Abstract：
There is substantial inter-individual variability in the risk of non-alcoholic fatty liver disease (NAFLD). Part of which is explained by insulin resistance (IR) (\'MetComp\') and part by common modifiers of genetic risk (\'GenComp\'). We examined how IR on the one hand and genetic risk on the other contribute to the pathogenesis of NAFLD.
We studied 846 individuals: 492 were obese patients with liver histology and 354 were individuals who underwent intrahepatic triglyceride measurement by proton magnetic resonance spectroscopy. A genetic risk score was calculated using the number of risk alleles in PNPLA3, TM6SF2, MBOAT7, HSD17B13 and MARC1. Substrate concentrations were assessed by serum NMR metabolomics. In subsets of participants, non-esterified fatty acids (NEFAs) and their flux were assessed by D5-glycerol and hyperinsulinemic-euglycemic clamp (n = 41), and hepatic de novo lipogenesis (DNL) was measured by D2O (n = 61).
We found that substrate surplus (increased concentrations of 28 serum metabolites including glucose, glycolytic intermediates, and amino acids; increased NEFAs and their flux; increased DNL) characterized the \'MetComp\'. In contrast, the \'GenComp\' was not accompanied by any substrate excess but was characterized by an increased hepatic mitochondrial redox state, as determined by serum β-hydroxybutyrate/acetoacetate ratio, and inhibition of hepatic pathways dependent on tricarboxylic acid cycle activity, such as DNL. Serum β-hydroxybutyrate/acetoacetate ratio correlated strongly with all histological features of NAFLD. IR and hepatic mitochondrial redox state conferred additive increases in histological features of NAFLD.
These data show that the mechanisms underlying \'Metabolic\' and \'Genetic\' components of NAFLD are fundamentally different. These findings may have implications with respect to the diagnosis and treatment of NAFLD.
The pathogenesis of non-alcoholic fatty liver disease can be explained in part by a metabolic component, including obesity, and in part by a genetic component. Herein, we demonstrate that the mechanisms underlying these components are fundamentally different: the metabolic component is characterized by hepatic oversupply of substrates, such as sugars, lipids and amino acids. In contrast, the genetic component is characterized by impaired hepatic mitochondrial function, making the liver less able to metabolize these substrates.
We studied 846 individuals: 492 were obese patients with liver histology and 354 were individuals who underwent intrahepatic triglyceride measurement by proton magnetic resonance spectroscopy. A genetic risk score was calculated using the number of risk alleles in PNPLA3, TM6SF2, MBOAT7, HSD17B13 and MARC1. Substrate concentrations were assessed by serum NMR metabolomics. In subsets of participants, non-esterified fatty acids (NEFAs) and their flux were assessed by D5-glycerol and hyperinsulinemic-euglycemic clamp (n = 41), and hepatic de novo lipogenesis (DNL) was measured by D2O (n = 61).
We found that substrate surplus (increased concentrations of 28 serum metabolites including glucose, glycolytic intermediates, and amino acids; increased NEFAs and their flux; increased DNL) characterized the \'MetComp\'. In contrast, the \'GenComp\' was not accompanied by any substrate excess but was characterized by an increased hepatic mitochondrial redox state, as determined by serum β-hydroxybutyrate/acetoacetate ratio, and inhibition of hepatic pathways dependent on tricarboxylic acid cycle activity, such as DNL. Serum β-hydroxybutyrate/acetoacetate ratio correlated strongly with all histological features of NAFLD. IR and hepatic mitochondrial redox state conferred additive increases in histological features of NAFLD.
These data show that the mechanisms underlying \'Metabolic\' and \'Genetic\' components of NAFLD are fundamentally different. These findings may have implications with respect to the diagnosis and treatment of NAFLD.
The pathogenesis of non-alcoholic fatty liver disease can be explained in part by a metabolic component, including obesity, and in part by a genetic component. Herein, we demonstrate that the mechanisms underlying these components are fundamentally different: the metabolic component is characterized by hepatic oversupply of substrates, such as sugars, lipids and amino acids. In contrast, the genetic component is characterized by impaired hepatic mitochondrial function, making the liver less able to metabolize these substrates.
