Profiling the oxylipidome in aged mice after chronic ethanol feeding: Identifying lipid metabolites as drivers of hepatocyte stress.
Profiling the oxylipidome in aged mice after chronic ethanol feeding: Identifying lipid metabolites as drivers of hepatocyte stress.
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DOI：
10.1016/j.alcohol.2022.08.012
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发表时间：
2023-03
期刊：
影响因子：
2.3
通讯作者：
McCullough, Rebecca L.
中科院分区：
文献类型：
--
作者：
Anton, Paige E.;Rutt, Lauren N.;Capper, Courtney;Orlicky, David J.;McCullough, Rebecca L.
全球65岁以上的人口正在增加，预计到2050年将达到15亿。虽然衰老与包括痴呆症在内的许多慢性疾病有关，但老年人滥用酒精的潜在贡献尚未得到充分研究。长期慢性酒精滥用可导致酒精相关性肝病，包括脂肪变性和肝硬化等一系列病理;肝脏疾病可因非消退性炎症而迅速加速。尽管有这些知识，但酒精引起的老年人宿主免疫失调和加速肝病进展的机制基础尚不清楚。老年人滥用酒精的情况正在增加，衰老与促炎细胞因子产生的逐步增加有关。本研究的目的是通过在3月龄和20月龄小鼠中使用乙醇诱导的肝病小鼠模型，通过定量分析肝脏、脑和血浆中选定的氧化脂质来表征炎症的生物活性脂质介质。慢性乙醇暴露后，与年轻成年小鼠相比，老年小鼠的肝损伤、脂肪变性和衰老标志物显著增加。促炎细胞因子和脂质代谢酶的表达增加，在肝脏中的年龄和乙醇喂养。脂氧合酶衍生的脂质代谢产物9-和13-羟基十八碳二烯酸和15-羟基二十碳四烯酸在乙醇喂养的老年小鼠的肝脏和血浆中增加，并与肝损伤呈正相关。在血浆中，9，10-二羟基-十八碳烯酸/环氧-十八碳烯酸血浆比例与乙醇喂养的老年小鼠的肝损伤相关。最后，15-羟基二十碳四烯酸和9，10-二羟基十八碳烯酸在肝脏和血浆中呈正相关。重要的是，白三烯E4，9，10-二羟基-十八碳烯酸和15-羟基二十碳四烯酸增加了培养的AML 12肝细胞中的脂质积累和ER应激。这些数据突出了脂质代谢网络的复杂性，但确定了可用于所有年龄段患者酒精相关肝病早期诊断和预后标志物的关键介质。
The global population of people over the age of 65 is increasing and expected to reach 1.5 billion by 2050. While aging is associated with a number of chronic illnesses including dementia, the underlying contribution of alcohol misuse in the elderly is understudied. Long-term chronic alcohol misuse can lead to alcohol-associated liver disease, consisting of a spectrum of pathologies including steatosis and cirrhosis; liver disease can be rapidly accelerated by non-resolving inflammation. Despite this knowledge, the mechanistic underpinnings of dysregulated host immunity and accelerated liver disease progression in the aged by alcohol is unknown. Alcohol misuse in the elderly is on the rise and aging is associated with progressive increases in pro-inflammatory cytokine production. The goals of current study are to characterize bioactive lipid mediators of inflammation by making use of a murine model of ethanol-induced liver disease in 3-month old and 20-month old mice by quantitatively profiling selected oxylipins in liver, brain and plasma. Following chronic ethanol exposure, liver injury, steatosis, and senescence markers were robustly increased in aged mice compared to young adult mice. Expression of proinflammatory cytokines and lipid metabolizing enzymes were increased in liver by both age and ethanol feeding. Lipoxygenase-derived lipid metabolites 9- and 13-hydroxy-octadecadienoic acid and 15-hydroxyeicosatetraenoic acid were increased in liver and plasma in ethanol-fed aged mice and positively correlated with liver injury. In plasma, 9,10-dihydroxy-octadecenoic acid/epoxy-octadecenoic acid plasma ratios correlated with liver injury in ethanol-fed aged mice. Finally, 15-hydroxyeicosatetraenoic acid and 9,10-dihydroxy-octadecenoic acid positively correlated between liver and plasma. Importantly, leukotriene E4, 9,10-dihydroxy-octadecenoic acid and 15-hydroxyeicosatetraenoic acid increased lipid accumulation and ER stress in cultured AML12 hepatocytes. These data highlight the complexity of lipid metabolite networks but identify key mediators that may be used for diagnostic and prognostic markers in early stages of alcohol-related liver disease in patients of all ages.
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2.4
作者：
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