[Effect of targeted inhibition of hypoxia-inducible factor-1α by 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole on the progression of non-alcoholic fatty liver disease in rats].

ABSTRACT

Objective: To investigate the effect of targeted inhibition of hypoxia-inducible factor-1α (HIF-1α) by 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) on the progression of non-alcoholic fat liver diseases (NAFLD) in rats. Methods: A total of 72 male Sprague-Dawley rats were randomly divided into normal group, model group, and intervention group, and the rats were given high-fat feed to establish the rat model of fatty liver disease. After the establishment of the model, the rats in the intervention group were given intraperitoneally injected YC-1 (at a dose of 2 mg/kg) every two weeks and were observed at 4, 8, 12, and 16 weeks. Blood samples and liver tissues were collected after the end of intervention, and blood lipid, biochemical markers for liver function, fasting blood glucose, and insulin were measured. Histopathological examinations were performed, and insulin resistance index was calculated. Real-time PCR was used to measure the mRNA transcriptional levels of HIF-1α, peroxisome proliferator-activated receptor α, and nuclear factor-kappa B (NF-κB), and Western blot was used to measure their protein expression levels. An analysis of variance with group design and the Kruskal-Wallis H test were used for comparison of continuous data between multiple groups, and the least significant difference method was used for comparison between any two groups. P <0.05 was considered statistically significant. Results: Compared with the model group, the intervention group had significant reductions in the serum levels of alanine aminotransferase, aspartate aminotransferase, triglyceride, and total cholesterol after 12 weeks of continuous administration (P < 0.05); after 8 weeks of continuous injection of YC-1, the intervention group had significant alleviation in hepatic steatosis and significant improvement in inflammation degree (P < 0.05), and after 12 weeks of continuous injection of YC-1, the intervention group had a significant reduction in liver fibrosis degree (P < 0.05); after 12 and 16 weeks of continuous administration, the intervention group had a significant increase in the mRNA expression of peroxisome proliferator-activated receptor α and a significant reduction in the mRNA expression of NF-κB. The protein expression of HIF-1α, peroxisome proliferator-activated receptor α, and NF-κB in fatty liver tissues at different time points showed similar results as the mRNA expression. There were no significant differences in insulin resistance index at each time point between the model group and the intervention group. Conclusion: Targeted inhibition of YC-1 can effectively delay the progression of experimental fatty liver disease and improve lipid metabolism, but it has no significant effect on insulin resistance.