Int J Biol Sci 2021; 17(15):4459-4473. doi:10.7150/ijbs.65485 This issue

Research Paper

miRNA-223 Suppresses Mouse Gallstone Formation by Targeting Key Transporters in Hepatobiliary Cholesterol Secretion Pathway

Feng Zhao1✉, Shiyu Ma1, Yuling Zhou2, Bailing Wei1, Zhen Hao1, Xiaolin Cui1, Lina Xing1, Gang Liu1, Lingling Jin1, Tonghui Ma1✉, Lei Shi1✉

1. College of Basic Medical Sciences, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, China.
2. Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, 361004, China.

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Citation:
Zhao F, Ma S, Zhou Y, Wei B, Hao Z, Cui X, Xing L, Liu G, Jin L, Ma T, Shi L. miRNA-223 Suppresses Mouse Gallstone Formation by Targeting Key Transporters in Hepatobiliary Cholesterol Secretion Pathway. Int J Biol Sci 2021; 17(15):4459-4473. doi:10.7150/ijbs.65485. Available from https://www.ijbs.com/v17p4459.htm

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Abstract

Graphic abstract

miRNA-223 has been previously reported to play an essential role in hepatic cholesterol homeostasis. However, its role in regulation of biliary cholesterol secretion and gallstone formation remains unknown. Hence, mice with conventional knockout (KO), hepatocyte-specific knockout (ΔHepa) / knockdown (KD) or gain expression of miRNA-223 were included in the study and were subjected to lithogenic diet (LD) for various weeks. The gall bladders and liver tissues were harvested for cholesterol crystal imaging, gallstone mass measurement and molecular analysis. Levels of cholesterol, bile salt, phospholipids, and triglyceride were determined in serum, liver tissues, and bile by enzyme color reactive assays. A 3' UTR reporter gene assay was used to verify the direct target genes for miRNA-223. LD-induced gallstone formation was remarkably accelerated in miRNA-223 KO, ΔHepa, and KD mice with concurrent enhancement in total cholesterol levels in liver tissues and bile. Key biliary cholesterol transporters ABCG5 and ABCG8 were identified as direct targets of miRNA-223. Reversely, AAV-mediated hepatocyte-specific miRNA-223 overexpression prevented gallstone progression with reduced targets expression. Therefore, the present study demonstrates a novel role of miRNA-223 in the gallstone formation by targeting ABCG5 and ABCG8 and elevating miRNA-223 would be a potentially novel approach to overcome the sternness of cholesterol gallstone disease.

Keywords: miRNA-223, gallstone, ABCG5 and ABCG8