Paraoxonase‑1 Deficiency Is Associated with Severe Liver Steatosis in Mice Fed a High-fat High-cholesterol Diet: A Metabolomic Approach

Oxidative stress is a determinant of liver steatosis and the progression to more severe forms of disease. The present study investigated the effect of paraoxonase-1 (PON1) deficiency on histological alterations and hepatic metabolism in mice fed a high-fat high-cholesterol diet. We performed nontargeted metabolomics on liver tissues from 8 male PON1-deficient mice and 8 wild-type animals fed a high-fat, high-cholesterol diet for 22 weeks. We also measured 8-oxo-20-deoxyguanosine, reduced and oxidized glutathione, malondialdehyde, 8-isoprostanes and protein carbonyl concentrations. Results indicated lipid droplets in 14.5% of the hepatocytes of wild-type mice and in 83.3% of the PON1-deficient animals (P < 0.001). The metabolomic assay included 322 biochemical compounds, 169 of which were significantly decreased and 16 increased in PON1-deficient mice. There were significant increases in lipid peroxide concentrations and oxidative stress markers. We also found decreased glycolysis and the Krebs cycle. The urea cycle was decreased, and the pyrimidine cycle had a significant increase in orotate. The pathways of triglyceride and phospholipid synthesis were significantly increased. We conclude that PON1 deficiency is associated with oxidative stress and metabolic alterations leading to steatosis in the livers of mice receiving a high-fat high-cholesterol diet.

氧化应激是肝脂肪变性及疾病进展至更严重阶段的决定性因素。本研究探究了对氧磷酶-1（paraoxonase-1, PON1）缺陷对高脂高胆固醇饮食喂养小鼠的组织学改变与肝脏代谢的影响。我们对喂食高脂高胆固醇饮食22周的8只雄性PON1缺陷小鼠及8只野生型小鼠的肝组织开展了非靶向代谢组学分析。同时检测了8-氧代-20-脱氧鸟苷、还原型与氧化型谷胱甘肽、丙二醛、8-异前列腺素及蛋白质羰基含量。结果显示，野生型小鼠肝细胞脂滴检出率为14.5%，而PON1缺陷小鼠肝细胞脂滴检出率达83.3%（P < 0.001）。本次代谢组检测共涵盖322种生化化合物，其中PON1缺陷小鼠体内169种化合物水平显著下调，16种显著上调。脂质过氧化物浓度与氧化应激标志物水平显著升高。本研究同时发现，糖酵解与三羧酸循环活性显著降低；尿素循环活性下降，而嘧啶循环中乳清酸水平显著升高。甘油三酯与磷脂合成通路活性显著上调。综上，在高脂高胆固醇饮食喂养的小鼠中，PON1缺陷与氧化应激及引发肝脂肪变性的代谢改变密切相关。