Division of Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Hepatology. 2011 Nov;54(5):1600-9. doi: 10.1002/hep.24553. Epub 2011 Jul 27.
In humans with nonalcoholic fatty liver, diabetes is associated with more advanced disease. We have previously shown that diabetic db/db mice are highly susceptible to methionine choline-deficient diet (MCD)-induced hepatic injury. Because activation of the unfolded protein response (UPR) is an important adaptive cellular mechanism in diabetes, obesity, and fatty liver, we hypothesized that dysregulation of the UPR may partially explain how diabetes could promote liver injury. Db/db and db/m mice were fed the MCD or control diet for 4 weeks to characterize differences in UPR activation and downstream injury. Wildtype mice (C57BLKS/J) fed the MCD or control diet were treated with SP600125; a c-Jun N-terminal kinase (JNK) inhibitor and its effect on liver injury and UPR activation was measured. The MCD diet resulted in global up-regulation of the UPR in both diabetic db/db and nondiabetic db/m mice. db/db mice had an inadequate activation of recovery pathways (GADD34, XBP-1(s)) and accentuated activation of injury pathways related to persistent eif2-α phosphorylation (activating transcription factor 4 [ATF-4], C/EBP homologous transcription factor [CHOP], oxireductase endoplasmic reticulum oxidoreductin-1 [ERO-1α], JNK, nuclear factor kappaB [NF-κB]) compared to db/m mice. This led to increased expression of inflammatory mediators such as tumor necrosis factor alpha (TNF-α), ICAM-1, and MCP-1 compared to db/m mice. Interestingly, whereas pharmacologic JNK inhibition did not prevent the development of MCD diet-induced steatohepatitis, it did attenuate UPR and downstream inflammatory signaling.
MCD-fed db/db mice develop a more proinflammatory milieu than db/m mice associated with an impaired ability to dephosphorylate eif2-α through GADD34, impairing cellular recovery. These data may enhance our understanding of why diabetics with nonalcoholic steatohepatitis are prone to develop more severe liver injury than nondiabetic patients.
在非酒精性脂肪肝患者中，糖尿病与更严重的疾病有关。我们之前已经表明，糖尿病 db/db 小鼠对蛋氨酸胆碱缺乏饮食（MCD）诱导的肝损伤高度敏感。由于未折叠蛋白反应（UPR）的激活是糖尿病、肥胖和脂肪肝中重要的适应性细胞机制，我们假设 UPR 的失调可能部分解释了糖尿病如何促进肝损伤。db/db 和 db/m 小鼠喂食 MCD 或对照饮食 4 周，以表征 UPR 激活和下游损伤的差异。喂食 MCD 或对照饮食的野生型小鼠（C57BLKS/J）用 SP600125 处理；一种 c-Jun N-末端激酶（JNK）抑制剂，测量其对肝损伤和 UPR 激活的影响。MCD 饮食导致糖尿病 db/db 和非糖尿病 db/m 小鼠的 UPR 全面上调。db/db 小鼠恢复途径（GADD34、XBP-1（s））的激活不足，与持续 eif2-α磷酸化相关的损伤途径（激活转录因子 4 [ATF-4]、C/EBP 同源转录因子 [CHOP]、氧化还原酶内质网氧化还原酶 1 [ERO-1α]、JNK、核因子 kappaB [NF-κB]）的激活加重与 db/m 小鼠相比。这导致炎症介质如肿瘤坏死因子-α（TNF-α）、ICAM-1 和 MCP-1 的表达增加与 db/m 小鼠相比。有趣的是，虽然药理 JNK 抑制不能预防 MCD 饮食诱导的脂肪性肝炎的发生，但它确实减弱了 UPR 和下游炎症信号。
与 db/m 小鼠相比，喂食 MCD 的 db/db 小鼠发展出更具促炎环境，与通过 GADD34 去磷酸化 eif2-α的能力受损有关，从而损害细胞恢复。这些数据可能增强我们对为什么非酒精性脂肪性肝炎的糖尿病患者比非糖尿病患者更容易发生更严重肝损伤的理解。
