Metabolic and Histological Implications of Intrahepatic Triglyceride Content in Nonalcoholic Fatty Liver Disease
Metabolic and Histological Implications of Intrahepatic Triglyceride Content in Nonalcoholic Fatty Liver Disease
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DOI：
10.1002/hep.28985
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发表时间：
2017-04-01
期刊：
影响因子：
13.5
通讯作者：
Cusi, Kenneth
中科院分区：
文献类型：
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作者：
Bril, Fernando;Barb, Diana;Cusi, Kenneth
基于一组健康个体的第95百分位数（即，>= 5.56%）。该阈值是否与代谢和组织学变化相关，以及IHTG的进一步蓄积是否与这些参数的恶化相关，尚未在大型患者队列中进行适当评估。在这项横断面研究中，352名受试者通过以下研究进行了仔细的表征：肝脏（HMRS）-H-1;正常血糖胰岛素钳夹法测量葡萄糖周转;口服葡萄糖耐量试验;和肝脏活检。肝脏胰岛素敏感性（胰岛素抑制内源性葡萄糖生成）在IHTG含量接近1.5%后早期受到影响，并保持一致受损（接近40%-45%），无论IHTG是否进一步蓄积。骨骼肌胰岛素敏感性在低程度的IHTG积累时表现出逐渐损害，但在IHTG含量达到类似于6 +/- 2%阈值后保持不变。与NAFLD典型相关的代谢变化，如高脂血症和低高密度脂蛋白胆固醇（HDL-C），也观察到类似的模式。相比之下，脂肪组织胰岛素敏感性（胰岛素抑制游离脂肪酸）显示在NAFLD的IHTG积累谱中持续恶化（r = -0.38; P < 0.001）。肝脏疾病的组织学严重程度（炎症、气球样变和纤维化）与IHTG含量无关。结论：IHTG蓄积与脂肪组织胰岛素抵抗（IR）密切相关，支持目前的脂毒性理论作为IHTG蓄积的驱动因素。一旦IHTG蓄积达到6 +/-2%，骨骼肌IR、高甘油三酯血症和低HDL-C将完全确立。组织学活动似乎有一个早期阈值，并没有显着影响IHTG积累量的增加。
The cut-off point of intrahepatic triglyceride (IHTG) content to define nonalcoholic fatty liver disease (NAFLD) by proton magnetic resonance spectroscopy (H-1-MRS) was established based on the 95th percentile in a group of healthy individuals (i.e., >= 5.56%). Whether this threshold correlates with metabolic and histological changes and whether a further accumulation of IHTG is associated with worsening of these parameters has not been properly assessed in a large cohort of patients. In this cross-sectional study, 352 subjects were carefully characterized with the following studies: liver (HMRS)-H-1; euglycemic insulin clamp with measurement of glucose turnover; oral glucose tolerance test; and a liver biopsy. Hepatic insulin sensitivity (suppression of endogenous glucose production by insulin) was affected early on after IHTG content was similar to 1.5% and remained uniformly impaired (similar to 40%-45%), regardless of further IHTG accumulation. Skeletal muscle insulin sensitivity showed a gradual impairment at low degrees of IHTG accumulation, but remained unchanged after IHTG content reached the similar to 6 +/- 2% threshold. A similar pattern was observed for metabolic changes typically associated with NAFLD, such as hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C). In contrast, adipose tissue insulin sensitivity (suppression of free fatty acids by insulin) showed a continuous worsening across the spectrum of IHTG accumulation in NAFLD (r = -0.38; P < 0.001). Histological severity of liver disease (inflammation, ballooning, and fibrosis) was not associated with the amount of IHTG content. Conclusion: IHTG accumulation is strongly associated with adipose tissue insulin resistance (IR), supporting the current theory of lipotoxicity as a driver of IHTG accumulation. Once IHTG accumulation reaches similar to 6 +/- 2%, skeletal muscle IR, hypertriglyceridemia, and low HDL-C become fully established. Histological activity appears to have an early threshold and is not significantly influenced by increasing amounts of IHTG accumulation.