Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), 40225, Düsseldorf, Germany; Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany.
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), 40225, Düsseldorf, Germany.
Cell Metab. 2015 May 5;21(5):739-46. doi: 10.1016/j.cmet.2015.04.004.
The association of hepatic mitochondrial function with insulin resistance and non-alcoholic fatty liver (NAFL) or steatohepatitis (NASH) remains unclear. This study applied high-resolution respirometry to directly quantify mitochondrial respiration in liver biopsies of obese insulin-resistant humans without (n = 18) or with (n = 16) histologically proven NAFL or with NASH (n = 7) compared to lean individuals (n = 12). Despite similar mitochondrial content, obese humans with or without NAFL had 4.3- to 5.0-fold higher maximal respiration rates in isolated mitochondria than lean persons. NASH patients featured higher mitochondrial mass, but 31%-40% lower maximal respiration, which associated with greater hepatic insulin resistance, mitochondrial uncoupling, and leaking activity. In NASH, augmented hepatic oxidative stress (H2O2, lipid peroxides) and oxidative DNA damage (8-OH-deoxyguanosine) was paralleled by reduced anti-oxidant defense capacity and increased inflammatory response. These data suggest adaptation of the liver ("hepatic mitochondrial flexibility") at early stages of obesity-related insulin resistance, which is subsequently lost in NASH.
肝脏线粒体功能与胰岛素抵抗以及非酒精性脂肪性肝病（NAFL）或非酒精性脂肪性肝炎（NASH）的关系尚不清楚。本研究应用高分辨率呼吸测量法直接定量肥胖胰岛素抵抗人群肝活检组织中的线粒体呼吸，这些人群分为无组织学证实的 NAFL 或 NASH（n=18）、有 NAFL（n=16）和有 NASH（n=7），以及与之相对应的瘦人组（n=12）。尽管线粒体含量相似，但肥胖者无论是否有 NAFL，其分离的线粒体最大呼吸速率比瘦人高 4.3-5.0 倍。NASH 患者的线粒体质量更高，但最大呼吸速率低 31%-40%，这与肝胰岛素抵抗、线粒体解偶联和漏出现象增加有关。在 NASH 中，肝氧化应激（H2O2、脂质过氧化物）和氧化 DNA 损伤（8-OH-脱氧鸟苷）增加的同时，抗氧化防御能力降低和炎症反应增加。这些数据表明，在肥胖相关胰岛素抵抗的早期阶段，肝脏发生了适应性变化（“肝线粒体灵活性”），而在 NASH 中这种适应性会丧失。
