Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Louisville, Louisville, Kentucky, USA.
Alcohol Clin Exp Res (Hoboken). 2023 Jan;47(1):60-75. doi: 10.1111/acer.14976. Epub 2022 Dec 1.
The prevalence of alcohol-associated liver disease (ALD), a subtype of fatty liver disease (FLD), continues to rise. ALD is a major cause of preventable death. Polychlorinated biphenyl (PCB) 126 is an environmentally relevant, dioxin-like pollutant whose negative metabolic effects have been well documented. In human and animal studies, PCB has been associated with the severity of nonalcoholic fatty liver disease (NAFLD). However, few studies have investigated whether exposures to environmental toxicants can worsen ALD. Thus, the objective of the current study was to develop an alcohol-plus-toxicant model to study how an environmental pollutant, PCB 126, impacts rodent ALD pathology.
Briefly, male C57BL/6J mice were exposed to 0.2 mg/kg PCB 126 or corn oil vehicle four days prior to ethanol feeding using the chronic-binge (10-plus-one) model.
Concentrations of macromolecules, including hepatic lipids, carbohydrates, and protein (albumin) were impacted. Exposure to PCB 126 exacerbated hepatic steatosis and hepatomegaly in mice exposed to the chemical and fed an ethanol diet. Gene expression and the analysis of blood chemistry showed a potential net increase and retention of hepatic lipids and reductions in lipid oxidation and clearance capabilities. Depletion of glycogen and glucose was evident, which contributes to disease progression by generating systemic malnutrition. Granulocytic immune infiltrates were present but driven solely by ethanol feeding. Hepatic albumin gene expression and plasma levels were decreased by ~50% indicating a potential compromise of liver function. Finally, gene expression analyses indicated that the aryl hydrocarbon receptor and constitutive androstane receptor were activated by PCB 126 and ethanol, respectively.
Various environmental toxicants are known to modify or enhance FLD in high-fat diet models. Findings from the present study suggest that they interact with other lifestyle factors such as alcohol consumption to reprogram intermediary metabolism resulting in exacerbated ethanol-associated systemic malnutrition in ALD.
酒精相关性肝病（ALD），即脂肪肝疾病（FLD）的一个亚型，其患病率持续上升。ALD 是可预防死亡的主要原因。多氯联苯（PCB）126 是一种与环境相关的、类似二恶英的污染物，其负面代谢影响已有充分记录。在人体和动物研究中，PCB 与非酒精性脂肪性肝病（NAFLD）的严重程度有关。然而，很少有研究调查环境毒物暴露是否会加重 ALD。因此，本研究的目的是开发一种酒精加毒物模型，以研究环境污染物 PCB 126 如何影响啮齿动物的 ALD 病理学。
简要地说，雄性 C57BL/6J 小鼠在接受乙醇喂养之前的四天，用慢性 binge（10 加 1）模型接受 0.2mg/kg PCB 126 或玉米油载体暴露。
包括肝内脂质、碳水化合物和蛋白质（白蛋白）在内的大分子浓度受到影响。暴露于 PCB 126 加剧了暴露于该化学物质并喂食乙醇饮食的小鼠的肝脂肪变性和肝肿大。基因表达和血液化学分析显示，肝内脂质的潜在净增加和保留，以及脂质氧化和清除能力的降低。肝内糖原和葡萄糖的耗竭明显，通过产生全身营养不良促进疾病进展。粒细胞免疫浸润存在，但仅由乙醇喂养驱动。肝白蛋白基因表达和血浆水平降低了约 50%，表明肝功能可能受损。最后，基因表达分析表明，芳香烃受体和组成型雄烷受体分别被 PCB 126 和乙醇激活。
各种环境毒物已知可修饰或增强高脂肪饮食模型中的 FLD。本研究的结果表明，它们与其他生活方式因素（如饮酒）相互作用，重新编程中间代谢，导致 ALD 中乙醇相关的全身营养不良加剧。
