Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan.
Sci Rep. 2022 Jan 10;12(1):449. doi: 10.1038/s41598-021-04036-7.
Therapeutic approach for NAFLD is limited and there are no approved drugs. Pioglitazone (PGZ), a thiazolidinedione (TZD) that acts via peroxisome proliferator activated receptor gamma (PPARγ) is the only agent that has shown consistent benefit and efficacy in clinical trials. However, the mechanism of its therapeutic effect on NAFLD remains unclear. The poor understanding may be due to problems with mouse, a species most used for animal experiments. TZDs exacerbate fatty liver in mouse models while they improve it in rat models like in human patients. Therefore, we compared the effects of TZDs including PGZ and rosiglitazone (RGZ) in ob/ob mice and Lep/Lep rats, models of leptin-deficient obesity, and A-ZIP/F-1 mice and seipin knockout (SKO) rats, models of generalized lipodystrophy. Pparg mRNA expression was markedly upregulated in fatty livers of mouse models while it was unchanged in rat models. TZDs exacerbated fatty liver in ob/ob and A-ZIP/F-1 mice, improved it in Lep/Lep rats and showed no effect in SKO rats. Gene expression analyses of Pparg and its target gene, Fsp27 revealed that PPARγ in the adipose tissue is the exclusive therapeutic target of TZDs in rats but PPARγ in the liver in addition to the adipose tissue is also a major site of actions for TZDs in mice. Although the response to TZDs in mice is the complete opposite of that in human patients, no report has pointed out the problem with TZD studies using mouse models so far. The present study might provide useful suggestions in research on TZDs.
NAFLD 的治疗方法有限，目前尚无获批的药物。吡格列酮（PGZ）是一种噻唑烷二酮（TZD），通过过氧化物酶体增殖物激活受体γ（PPARγ）发挥作用，是唯一在临床试验中显示出一致疗效的药物。然而，其治疗 NAFLD 的机制尚不清楚。这种治疗效果的机制理解不充分可能是由于在大多数动物实验中使用的物种——小鼠存在问题。TZD 在肥胖症模型小鼠中会加重脂肪肝，而在类似人类患者的肥胖症模型大鼠中则会改善脂肪肝。因此，我们比较了包括 PGZ 和罗格列酮（RGZ）在内的 TZD 在肥胖症模型小鼠（ob/ob 小鼠）和瘦素缺乏肥胖症模型大鼠（Lep/Lep 大鼠），以及全身性脂肪营养不良模型小鼠（A-ZIP/F-1 小鼠）和脂肪营养不良模型大鼠（seipin 敲除 SKO 大鼠）中的作用。在肥胖症模型小鼠的脂肪肝中，Pparg mRNA 表达明显上调，而在肥胖症模型大鼠中则保持不变。TZD 在 ob/ob 和 A-ZIP/F-1 小鼠中加重了脂肪肝，在 Lep/Lep 大鼠中改善了脂肪肝，在 SKO 大鼠中则没有影响。Pparg 和其靶基因 Fsp27 的基因表达分析表明，TZD 在大鼠脂肪组织中是 PPARγ 的唯一治疗靶点，但 PPARγ 在肝脏中除了脂肪组织之外，也是 TZD 在小鼠中的主要作用部位。尽管 TZD 在小鼠中的反应与人类患者完全相反，但迄今为止，尚无关于使用小鼠模型进行 TZD 研究的报告指出了这一问题。本研究可能为 TZD 的研究提供有用的建议。
