Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany.
J Clin Endocrinol Metab. 2018 Oct 1;103(10):3856-3868. doi: 10.1210/jc.2018-00999.
Exaggerated hepatic triglyceride accumulation (i.e., hepatic steatosis) represents a strong risk factor for type 2 diabetes mellitus and cardiovascular disease. Despite the clear association of hepatic steatosis with impaired insulin signaling, the precise molecular mechanisms involved are still under debate. We combined data from several metabolomics techniques to gain a comprehensive picture of molecular alterations related to the presence of hepatic steatosis in a diabetes-free sample (N = 769) of the population-based Study of Health in Pomerania.
Liver fat content (LFC) was assessed using MRI. Metabolome measurements of plasma and urine samples were done by mass spectrometry and nuclear magnetic resonance spectroscopy. Linear regression analyses were used to detect significant associations with either LFC or markers of hepatic damage. Possible mediations through insulin resistance, hypertriglyceridemia, and inflammation were tested. A predictive molecular signature of hepatic steatosis was established using regularized logistic regression.
The LFC-associated atherogenic lipid profile, tightly connected to shifts in the phospholipid content, and a prediabetic amino acid cluster were mediated by insulin resistance. Molecular surrogates of oxidative stress and multiple associations with urine metabolites (e.g., indicating altered cortisol metabolism or phase II detoxification products) were unaffected in mediation analyses. Incorporation of urine metabolites slightly improved classification of hepatic steatosis.
Comprehensive metabolic profiling allowed us to reveal molecular patterns accompanying hepatic steatosis independent of the known hallmarks. Novel biomarkers from urine (e.g., cortisol glucuronide) are worthwhile for follow-up in patients suffering from more severe liver impairment compared with our merely healthy population-based sample.
肝内甘油三酯过度积累（即肝脂肪变性）是 2 型糖尿病和心血管疾病的一个强烈危险因素。尽管肝脂肪变性与胰岛素信号受损之间存在明确关联，但涉及的精确分子机制仍存在争议。我们结合了几种代谢组学技术的数据，以全面了解人群为基础的波美拉尼亚健康研究（N=769）中无糖尿病个体中与肝脂肪变性相关的分子改变。
使用 MRI 评估肝脂肪含量（LFC）。通过质谱和核磁共振波谱法对血浆和尿液样本进行代谢组测量。线性回归分析用于检测与 LFC 或肝损伤标志物相关的显著关联。通过胰岛素抵抗、高甘油三酯血症和炎症测试可能的中介作用。使用正则逻辑回归建立肝脂肪变性的预测分子特征。
与 LFC 相关的致动脉粥样硬化脂质谱与磷脂含量的变化紧密相关，以及糖尿病前期的氨基酸簇是由胰岛素抵抗介导的。氧化应激的分子替代物以及与尿液代谢物的多种关联（例如，表明皮质醇代谢改变或 II 期解毒产物）在中介分析中不受影响。尿液代谢物的纳入略微改善了肝脂肪变性的分类。
综合代谢谱分析使我们能够揭示与已知特征无关的伴随肝脂肪变性的分子模式。来自尿液的新型生物标志物（例如皮质醇葡萄糖醛酸苷）在与我们仅基于人群的健康样本相比，在患有更严重肝损伤的患者中值得进一步随访。
