当前位置: X-MOL 学术Cell. Mol. Gastroenterol. Hepatol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
A mitochondrial DNA variant elevates the risk of gallstone disease by altering mitochondrial function
Cellular and Molecular Gastroenterology and Hepatology ( IF 7.1 ) Pub Date : 2020-12-04 , DOI: 10.1016/j.jcmgh.2020.11.015
Dayan Sun 1 , Zhenmin Niu 2 , Hong-Xiang Zheng 3 , Fei Wu 4 , Liuyiqi Jiang 4 , Tian-Quan Han 5 , Yang Wei 4 , Jiucun Wang 6 , Li Jin 6
Affiliation  

Background and aims

Gallstone disease (cholelithiasis) is a cholesterol-related metabolic disorders with strong familial predisposition. Mitochondrial DNA (mtDNA) variants accumulated during human evolution are associated with some metabolic disorders related to modified mitochondrial function. The mechanistic links between mtDNA variants and gallstone formation need further exploration.

Methods

In this study, we explored the possible associations of mtDNA variants with gallstone disease by comparing 104 probands and 300 controls in a Chinese population. We constructed corresponding cybrids using trans-mitochondrial technology to investigate the underlying mechanisms of these associations. Mitochondrial respiratory chain complex activity and function and cholesterol metabolism were assessed in the trans-mitochondrial cell models.

Results

Here, we found a significant association of mtDNA 827A>G with an increased risk of familial gallstone disease in a Chinese population (odds ratio [OR]: 4.5, 95% confidence interval [CI]: 2.1-9.4, P=1.2×10-4). Compared with 827A cybrids (haplogroups B4a and B4c), 827G cybrids (haplogroups B4b and B4d) had impaired mitochondrial respiratory chain complex activity and function and activated JNK and AMPK signaling pathways. Additionally, the 827G cybrids showed disturbances in cholesterol transport and accelerated development of gallstones. Specifically, cholesterol transport through the transporter ABCG5/8 was increased via activation of the AMPK signaling pathway in 827G cybrids.

Conclusions

Our findings reveal that mtDNA 827A>G induces aberrant mitochondrial function and abnormal cholesterol transport, resulting in increased occurrence of gallstones. The results provide an important biological basis for the clinical diagnosis and prevention of gallstone disease in the future.

更新日期:2020-12-04
down
wechat
bug