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The loss of paraoxonase-2 activity aggravates lipid accumulation, mitochondrial dysfunction, and oxidative stress through the impaired autophagy pathway in in vitro fatty liver model

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent immunometabolic disease that can progress to hepatic cirrhosis and cancer. NAFLD pathogenesis is extremely complex and is associated with diverse features including oxidative stress, impaired mitochondrial function andlipid metabolism, and cellular inflammation. Thus, in-depth research on its underlying mechanisms and investigation into a potential drug target that has overarching effects on these features will provide benefits towards discovering effective treatments for NAFLD. Here, we examined the role of endogenous paraoxonase-2 (PON2), a membrane protein with reported antioxidant activity, in in vitro fatty liver model. We found that the hepatic loss of PON2 activity aggravated steatosis and oxidative stress under lipotoxic condition, and our transcriptome analysis revealed that PON2 deficiency disrupts the activation of numerous functional pathways closely related to NAFLD pathogenesis, including mitochondrial respiratory capacity, lipid metabolism, liver fibrosis, and hepatic inflammation. PON2 promoted the activation of overall autophagy pathway, especially mitophagy cargo sequestration, which may be considered as an underlying mechanism that contributed to the role of PON2 in alleviating oxidative stress, mitochondrial dysfunction, lipid accumulation, and inflammation. These results provide mechanistic foundation on the prospect of targeting PON2 for the development of novel therapeutics for NAFLD in the future.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213653 | GEO | 2022/09/26

REPOSITORIES: GEO

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Project description:Background & Aims: Overnutrition is one of the major causes of non-alcoholic fatty liver disease (NAFLD) and its advanced form non-alcoholic steatohepatitis (NASH). Besides the quantity of consumed calories, distinct dietary components are increasingly recognized as important contributor to the pathogenesis of NASH. We aimed to develop and characterize a hitherto missing murine model which resembles both the pathology and nutritional situation of NASH-patients in Western societies. Methods: We developed a NASH-inducing diet (ND) enriched with sucrose, cholesterol and a high concentration of fats rich in saturated fatty acids in a composition which mimics Western food. C57Bl6/N mice were fed with the ND or control chow for 12 weeks. Biochemical, real-time polymerase chain reaction, Western Blot and immunohistochemical analyses were performed to characterize systemic and hepatic changes induced by ND-feeding. Immunohistochemistry was used to assess c-Jun levels and activation in 110 human NAFLD and control liver specimens applying tissue micro array technology. Results: ND-fed mice showed significant body weight gain, impaired glucose tolerance, elevated fasting blood glucose levels as well as decreased adiponectin and increased leptin serum levels compared to control mice. In the liver, ND-feeding led to marked steatosis, enhanced cholesterol levels, distinct signs of oxidative stress, hepatocellular damage, inflammation, activation of hepatic stellate cells, and beginning fibrosis. Transcriptome-wide hepatic gene expression analysis comparing ND-fed mice and control mice indicated main alterations in lipid metabolism and inflammatory processes. Search for over-represented transcription factor target sites among the differentially expressed genes identified AP-1 as the most likely factor to cause the transcriptional changes in ND-livers. Combining differentially expressed gene and protein-protein interaction network analysis identified c-Jun (a component of the AP-1 complex) as hub in the largest connected deregulated sub-network in ND-livers. In accordance, ND-livers revealed c-Jun-phosphorylation and nuclear translocation. Moreover, hepatic c-Jun RNA and protein expression was enhanced in ND-fed compared to control mice. Also NAFLD-patients showed enhanced hepatic c-Jun levels, which correlated with inflammation, and notably, with the degree of hepatic steatosis. Conclusions: The new dietary mouse-model shows important pathological changes also found in human NASH and indicates c-jun/AP-1 activation as critical regulator of hepatic alterations. Abundance of c-jun in NAFLD likely facilitates development and progression of NASH, and thus, c-jun appears as attractive prognostic and therapeutic target of NAFLD progression. 14-weeks old male C57BL/6N mice were fed with either regular diet or a newly designed NASH-inducing diet for 12 weeks. Hepatic gene expression levels were measured thereafter.

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The loss of paraoxonase-2 activity aggravates lipid accumulation, mitochondrial dysfunction, and oxidative stress through the impaired autophagy pathway in in vitro fatty liver model

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