Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University.
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University.
Biol Pharm Bull. 2024;47(5):886-894. doi: 10.1248/bpb.b23-00837.
The number of patients with lifestyle-related diseases such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), has continued to increase worldwide. Therefore, development of innovative therapeutic methods targeting lifestyle-related diseases is required. Gene therapy has attracted considerable attention as an advanced medical treatment. Safe and high-performance vectors are essential for the practical application of gene therapy. Replication-incompetent adenovirus (Ad) vectors are widely used in clinical gene therapy and basic research. Here, we developed a novel Ad vector, named Ad-E4-122aT, exhibiting higher and longer-term transgene expression and lower hepatotoxicity than conventional Ad vectors. We also elucidated the mechanisms underlying Ad vector-induced hepatotoxicity during the early phase using Ad-E4-122aT. Next, we examined the therapeutic effects of the genes of interest, namely zinc finger AN1-type domain 3 (ZFAND3), lipoprotein lipase (LPL), and lysophospholipid acyltransferase 10 (LPLAT10), on lifestyle-related diseases using Ad-E4-122aT. We showed that the overexpression of ZFAND3 in the liver improved glucose tolerance and insulin resistance. Liver-specific LPL overexpression suppressed hepatic lipid accumulation and improved glucose metabolism. LPLAT10 overexpression in the liver suppressed postprandial hyperglycemia by increasing glucose-stimulated insulin secretion. Furthermore, we also focused on foods to advance research on the pathophysiology and treatment of lifestyle-related diseases. Cranberry and calamondin, which are promising functional foods, attenuated the progression of MASLD/NAFLD. Our findings will aid the development of new therapeutic methods, including gene therapy, for lifestyle-related diseases such as T2DM and MASLD/NAFLD.
全球范围内，2 型糖尿病（T2DM）和代谢相关脂肪性肝病（MASLD）等生活方式相关疾病患者的数量持续增加，MASLD 以前被称为非酒精性脂肪性肝病（NAFLD）。因此，需要开发针对生活方式相关疾病的创新治疗方法。基因治疗作为一种先进的医疗方法受到了广泛关注。安全且高性能的载体对于基因治疗的实际应用至关重要。复制缺陷型腺病毒（Ad）载体在临床基因治疗和基础研究中得到了广泛应用。在这里，我们开发了一种新型 Ad 载体，命名为 Ad-E4-122aT，与传统的 Ad 载体相比，它具有更高和更持久的转基因表达和更低的肝毒性。我们还利用 Ad-E4-122aT 阐明了 Ad 载体诱导早期肝毒性的机制。接下来，我们使用 Ad-E4-122aT 检查了锌指 AN1 型结构域 3（ZFAND3）、脂蛋白脂肪酶（LPL）和溶血磷脂酰基转移酶 10（LPLAT10）等感兴趣基因对生活方式相关疾病的治疗效果。我们表明，肝脏中 ZFAND3 的过表达改善了葡萄糖耐量和胰岛素抵抗。肝特异性 LPL 过表达抑制了肝内脂质积累并改善了葡萄糖代谢。肝脏中 LPLAT10 的过表达通过增加葡萄糖刺激的胰岛素分泌来抑制餐后高血糖。此外，我们还关注食物，以推进生活方式相关疾病的病理生理学和治疗研究。蔓越莓和椪柑作为有前途的功能性食品，可减轻 MASLD/NAFLD 的进展。我们的研究结果将有助于开发针对 T2DM 和 MASLD/NAFLD 等生活方式相关疾病的新治疗方法，包括基因治疗。
