Endocrine Abstracts

Introduction: Metabolic dysfunction-associated fatty liver disease (MAFLD) is characterized by the presence of hepatic steatosis, which can progress to non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma. There are no licensed therapies to halt MAFLD progression, despite it is becoming the most important etiology for advanced liver disease.

Aim: The aim of the study was to evaluate the therapeutic potential of inorganic nanoparticles (NPs) (cerium oxide [CeO₂NPs], gold [AuNPs] and their combination in the same nanostructure [AuCeO2NPs]) in an experimental model of fatty liver disease.

Methods: Steatohepatitis was induced in Wistar rats by a methionine-choline-deficient (MCD) diet. A first pilot protocol included 10 rats on MCD diet for 3 weeks, which were randomly administered intravenously (iv) with CeO₂NPs (0.25 mg/kg; n=5) or vehicle (n=5) at weeks 1 and 2. CeO₂NPs significantly reduced hepatic steatosis and IL1β expression, although without changes in transaminases. Therefore, in a second protocol, mesoporous silica (mSiO₂) coating of the inorganic NPs was designed to improve their stability and biological effects. The NPs were administered iv (weeks 1 and 2) in 5 groups of 8 animals on MCD diet for 3 weeks (group1: CeO₂NPs@mSiO₂, group 2: AuNPs@mSiO₂, group 3: AuCeO₂NPs@mSiO₂, group 4: AuCeO₂NPs, and group 5 [vehicle]: mSiO₂). Biodistribution of NPs was analyzed by inductively coupled plasma mass spectrometry (ICP-MS). Standard parameters of liver and renal function and lipid profile were measured in a chemistry analyzer (Mindray). The effects on liver steatosis, infla mmation and metabolism were assessed by histological examination, gas chromatography mass spectrometry and the analysis of the expression of 88 genes related to liver steatosis and infla mmation (customized Rat Fatty Liver RT² Profiler^TM PCR Array, Qiagen).

Results: Biodistribution analysis revealed that cerium and gold accumulated mainly in the liver and spleen. Treatments with AuNPs@mSiO₂ and AuCeO₂NPs@mSiO₂ were the most effective in reducing hepatic steatosis (49±2%, 50±1% vs 55.0±1%; P<0.05) and ALT levels (114±10, 110±9 vs 190±29 U/l; P<0.05). These effects were associated with a significant improvement (fold regulation >1.50; P<0.05) on the hepatic expression of 21 (Au@mSiO₂) and 50 (AuCeO₂NPs@mSiO₂) of the 88 analyzed genes, which were mainly related with reduced infla mmatory response and adipokine signalling, and improvements in metabolic pathways involved in oxidative phosphorylation and lipid metabolism and transport.

Conclusion: Treatment with gold and cerium oxide NPs coated with mSiO₂ improve hepatic steatosis and infla mmation in an experimental model of steatohepatitis.