N-acetylcysteine acts as a potent anti-inflammatory agent altering the eicosanoid profile in the development of simple steatosis and its progression to hepatitis.

Abstract

We aimed to examine the influence of N-acetylcysteine (NAC) on the development of metabolic dysfunction-associated steatotic liver disease (MASLD) in rats with a specific focus on the eicosanoid pathway. The experiment was conducted on male Wistar rats fed a standard diet or a high-fat diet (HFD) for eight weeks. In the entire experiment, half of rats from both groups received intragastrically NAC solution prepared in normal saline. H + E staining was used for the histological assessment of liver tissue. The gas-liquid chromatography (GLC) technique was used for the assessment of the activity of n-3 and n-6 polyunsaturated fatty acid (PUFA) pathways and arachidonic acid concentration. ELISA and multiplex immunoassay kits were applied for the measurement of eicosanoid, cytokine, and chemokine levels. The Western blot technique was applied to determine the expression of proteins involved in the inflammation pathway. NAC decreased hepatic n-6 PUFA activity in all examined lipid pools and decreased the hepatic content of arachidonic acid as a pro-inflammatory precursor in each lipid pool, especially in the phospholipid fraction in rats with fatty lipid disease. NAC administration abolished 5-LOX expression, leading to a decrease in the content of pro-inflammatory leukotriene B4 and leukotriene C4. In rats with steatosis, NAC weakened NF-κB expression and raised Nrf-2 expression, inhibiting the synthesis of pro-inflammatory cytokines and chemokines. NAC treatment significantly rate-limited the progression of simple hepatic steatosis to hepatitis in a rat model of MASLD.