Cisd2 Protects the Liver from Oxidative Stress and Ameliorates Western Diet-Induced Nonalcoholic Fatty Liver Disease

被引:15
|
作者
Huang, Yi-Long [1 ,2 ,3 ]
Shen, Zhao-Qing [1 ,2 ]
Huang, Chen-Hua [1 ,2 ]
Teng, Yuan-Chi [1 ,2 ]
Lin, Chao-Hsiung [1 ,2 ,3 ]
Tsai, Ting-Fen [1 ,2 ,3 ,4 ,5 ]
机构
[1] Natl Yang Ming Chiao Tung Univ, Dept Life Sci, Taipei 112, Taiwan
[2] Natl Yang Ming Chiao Tung Univ, Inst Genome Sci, Taipei 112, Taiwan
[3] Natl Yang Ming Chiao Tung Univ, Aging & Hlth Res Ctr, Taipei 112, Taiwan
[4] Natl Hlth Res Inst, Inst Mol & Genom Med, Zhunan 350, Taiwan
[5] Natl Hlth Res Inst, Inst Biotechnol & Pharmaceut Res, Zhunan 350, Taiwan
关键词
nonalcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis (NASH); Cisd2; Western diet; transcriptomics; hepatocyte-specific knockout; LIFE-SPAN; EXPRESSION; NASH; STEATOHEPATITIS; MITOCHONDRIA; PATHOGENESIS;
D O I
10.3390/antiox10040559
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), are the most common chronic liver diseases worldwide. However, drugs to treat NAFLD and NASH are an unmet clinical need. This study sought to provide evidence that Cisd2 is a molecular target for the development of treatments targeting NAFLD and NASH. Several discoveries are pinpointed. The first is that Cisd2 dosage modulates the severity of Western diet-induced (WD-induced) NAFLD. Specifically, Cisd2 haploinsufficiency accelerates NAFLD development and exacerbates progression toward NASH. Conversely, an enhanced Cisd2 copy number attenuates liver pathogenesis. Secondly, when a WD is fed to mice, transcriptomic analysis reveals that the major alterations affecting biological processes are related to inflammation, lipid metabolism, and DNA replication/repair. Thirdly, among these differentially expressed genes, the most significant changes involve Nrf2-mediated oxidative stress, cholesterol biosynthesis, and fatty acid metabolism. Finally, increased Cisd2 expression protects the liver from oxidative stress and reduces the occurrence of mitochondrial DNA deletions. Taken together, our mouse model reveals that Cisd2 plays a crucial role in protecting the liver from WD-induced damages. The development of therapeutic agents that effectively enhance Cisd2 expression is one potential approach to the treatment of WD-induced fatty liver diseases.
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页数:13
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