Silica nanoparticles aggravated the metabolic associated fatty liver disease through disturbed amino acid and lipid metabolisms-mediated oxidative stress
Redox biology(2023)
Abstract
The metabolic associated fatty liver disease (MAFLD) is a public health challenge, leading to a global increase in chronic liver disease. The respiratory exposure of silica nanoparticles (SiNPs) has revealed to induce hepato-toxicity. However, its role in the pathogenesis and progression of MAFLD was severely under-studied. In this context, the hepatic impacts of SiNPs were investigated in vivo and in vitro through using ApoE-/-mice and free fatty acid (FFA)-treated L02 hepatocytes. Histopathological examinations and biochemical analysis showed SiNPs exposure via intratracheal instillation aggravated hepatic steatosis, lipid vacuolation, inflammatory infiltration and even collagen deposition in ApoE-/-mice, companied with increased hepatic ALT, AST and LDH levels. The enhanced fatty acid synthesis and inhibited fatty acid beta-oxidation and lipid efflux may account for the increased hepatic TC/TG by SiNPs. Consistently, SiNPs induced lipid deposition and elevated TC in FFA-treated L02 cells. Further, the activation of hepatic oxidative stress was detected in vivo and in vitro, as evidenced by ROS accumulation, elevated MDA, declined GSH/GSSG and down-regulated Nrf2 signaling. Endoplasmic reticulum (ER) stress was also triggered in response to SiNPs-induced lipid accumulation, as reflecting by the remarkable ER expansion and increased BIP expression. More importantly, an UPLC-MS-based metabolomics analysis revealed that SiNPs disturbed the hepatic metabolic profile in ApoE-/-mice, prominently on amino acids and lipid metabolisms. In particular, the identified differential metabolites were strongly correlated to the activation of oxidative stress and ensuing hepatic TC/TG accumulation and liver injuries, contributing to the progression of liver diseases. Taken together, our study showed SiNPs promoted hepatic steatosis and liver damage, resulting in the aggravation of MAFLD progression. More importantly, the disturbed amino acids and lipid metabolisms-mediated oxidative stress was a key contributor to this phenomenon from a metabolic perspective.
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Key words
Silica nanoparticle,Hepatotoxicity,Metabolomics,Metabolic associated fatty liver disease,Oxidative stress
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