Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón-Universidad de Zaragoza, Zaragoza, Spain.
Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, Zaragoza, Spain.
Am J Physiol Gastrointest Liver Physiol. 2024 Apr 1;326(4):G411-G425. doi: 10.1152/ajpgi.00264.2023. Epub 2024 Feb 20.
Recently, the development of nonalcoholic steatohepatitis (NASH) in common strains of pigs has been achieved using a diet high in saturated fat, fructose, cholesterol, and cholate and deficient in choline and methionine. The aim of the present work was to characterize the hepatic and plasma lipidomic changes that accompany the progression of NASH and its reversal by switching pigs back to a chow diet. One month of this extreme steatotic diet was sufficient to induce porcine NASH. The lipidomic platform using liquid chromatography-mass spectrometry analyzed 467 lipid species. Seven hepatic phospholipids [PC(30:0), PC(32:0), PC(33:0), PC(33:1), PC(34:0), PC(34:3) and PC(36:2)] significantly discriminated the time of dietary exposure, and PC(30:0), PC(33:0), PC(33:1) and PC(34:0) showed rapid adaptation in the reversion period. Three transcripts (, , and ) showed significant changes associated with hepatic triglycerides and PC(33:0). Plasma lipidomics revealed that these species [FA 16:0, FA 18:0, LPC(17:1), PA(40:5), PC(37:1), TG(45:0), TG(47:2) and TG(51:0)] were able to discriminate the time of dietary exposure. Among them, FA 16:0, FA 18:0, LPC(17:1) and PA(40:5) changed the trend in the reversion phase. Plasma LDL-cholesterol and IL12P40 were good parameters to study the progression of NASH, but their capacity was surpassed by hepatic [PC(33:0), PC(33:1), and PC(34:0)] or plasma lipid [FA 16:0, FA 18:0, and LPC(17:1)] species. Taken together, these lipid species can be used as biomarkers of metabolic changes in the progression and regression of NASH in this model. The lipid changes suggest that the development of NASH also affects peripheral lipid metabolism. A NASH stage was obtained in crossbred pigs. Hepatic [PC(33:0), PC(33:1) and PC(34:0)] or plasma [FA 16:0, FA 18:0 and LPC(17:1)] species were sensitive parameters to detect subtle changes in development and regression of nonalcoholic steatohepatitis (NASH). These findings may delineate the liquid biopsy to detect subtle changes in progression or in treatments. Furthermore, phospholipid changes according to the insult-inducing NASH may play an important role in accepting or rejecting fatty livers in transplantation.
最近，通过高脂肪、果糖、胆固醇和胆酸盐饮食以及缺乏胆碱和蛋氨酸的普通猪种，已经实现了非酒精性脂肪性肝炎（NASH）的发展。本研究的目的是描述伴随 NASH 进展及其通过将猪转回普通饮食而逆转的肝和血浆脂质组学变化。这种极端脂肪性饮食一个月足以诱导猪 NASH。使用液相色谱-质谱分析的脂质组学平台分析了 467 种脂质。七种肝磷脂 [PC(30:0)、PC(32:0)、PC(33:0)、PC(33:1)、PC(34:0)、PC(34:3)和 PC(36:2)] 显著区分了饮食暴露时间，PC(30:0)、PC(33:0)、PC(33:1)和 PC(34:0)在逆转期表现出快速适应。三种转录物 [、和] 与肝甘油三酯和 PC(33:0)相关显示出显著变化。血浆脂质组学显示，这些物质 [FA 16:0、FA 18:0、LPC(17:1)、PA(40:5)、PC(37:1)、TG(45:0)、TG(47:2)和 TG(51:0)] 能够区分饮食暴露时间。其中，FA 16:0、FA 18:0、LPC(17:1)和 PA(40:5)改变了逆转阶段的趋势。血浆 LDL-胆固醇和 IL12P40 是研究 NASH 进展的良好参数，但它们的能力被肝 [PC(33:0)、PC(33:1)和 PC(34:0)] 或血浆脂质 [FA 16:0、FA 18:0 和 LPC(17:1)] 物种所超越。总的来说，这些脂质物种可以作为该模型中 NASH 进展和消退代谢变化的生物标志物。脂质变化表明 NASH 的发展也会影响外周脂质代谢。在杂交猪中获得了 NASH 阶段。肝 [PC(33:0)、PC(33:1)和 PC(34:0)] 或血浆 [FA 16:0、FA 18:0 和 LPC(17:1)] 物种是检测非酒精性脂肪性肝炎 (NASH) 发展和消退中细微变化的敏感参数。这些发现可能描绘了液体活检以检测进展或治疗中的细微变化。此外，根据诱导 NASH 的损伤，磷脂变化可能在接受或拒绝肝移植中的脂肪肝方面发挥重要作用。
