Heterozygous Disruption of Beclin 1 Alleviates Zinc Oxide Nanoparticles-Induced Disturbance of Cholesterol Biosynthesis in Mouse Liver

Abstract

Purpose

Liver is regarded as one of the primary target organs for zinc oxide nanoparticles (ZnONPs) toxicity. Since liver represents the leading site for de novo cholesterol biosynthesis in mammals, the injuries of liver could result in the disruption of cholesterol biosynthesis. In this study, we aimed to investigate whether pulmonary ZnONPs exposure induces disturbance of cholesterol biosynthesis in mouse liver.

Methods and results

Our data demonstrated intratracheally instilled with a single dose of 3, 6, and 12 μg/animal ZnONPs could induce histopathological deterioration in mouse liver in a dose-related manner at 3 days, but remission was observed at 7 days after treatment. Moreover, ZnONPs caused the disturbance of cholesterol biosynthesis by increasing both 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and sterol regulatory element-binding protein 2 (SREBP2) protein expressions. To further reveal the underlying toxic mechanisms, we detected the biomarkers of autophagy and found that pulmonary ZnONPs exposure led to the elevation of LC3B-II and Beclin 1, suggesting ZnONPs might trigger autophagy in liver tissues. By using both beclin 1^+/+ and beclin 1^+/- mice, we demonstrated that inhibition of autophagy by heterozygous disruption of beclin 1 attenuated the disturbance of cholesterol biosynthesis induced by ZnONPs in liver.

Conclusion

Pulmonary exposure of ZnONPs would induce the cholesterol biosynthesis disturbance in mouse liver through Beclin-1-dependent autophagy activation, suggesting that inhibition of autophagy may contribute to preventing the cholesterol biosynthesis disturbance and its associated pathologies induced by ZnONPs in liver.

Keywords:

• zinc oxide nanoparticles
• cholesterol biosynthesis
• autophagy
• beclin 1
• liver

Acknowledgments

This research was partially supported by National Science Foundation of China (81602820, 81703187, 81903358), Foundation and Frontier Research Program of Chongqing Municipal Science and Technology Commission (cstc2017jcyjAX0162), and the Science and Technology Research Program of Chongqing Municipal Education Commission (KJQN201800434, KJQN201900418, KJQN201900419, KJQN201900421).

Disclosure

The authors report no conflicts of interest in this work.