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

Abstract

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.

Inhibition of CISD2 promotes ferroptosis through ferritinophagy-mediated ferritin turnover and regulation of p62–Keap1–NRF2 pathway

“…MitoNEET located in mitochondrial outer membrane was identified to function as an exporter of iron-sulfur clusters or iron between the cytoplasm and the mitochondria. CISD2 expression could protect the liver from oxidative stress, reduce the occurrence of mitochondrial DNA deletions, and protect the liver from the nonalcoholic fatty liver disease [33]. Sohn et al demonstrated that the NEET proteins were central to human breast cancer cells, and rendered them resistant to oxidative stress by mediating iron and ROS homeostasis in mitochondria [34].…”

Cisd2 Preserves the Youthful Pattern of the Liver Proteome during Natural Aging of Mice

“…Our previous study revealed that Cisd2 plays an important role in maintaining a normal redox status [ 18 ]. To further analyze intracellular redox status and oxidative stress and evaluate the protective function of Cisd2 in the antioxidant defense during natural aging, we carried out Western blot analyses of liver extracts using antibodies targeting either cysteine S-sulfonation or tyrosine nitration.…”

“…By way of contrast, a persistently high level of Cisd2 in the Cisd2TG mice preserves mitochondrial function and protects the activity of Complexes I–V in the skeletal muscles of old mice [ 12 ]. Moreover, using the Western pattern diet-induced NAFLD, the levels of reactive species, including ROS and RNS, are significantly increased in the livers of heterozygous mice carrying hepatocyte-specific knockout of Cisd2 (Cisd2hKO+/–) while overexpression of Cisd2 alleviates the Western pattern diet-induced oxidative stress in Cisd2TG mice [ 18 ].…”

CDGSH iron sulfur domain 2 over‐expression alleviates neuronal ferroptosis and brain injury by inhibiting lipid peroxidation via AKT/mTOR pathway following intracerebral hemorrhage in mice

“…It also maintained the structure of the liver and protected it from age‐related pathological damage (Huang, Shen, Huang, Lin, & Tsai, 2021). Several studies have identified that CISD2 played a protective role in fatty liver disease and spinal cord injury (Huang, Shen, Huang, Teng, et al, 2021; Kung et al, 2020). In addition, CISD2 alleviated hypoxia/reoxygenation‐induced oxidative stress and inflammatory responses in HT22 hippocampal neurons via the Akt‐Nrf2‐activated pathway (Ren et al, 2022).…”