Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities
Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities
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DOI：
10.1053/gast.2001.23256
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发表时间：
2001-04-01
期刊：
影响因子：
29.4
通讯作者：
Clore, JN
中科院分区：
文献类型：
--
作者：
Sanyal, AJ;Campbell-Sargent, C;Clore, JN
背景与目的：非酒精性脂肪性肝炎（NASH）的发病机制尚不清楚。我们检验了NASH与2种缺陷相关的假设：（1）外周胰岛素抵抗，其增加脂解、游离脂肪酸（FFA）向肝脏的递送和肝脂肪酸β氧化，从而产生氧化应激;和（2）肝细胞内的异常，其可能使肝细胞更容易受到氧化应激的损伤。方法：通过评价（1）胰岛素抵抗（2步高胰岛素血症（10和40 mU））来检验假设。m（-2）min（-1））正葡萄糖钳夹;（2）胰岛素通过[U-C-13]甘油富集对脂解的影响;（3）体内肝细胞线粒体结构缺陷的频率和严重程度;（4）来自血清IF-OH丁酸盐的脂肪酸β氧化，培养的成纤维细胞从H-3-棕榈酸盐释放水溶性放射性和尿二羧酸排泄;（5）9-硝基酪氨酸（3-NT）免疫组化染色观察肝脏脂质过氧化反应。NASH受试者结果：HASH和脂肪肝均与胰岛素抵抗相关，平均葡萄糖输注率（GLU）均高于正常对照组（P < 0. 05）。（正常/脂肪肝/NASH）第1步为4.5/1，6/0.9;第2步为9.5/7.7/4.5（两步均P < 0.03）。尽管NASH患者甘油出现的基线率高于脂肪肝患者（平均值分别为14.6和21.6 μ mol . kg（-l）。min（-1）; P < 0.05），在10 mU m-2 min-1的胰岛素输注速率下，两组均未显著抑制甘油的出现。NASH与10例受试者中9例的线粒体嵴和次晶包涵体丢失相关，而6例脂肪肝受试者中0例。然而，在任何组中均未发现脂肪酸P氧化普遍缺陷的证据。此外，平均[β-OH丁酸]在NASH患者中最高（平均值，90 vs. 110 vs. 160 μ mol/L; P <0.04）。脂肪肝中3-NT染色增加，NASH中染色更强。结论：这些数据表明，外周胰岛素抵抗，增加脂肪酸P氧化，和肝氧化应激存在于脂肪肝和NASH，但HASH单独与线粒体结构缺陷。
Background & Aims: The pathogenesis of nonalcoholic steatohepatitis (NASH) is unknown. We tested the hypothesis that NASH is associated with 2 defects: (1) peripheral insulin resistance, which increases lipolysis, delivery of free fatty acids (FFA) to the liver, and hepatic fatty acid beta oxidation, thereby creating oxidative stress; and (2) an abnormality within the hepatocytes that might render them more susceptible to injury from oxidative stress. Methods: The hypothesis was tested by evaluation of (1) insulin resistance by a 2-step hyperinsulinemic (10 and 40 mU . m(-2) min(-1)) euglycemic clamp; (2) insulin effects on lipolysis by enrichment of [U-C-13]glycerol; (3) frequency and severity of structural defects in hepatocyte mitochondria in vivo; (4) fatty acid beta oxidation from serum IF-OH butyrate], release of water-soluble radioactivity from H-3-palmitate by cultured fibroblasts and urinary dicarboxylic acid excretion; and (5) hepatic lipid peroxidation by immunohistochemical staining for 9-nitrotyrosine (3-NT). Subjects with NASH (n = 6-10 for different studies) were compared with those with fatty liver (n = 6) or normal controls (n = 6), Results: HASH and fatty liver were both associated with insulin resistance, with mean glucose infusion rates (normal/fatty liver/NASH) of step 1, 4.5/1,6/0.9; step 2, 9.5/7.7/4.5 (P < 0.03 for both steps). Although baseline rates of glycerol appearance were higher in those with NASH than in those with fatty liver (means, 14.6 vs. 21.6 mu mol . kg(-l) . min(-1); P < 0.05), neither group significantly suppressed glycerol appearance at insulin infusion rates of 10 mU m-2 min-l. NASH was associated with loss of mitochondrial cristae and paracrystalline inclusions in 9 of 10 subjects, compared with 0 of 6 subjects with fatty liver. However, no evidence of a generalized defect in fatty acid P oxidation was noted in any group. Also, mean [beta-OH butyrate] was highest in those with NASH (means, 90 vs. 110 vs. 160 mu mol/L; P < 0,04). Increased staining for 3-NT was present in fatty liver, and even greater staining was seen in NASH. Conclusions: These data indicate that peripheral insulin resistance, increased fatty acid P oxidation, and hepatic oxidative stress are present in both fatty liver and NASH, but HASH alone is associated with mitochondrial structural defects.