Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium.
Department of Abdominal Surgery, University Hospitals KU Leuven, Leuven, Belgium.
Gut. 2015 Apr;64(4):673-83. doi: 10.1136/gutjnl-2014-306748. Epub 2014 Jun 10.
No therapy for non-alcoholic steatohepatitis (NASH) has been approved so far. Roux-en-y gastric bypass (RYGB) is emerging as a therapeutic option, although its effect on NASH and related hepatic molecular pathways is unclear from human studies. We studied the effect of RYGB on pre-existent NASH and hepatic mitochondrial dysfunction-a key player in NASH pathogenesis-in a novel diet-induced mouse model nicely mimicking human disease.
C57BL/6J mice were fed a high-fat high-sucrose diet (HF-HSD).
HF-HSD led to early obesity, insulin resistance and hypercholesterolaemia. HF-HSD consistently induced NASH (steatosis, hepatocyte ballooning and inflammation) with fibrosis already after 12-week feeding. NASH was accompanied by hepatic mitochondrial dysfunction, characterised by decreased mitochondrial respiratory chain (MRC) complex I and IV activity, ATP depletion, ultrastructural abnormalities, together with higher 4-hydroxynonenal (HNE) levels, increased uncoupling protein 2 (UCP2) and tumour necrosis factor-α (TNF-α) mRNA and free cholesterol accumulation. In our model of NASH and acquired mitochondrial dysfunction, RYGB induced sustained weight loss, improved insulin resistance and inhibited progression of NASH, with a marked reversal of fibrosis. In parallel, RYGB preserved hepatic MRC complex I activity, restored ATP levels, limited HNE production and decreased TNF-α mRNA.
Progression of NASH and NASH-related hepatic mitochondrial dysfunction can be prevented by RYGB. RYGB preserves respiratory chain complex activity, thereby restoring energy output, probably by limiting the amount of oxidative stress and TNF-α. These data suggest that modulation of hepatic mitochondrial function contributes to the favourable effect of RYBG on established NASH.
目前尚无治疗非酒精性脂肪性肝炎（NASH）的方法。Roux-en-y 胃旁路手术（RYGB）作为一种治疗选择正在出现，尽管其对 NASH 和相关肝分子途径的影响尚不清楚。我们在一种新的、模拟人类疾病的饮食诱导的小鼠模型中，研究了 RYGB 对预先存在的 NASH 和肝线粒体功能障碍（NASH 发病机制中的关键因素）的影响。
C57BL/6J 小鼠喂食高脂肪高蔗糖饮食（HF-HSD）。
HF-HSD 导致早期肥胖、胰岛素抵抗和高胆固醇血症。HF-HSD 持续诱导 NASH（脂肪变性、肝细胞气球样变和炎症），在 12 周喂养后即可发生纤维化。NASH 伴有肝线粒体功能障碍，表现为线粒体呼吸链（MRC）复合物 I 和 IV 活性降低、ATP 耗竭、超微结构异常，同时伴有更高的 4-羟基壬烯醛（HNE）水平、解偶联蛋白 2（UCP2）和肿瘤坏死因子-α（TNF-α）mRNA 增加以及游离胆固醇堆积。在我们的 NASH 和获得性线粒体功能障碍模型中，RYGB 诱导持续的体重减轻、改善胰岛素抵抗和抑制 NASH 的进展，显著逆转纤维化。同时，RYGB 维持肝 MRC 复合物 I 活性，恢复 ATP 水平，限制 HNE 产生并降低 TNF-α mRNA。
RYGB 可预防 NASH 的进展和 NASH 相关的肝线粒体功能障碍。RYGB 维持呼吸链复合物活性，从而恢复能量输出，可能通过限制氧化应激和 TNF-α 的量来实现。这些数据表明，肝线粒体功能的调节有助于 RYGB 对已建立的 NASH 的有利影响。
