独一无二的人类来解决这一假设 样本是由NIAAA资助的阿肯色州U01-财团产生的。 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 在急性肝炎中升高，并将这些水平与肠道通透性、肝细胞死亡/损伤和 疾病的严重性。 特定目标#2：确定人类AH患者血清OXLAMS水平是否升高，并与 这些水平与急性肝炎严重程度、肝细胞死亡和肠道通透性等生物标志物有关。确定是否 急性肝炎患者血清溶血素水平降低及体外给药与否 减少促炎细胞因子。 具体目标#3：测定急性肝炎患者粪便中短链脂肪酸的水平(重点是丁酸)， 并测定急性急性肝炎患者和恢复后的丁酸产生菌的丰度。 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。 啊，病人。 好了！

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. !