摘要：
非酒精性脂肪性肝病（NAFLD）的风险存在很大的个体间差异。其中一部分由胰岛素抵抗（IR）（“MetComp”）解释，一部分由遗传风险的常见修饰因子（“GenComp”）解释。我们研究了IR和遗传风险如何导致NAFLD的发病机制。
我们研究了846名个体：492名肥胖患者的肝脏组织学和354名通过质子磁共振波谱进行肝内甘油三酯测量的个体。使用PNPLA3，TM6SF2，MBOAT7，HSD17B13和MARC1中的风险等位基因数计算遗传风险评分。通过血清NMR代谢组学评估底物浓度。在参与者的子集中，通过D5-甘油和高胰岛素-正血糖钳夹（n=41）评估非酯化脂肪酸（NEFA）及其通量，通过D2O测量肝脏从头脂肪生成（DNL）（n=61）。
我们发现底物过剩（包括葡萄糖在内的28种血清代谢物浓度增加，糖酵解中间体，和氨基酸；增加的NEFA及其通量；增加的DNL）表征了“MetComp”。相比之下,'GenComp'不伴有任何底物过量，但其特征是肝脏线粒体氧化还原状态增加，通过血清β-羟基丁酸酯/乙酰乙酸酯比率测定，和依赖于三羧酸循环活性的肝脏途径的抑制，比如DNL。血清β-羟基丁酸酯/乙酰乙酸酯比率与NAFLD的所有组织学特征密切相关。IR和肝线粒体氧化还原状态导致NAFLD组织学特征的累加增加。
这些数据表明，NAFLD的“代谢”和“遗传”成分的潜在机制根本不同。这些发现可能对NAFLD的诊断和治疗有影响。
非酒精性脂肪性肝病的发病机理可以部分解释为代谢成分，包括肥胖,部分原因是遗传因素。在这里，我们证明了这些成分的潜在机制是根本不同的：代谢成分的特点是肝脏供过于求的底物，比如糖，脂质和氨基酸。相比之下,遗传成分的特征是肝线粒体功能受损，使肝脏代谢这些底物的能力下降。
我们研究了846名个体：492名肥胖患者的肝脏组织学和354名通过质子磁共振波谱进行肝内甘油三酯测量的个体。使用PNPLA3，TM6SF2，MBOAT7，HSD17B13和MARC1中的风险等位基因数计算遗传风险评分。通过血清NMR代谢组学评估底物浓度。在参与者的子集中，通过D5-甘油和高胰岛素-正血糖钳夹（n=41）评估非酯化脂肪酸（NEFA）及其通量，通过D2O测量肝脏从头脂肪生成（DNL）（n=61）。
我们发现底物过剩（包括葡萄糖在内的28种血清代谢物浓度增加，糖酵解中间体，和氨基酸；增加的NEFA及其通量；增加的DNL）表征了“MetComp”。相比之下,'GenComp'不伴有任何底物过量，但其特征是肝脏线粒体氧化还原状态增加，通过血清β-羟基丁酸酯/乙酰乙酸酯比率测定，和依赖于三羧酸循环活性的肝脏途径的抑制，比如DNL。血清β-羟基丁酸酯/乙酰乙酸酯比率与NAFLD的所有组织学特征密切相关。IR和肝线粒体氧化还原状态导致NAFLD组织学特征的累加增加。
这些数据表明，NAFLD的“代谢”和“遗传”成分的潜在机制根本不同。这些发现可能对NAFLD的诊断和治疗有影响。
非酒精性脂肪性肝病的发病机理可以部分解释为代谢成分，包括肥胖,部分原因是遗传因素。在这里，我们证明了这些成分的潜在机制是根本不同的：代谢成分的特点是肝脏供过于求的底物，比如糖，脂质和氨基酸。相比之下,遗传成分的特征是肝线粒体功能受损，使肝脏代谢这些底物的能力下降。
