Abstract
Cisd2 (CDGSH iron sulfur domain 2) is a pro-longevity gene that extends the lifespan and health span of mice, ameliorates age-associated structural damage and limits functional decline in multiple tissues. Non-alcoholic fatty liver disease (NAFLD), which plays an important role in age-related liver disorders, is the most common liver disease worldwide. However, no medicines that can be used to specifically and effectively treat NAFLD are currently approved for this disease. Our aim was to provide pathological and molecular evidence to show that Cisd2 protects the liver from age-related dysregulation of lipid metabolism and protein homeostasis. This study makes four major discoveries. Firstly, a persistently high level of Cisd2 protects the liver from age-related fat accumulation. Secondly, proteomics analysis revealed that Cisd2 ameliorates age-related dysregulation of lipid metabolism, including lipid biosynthesis and β-oxidation, in mitochondria and peroxisomes. Thirdly, Cisd2 attenuates aging-associated oxidative modifications of proteins. Finally, Cisd2 regulates intracellular protein homeostasis by maintaining the functionality of molecular chaperones and protein synthesis machinery. Our proteomics findings highlight Cisd2 as a novel molecular target for the development of therapies targeting fatty liver diseases, and these new therapies are likely to help prevent subsequent malignant progression to cirrhosis and hepatocellular carcinoma.
Highlights
Our previous study revealed that a half dose of the Cisd2 protein in mice is insufficient to carry out its normal functions in the liver, which can be described as a state of Cisd2 haploinsufficiency; these mice develop a phenotype similar to the clinical manifestations of Non-alcoholic fatty liver disease (NAFLD) [16]
Since dysregulation of lipid metabolism is a common phenotype of livers during natural aging, we investigated whether enhanced Cisd2 expression can improve liver lipid metabolism and ameliorate age-related NAFLD
Mice (26-mo Cisd2 transgenic (Cisd2TG)) (n = 6 in each group). (C) Representative images of gross views of livers from the three groups. (D) Representative images of Oil Red O staining, IHC staining of glutamine synthetase (GS) and Hematoxylin and eosin (H&E) staining of liver sections prepared from samples from the three mice groups
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Aging is a process during which organisms gradually lose their ability to carry out normal functions and maintain homeostasis. The extent of age-associated perturbations in the structure and function of each organ is site-specific, indicating that aging is a multidimensional process in organisms [1]. The liver is a vital metabolic organ that orchestrates the energy metabolism of the whole body. In the liver, ageassociated fat accumulation and dysregulated lipid metabolism compromise normal hepatic function and lead to fatty liver, which is accompanied by histopathological damage [2]
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