Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, 14853, USA.
West Coast Metabolomics Center, University of California Davis Genome Center, Davis, CA, 95616, USA.
Sci Rep. 2017 Jul 21;7(1):6120. doi: 10.1038/s41598-017-05040-6.
Nonalcoholic fatty liver disease (NAFLD) in non-obese patients remains a clinical condition with unclear etiology and pathogenesis. Using a metabolomics approach in a mouse model that recapitulates almost all the characteristic features of non-obese NAFLD, we aimed to advance mechanistic understanding of this disorder. Mice fed high fat, high cholesterol, cholate (HFHCC) diet for three weeks consistently developed hepatic pathology similar to NAFLD and nonalcoholic steatohepatitis (NASH) without changes to body weight or fat pad weights. Gas- and liquid chromatography/mass spectrometry-based profiling of lipidomic and primary metabolism changes in the liver and plasma revealed that systemic mechanisms leading to steatosis and hepatitis in this non-obese NAFLD model were driven by a combination of effects directed by elevated free cholesterol, cholesterol esters and cholic acid, and associated changes to metabolism of sphingomyelins and phosphatidylcholines. These results demonstrate that mechanisms underlying cholesterol-induced non-obese NAFLD are distinct from NAFLD occurring as a consequence of metabolic syndrome. In addition, this investigation provides one of the first metabolite reference profiles for interpreting effects of dietary and hepatic cholesterol in human non-obese NAFLD/NASH patients.
非肥胖患者的非酒精性脂肪性肝病 (NAFLD) 仍然是一种病因和发病机制尚不清楚的临床病症。本研究采用代谢组学方法，在一种能够重现非肥胖性 NAFLD 的几乎所有特征的小鼠模型中，旨在深入了解这种疾病的发病机制。喂食高脂肪、高胆固醇、胆酸盐（HFHCC）饮食的小鼠持续 3 周后，肝脏病理表现与 NAFLD 和非酒精性脂肪性肝炎（NASH）相似，而体重或脂肪垫重量没有变化。基于气相和液相色谱/质谱的脂质组学和肝脏及血浆中初级代谢物变化分析显示，导致这种非肥胖性 NAFLD 模型发生脂肪变性和肝炎的全身性机制是由升高的游离胆固醇、胆固醇酯和胆酸以及鞘磷脂和磷脂酰胆碱代谢的相关变化共同作用所致。这些结果表明，胆固醇诱导的非肥胖性 NAFLD 的发病机制与代谢综合征引起的 NAFLD 不同。此外，该研究还提供了人类非肥胖性 NAFLD/NASH 患者解释饮食和肝脏胆固醇影响的首批代谢物参考图谱之一。
