Peroxisome proliferator-activated receptor-α agonist, Wy 14 643, improves metabolic indices, steatosis and ballooning in diabetic mice with non-alcoholic steatohepatitis
Peroxisome proliferator-activated receptor-α agonist, Wy 14 643, improves metabolic indices, steatosis and ballooning in diabetic mice with non-alcoholic steatohepatitis
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DOI：
10.1111/j.1440-1746.2011.06939.x
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发表时间：
2012-02-01
影响因子：
4.1
通讯作者：
Farrell, Geoffrey C.
中科院分区：
文献类型：
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作者：
Larter, Claire Z.;Yeh, Matthew M.;Farrell, Geoffrey C.
背景和目的：在非酒精性脂肪性肝炎（NASH）中，脂质积累先于肝细胞损伤和肝脏炎症。过氧化物酶体增殖物激活受体（PPAR）a调节肝脏脂质处理。我们研究了在高脂肪（HF）喂养的foz/foz肥胖/糖尿病小鼠中，PPARa的药理刺激是否能逆转与代谢综合征相关的NASH。方法：雌性foz/foz小鼠和野生型（WT）仔鼠分别饲喂HF饲粮16周以引发NASH，然后用Wy 14 643 （Wy）治疗10天或20天。通过组织学、血清丙氨酸转氨酶、感兴趣的基因（实时聚合酶链反应）和蛋白质（Western blot、酶联免疫吸附测定）和促炎信号通路评估肝脏疾病。结果：在糖尿病foz/foz小鼠中，NASH与血清MCP1升高和肝核因子(NF)- κ B和c-Jun n -末端激酶的激活有关，但与氧化或内质网应激无关。Wy治疗减少了脂肪变性和损伤，尽管PPARa反应性脂肪酸氧化基因的诱导比例低于WT。PPARa激动剂降低了血清胰岛素，纠正了高血糖，抑制了碳水化合物依赖性脂肪生成转录因子，碳水化合物反应元件结合蛋白。脂肪变性的消退与NF-kB和JNK活化的抑制以及肝巨噬细胞和中性粒细胞的减少有关。尽管如此，组织学炎症评分仍然很高，与血清单核细胞趋化蛋白（MCP） 1升高有关，MCP1是一种促炎趋化因子，与较高的脂肪有关，而与肝脏MCP1 mRNA表达无关。结论：PPARa的药理激活可改善糖尿病相关NASH的代谢环境、脂肪变性、水肿，并对抗NF-kB和JNK激活、中性粒细胞和F4/80巨噬细胞募集。然而，由于未抑制的脂肪炎症导致的持续肝脏炎症伴高血清MCP1可能会限制PPARa激动剂作为NASH治疗的疗效。
Background and Aims: Lipid accumulation precedes hepatocellular injury and liver inflammation in non-alcoholic steatohepatitis (NASH). The peroxisome proliferator-activated receptor (PPAR)a regulates hepatic lipid disposal. We studied whether pharmacological stimulation of PPARa reverses NASH associated with metabolic syndrome in high-fat (HF)-fed foz/foz obese/diabetic mice. Methods: Female foz/foz mice and wildtype (WT) littermates were fed HF diet for 16 weeks to initiate NASH then treated withWy 14 643 (Wy) for 10 days or 20 days. Liver disease was assessed by histology, serum alanine aminotransferase, genes (real-time polymerase chain reaction) and proteins (Western blot, enzyme-linked immunosorbent assay) of interest and pro-inflammatory signaling pathways were determined. Results: In diabetic foz/foz mice, NASH was associated with elevated serum MCP1 and hepatic activation of nuclear factor (NF)-kappa B and c-Jun N-terminal kinase, but not oxidative or endoplasmic reticulum stress. Wy treatment decreased steatosis and injury, although induction of PPARa-responsive fatty acid oxidation genes was proportionally less than in WT. The PPARa agonist lowered serum insulin, corrected hyperglycemia, and suppressed the carbohydrate-dependent lipogenic transcription factor, carbohydrate response element binding protein. Steatosis resolution was associated with suppression of NF-kB and JNK activation and decreased hepatic macrophages and neutrophils. Despite this, histology inflammation score remained high, associated with serum monocyte chemoattractant protein (MCP) 1 elevation, a pro-inflammatory chemokine related to higher adipose, not liver MCP1 mRNA expression. Conclusions: Pharmacological activation of PPARa improves metabolic milieu, steatosis, ballooning, and combats NF-kB and JNK activation, neutrophil and F4/80 macrophage recruitment in diabetes-related NASH. However, persistent liver inflammation with high serum MCP1 due to unsuppressed adipose inflammation may limit PPARa agonists' efficacy as therapy for NASH.