Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Anhui Medical University, Hefei, China.
Department of Pharmacy, the Second Affiliated Hospital of Anhui Medical University, China.
Biomed Pharmacother. 2024 Sep;178:117184. doi: 10.1016/j.biopha.2024.117184. Epub 2024 Aug 13.
A two-way relationship exists between type 2 diabetes (T2DM) and human nonalcoholic steatohepatitis (NASH). Several diabetic NASH models have the disadvantages of long cycles or inconsistent with the actual incidence of human disease, which would be costly and time-consuming to investigate disease pathogenesis and develop drugs. Therefore, there is an urgent need to establish a diabetic NASH mouse model.
The combination between Fructose-palmitate-cholesterol diet (FPC) and Streptozotocin (STZ) (FPC+STZ) was used to construct diabetic NASH mouse model. The in vivo effects of silencing acid-sensitive Ion Channel 1a (ASIC1a) were examined with an adeno-associated virus 9 (AAV9) carrying ASIC1a short hairpin RNA (shRNA) in FPC+STZ model.
The mice fed with FPC for 12 weeks had insulin resistance, hyperinsulinemia, lipid accumulation, and increased hepatic levels of inflammatory factors. However, it still did not develop remarkable liver fibrosis. Most interestingly, noticeable fibrotic scars were observed in the liver of mice from FPC+STZ group. Furthermore, insulin therapy significantly ameliorated FPC+STZ-induced NASH-related liver fibrosis, indicating that hyperglycemia is of great significance in NASH development and progression. Importantly, ASIC1a was found to be involved in the pathogenesis of diabetic NASH as demonstrated that silencing ASIC1a in HSCs significantly ameliorated FPC+STZ-induced NASH fibrosis. Mechanistically, ASIC1a interacted with Poly Adp-adenosine ribose polymerase (PARP1) to promote HSC activation by inducing autophagy.
A FPC diet combined with an injection of STZ induces a diabetic NASH mouse model in a shorter period. Targeting ASIC1a may provide a novel therapeutic target for the treatment of diabetic NASH.
2 型糖尿病（T2DM）和人类非酒精性脂肪性肝炎（NASH）之间存在双向关系。几种糖尿病性 NASH 模型存在周期长或与人类疾病实际发病率不一致的缺点，研究疾病发病机制和开发药物既昂贵又耗时。因此，迫切需要建立糖尿病性 NASH 小鼠模型。
采用果糖-棕榈酸-胆固醇饮食（FPC）联合链脲佐菌素（STZ）（FPC+STZ）构建糖尿病性 NASH 小鼠模型。利用携带 ASIC1a 短发夹 RNA（shRNA）的腺相关病毒 9（AAV9）在 FPC+STZ 模型中检测沉默酸敏感离子通道 1a（ASIC1a）的体内作用。
12 周 FPC 喂养的小鼠出现胰岛素抵抗、高胰岛素血症、脂质堆积和肝内炎症因子水平升高，但仍未出现明显的肝纤维化。最有趣的是，FPC+STZ 组小鼠肝脏可见明显的纤维瘢痕。此外，胰岛素治疗显著改善了 FPC+STZ 诱导的 NASH 相关肝纤维化，表明高血糖在 NASH 的发生和进展中具有重要意义。重要的是，ASIC1a 参与了糖尿病性 NASH 的发病机制，沉默 HSCs 中的 ASIC1a 可显著改善 FPC+STZ 诱导的 NASH 纤维化。机制上，ASIC1a 通过诱导自噬与多聚腺苷二磷酸核糖聚合酶（PARP1）相互作用，促进 HSC 激活。
FPC 饮食联合 STZ 注射可在更短的时间内诱导糖尿病性 NASH 小鼠模型。靶向 ASIC1a 可能为治疗糖尿病性 NASH 提供新的治疗靶点。
