Van den Bossche Lindsay, Schoonenberg Vivien A C, Burgener Iwan A, Penning Louis C, Schrall Ingrid M, Kruitwagen Hedwig S, van Wolferen Monique E, Grinwis Guy C M, Kummeling Anne, Rothuizen Jan, van Velzen Jeroen F, Stathonikos Nikolas, Molenaar Martijn R, Helms Bernd J, Brouwers Jos F H M, Spee Bart, van Steenbeek Frank G
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
PLoS One. 2017 Oct 19;12(10):e0186491. doi: 10.1371/journal.pone.0186491. eCollection 2017.
Non-alcoholic fatty liver disease (NAFLD) is a poorly understood multifactorial pandemic disorder. One of the hallmarks of NAFLD, hepatic steatosis, is a common feature in canine congenital portosystemic shunts. The aim of this study was to gain detailed insight into the pathogenesis of steatosis in this large animal model. Hepatic lipid accumulation, gene-expression analysis and HPLC-MS of neutral lipids and phospholipids in extrahepatic (EHPSS) and intrahepatic portosystemic shunts (IHPSS) was compared to healthy control dogs. Liver organoids of diseased dogs and healthy control dogs were incubated with palmitic- and oleic-acid, and lipid accumulation was quantified using LD540. In histological slides of shunt livers, a 12-fold increase of lipid content was detected compared to the control dogs (EHPSS P<0.01; IHPSS P = 0.042). Involvement of lipid-related genes to steatosis in portosystemic shunting was corroborated using gene-expression profiling. Lipid analysis demonstrated different triglyceride composition and a shift towards short chain and omega-3 fatty acids in shunt versus healthy dogs, with no difference in lipid species composition between shunt types. All organoids showed a similar increase in triacylglycerols after free fatty acids enrichment. This study demonstrates that steatosis is probably secondary to canine portosystemic shunts. Unravelling the pathogenesis of this hepatic steatosis might contribute to a better understanding of steatosis in NAFLD.
非酒精性脂肪性肝病（NAFLD）是一种了解甚少的多因素大流行疾病。NAFLD的一个标志，即肝脂肪变性，是犬先天性门体分流的常见特征。本研究的目的是深入了解这种大型动物模型中脂肪变性的发病机制。将肝脂质蓄积、基因表达分析以及肝外（EHPSS）和肝内门体分流（IHPSS）中性脂质和磷脂的HPLC-MS分析结果与健康对照犬进行比较。将患病犬和健康对照犬的肝类器官与棕榈酸和油酸一起孵育，并使用LD540对脂质蓄积进行定量。在分流肝脏的组织学切片中，与对照犬相比，脂质含量增加了12倍（EHPSS P<0.01；IHPSS P = 0.042）。使用基因表达谱分析证实了脂质相关基因参与门体分流中的脂肪变性。脂质分析表明，与健康犬相比，分流犬的甘油三酯组成不同，且向短链和ω-3脂肪酸转变，不同分流类型之间的脂质种类组成没有差异。所有类器官在游离脂肪酸富集后甘油三酯均有类似增加。本研究表明，脂肪变性可能继发于犬门体分流。阐明这种肝脂肪变性的发病机制可能有助于更好地理解NAFLD中的脂肪变性。
