Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease.
Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease.
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DOI：
10.1016/j.jhep.2021.10.013
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发表时间：
2022-03
影响因子：
25.7
通讯作者：
Yki-Järvinen H
中科院分区：
文献类型：
--
作者：
Luukkonen PK;Qadri S;Ahlholm N;Porthan K;Männistö V;Sammalkorpi H;Penttilä AK;Hakkarainen A;Lehtimäki TE;Gaggini M;Gastaldelli A;Ala-Korpela M;Orho-Melander M;Arola J;Juuti A;Pihlajamäki J;Hodson L;Yki-Järvinen H
非酒精性脂肪性肝病（NAFLD）的风险存在很大的个体间差异。部分原因是胰岛素抵抗（IR）（“MetComp”），部分原因是遗传风险的常见修饰因子（“GenComp”）。我们研究了IR和遗传风险如何影响NAFLD的发病机制。我们研究了846人：492名肥胖患者的肝脏组织学和354人进行了肝内甘油三酯测量的质子磁共振波谱。使用PNPLA 3、TM 6SF 2、MBOAT 7、HSD 17 B13和MARC 1中的风险等位基因数量计算遗传风险评分。通过血清NMR代谢组学评估底物浓度。在参与者的亚组中，通过D5-甘油和高胰岛素-正葡萄糖钳夹（n = 41）评估非酯化脂肪酸（NEFA）及其流量，并通过D2 O（n = 61）测量肝脏新生脂肪生成（DNL）。我们发现，底物过剩（浓度增加的28种血清代谢物，包括葡萄糖，糖酵解中间体，和氨基酸;增加NEFA和它们的流量;增加DNL）的特点是'MetComp'。相比之下，“GenComp”不伴随任何底物过量，但其特征在于肝线粒体氧化还原状态增加，如通过血清β-羟基丁酸/乙酰乙酸比测定的，以及依赖于三羧酸循环活性的肝途径（如DNL）的抑制。血清β-羟丁酸/乙酰乙酸比值与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赋予NAFLD组织学特征的附加增加。这些数据表明，NAFLD的“代谢”和“遗传”成分的机制是根本不同的。这些发现可能对NAFLD的诊断和治疗产生影响。非酒精性脂肪性肝病的发病机制可以部分由代谢成分（包括肥胖）和部分由遗传成分解释。在此，我们证明了这些成分的机制是根本不同的：代谢成分的特点是肝脏供过于求的底物，如糖，脂质和氨基酸。相比之下，遗传组分的特征在于肝线粒体功能受损，使得肝脏不太能够代谢这些底物。NAFLD的发病机制可以部分由代谢成分和部分由遗传成分解释。这些组成部分的机制是根本不同的。代谢组分的特征在于底物过剩以及脂肪组织脂解和肝DNL的速率增加。遗传组分的特征在于增加的肝线粒体氧化还原状态和抑制依赖于TCA循环活性的途径，如DNL。这些成分增加了NAFLD的严重程度。
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. The pathogenesis of NAFLD can be partly explained by a metabolic component and partly by a genetic component. The mechanisms underlying these components are fundamentally different. The metabolic component is characterized by a substrate surplus and increased rates of adipose tissue lipolysis and hepatic DNL. The genetic component is characterized by increased hepatic mitochondrial redox state and inhibition of pathways dependent on TCA cycle activity, such as DNL. These components additively increase the severity of NAFLD.
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影响因子：
29.4
作者：
Lambert JE;Ramos-Roman MA;Browning JD;Parks EJ
通讯作者：
Parks EJ
影响因子：
25.7
作者：
SAIBARA, T;MAEDA, T;YAMAMOTO, Y
通讯作者：
YAMAMOTO, Y
影响因子：
6.7
作者：
Qadri, Sami;Lallukka-Bruck, Susanna;Yki-Jarvinen, Hannele
通讯作者：
Yki-Jarvinen, Hannele
影响因子：
29.4
作者：
Mancina RM;Dongiovanni P;Petta S;Pingitore P;Meroni M;Rametta R;Borén J;Montalcini T;Pujia A;Wiklund O;Hindy G;Spagnuolo R;Motta BM;Pipitone RM;Craxì A;Fargion S;Nobili V;Käkelä P;Kärjä V;Männistö V;Pihlajamäki J;Reilly DF;Castro-Perez J;Kozlitina J;Valenti L;Romeo S
通讯作者：
Romeo S
影响因子：
11.1
作者：
Dongiovanni P;Stender S;Pietrelli A;Mancina RM;Cespiati A;Petta S;Pelusi S;Pingitore P;Badiali S;Maggioni M;Mannisto V;Grimaudo S;Pipitone RM;Pihlajamaki J;Craxi A;Taube M;Carlsson LMS;Fargion S;Romeo S;Kozlitina J;Valenti L
通讯作者：
Valenti L