KLF4-circADAMTS17-HO-1轴的抑制在糖尿病肝损伤中的作用研究

Oxidative stress is a major mechanism for diabetic liver injury. The transcription factor KLF4 has antioxidant effects, but the relationship between KLF4 and diabetic liver oxidative stress remains to be determined. The applicant's preliminary data found that 1) the decreased expression of KLF4 is along with the down-regulated expression of HO-1, an antioxidant enzyme and the rise of ROS levels in the liver of rats with type 2 diabetes mellitus induced by high-fat and high-sugar diet combined low dose of STZ; 2) Unlike KLF4 as a transcription factor, overexpression of KLF4 significantly increases HO-1 protein expression without affecting its mRNA expression; 3) KLF4 dramatically promotes the expression of circADAMTS17, a circular RNA and circADAMTS17 obviously induces HO-1 protein expression. We hypothesize that the decreased expression of KLF4 contributes to the reduction of circADAMTS17 and subsequent down-regulation of HO-1, thereby aggravating oxidative stress and eventually leading to liver injury. To test this hypothesis, we are going to study the antioxidant mechanism of KLF4 and its relationship with diabetic liver injury, and the results will contribute to the development of new treatment strategies for diabetic liver injury.

氧化应激是导致2型糖尿病肝损伤的重要机制。转录因子KLF4参与机体的抗氧化，但KLF4与糖尿病肝脏氧化应激的关系仍不清楚。我们前期发现：1）高糖高脂饮食联合STZ诱导的2型糖尿病大鼠肝脏中，KLF4表达降低的同时，伴随着抗氧化酶HO-1的下调和ROS的升高；2）与KLF4作为转录因子的作用不同，过表达KLF4明显上调HO-1的蛋白表达，却不影响其mRNA的表达；3）KLF4显著促进环状RNA circADAMTS17的表达，而过表达circADAMTS17明显上调HO-1的蛋白表达。基于以上结果，我们提出糖尿病肝损伤的新机制，即：糖尿病状态下，由于肝脏KLF4的表达降低，使得circADAMTS17的形成减少，进而HO-1的表达下调，从而加重肝脏的氧化应激，最终发展为肝损伤。本项目将对KLF4的抗氧化机制及其与糖尿病肝损伤的关系进行研究，研究结果将有助于糖尿病肝损伤的新治疗策略的发展。

氧化应激是导致2型糖尿病肝损伤的重要机制。转录因子KLF4参与机体的抗氧化，但KLF4与糖尿病肝脏氧化应激的关系仍不清楚。本项目在前期结果的基础上，运用生物信息学、分子生物学、形态学检测方法，采用高糖高脂饮食联合STZ诱导的2型糖尿病大鼠和软脂酸或油酸诱导的肝细胞损伤模型为研究对象，重点探讨了KLF4与糖尿病肝损伤的关系及其机制，结果发现，糖尿病状态下，降低的KLF4可能通过三种机制促进肝脏损伤：1）抑制抗氧化酶HO-1的表达，引起肝脏氧化应激；2）抑制过氧化物酶体重要的酶DBP的表达，导致肝脏糖脂代谢失衡；3）抑制线粒体重要的酶CPT1a的表达，抑制脂质代谢，导致肝脏脂质沉积。这些结果表明KLF4的降低是糖尿病肝损伤中的重要环节，本研究不仅为了解糖尿病肝损伤的机制提供了直接科学依据，而且为以KLF4为靶点的糖尿病肝损伤的防治策略的提出提供了有力证据。