Preventive effect of eicosapentaenoic acid on the exacerbation of concanavalin A–induced liver injury aggravated by a short-term high-fat diet

Metabolic dysfunction-associated steatohepatitis is an advanced stage of metabolic dysfunction-associated steatotic liver disease (MASLD) and is associated with progression to cirrhosis and liver cancer. Although early intervention is crucial, studies focusing on the early stages of MASLD are limited. Patients with MASLD are expected to have an imbalance of n-3 and n-6 polyunsaturated fatty acids (PUFAs). In a previously developed short-term high-fat diet (HFD) model (C57BL/6, male), we demonstrated that only 4 d of HFD intake exacerbated concanavalin A (Con A)–induced liver injury (10 mg/kg), suggesting increased liver vulnerability even in the absence of clinical symptoms. Herein, alterations in n-3 and n-6 PUFA levels and related inflammatory mechanisms during early HFD exposure were investigated to explore early prevention strategies for MASLD. Liver and serum samples were collected from HFD-fed mice for 4 d and analyzed for n-3 and n-6 PUFA levels using gas chromatography–mass spectrometry. The results revealed that levels of eicosapentaenoic acid (EPA), an n-3 PUFA known for its anti-inflammatory effects, decreased in the liver and serum, whereas the levels of arachidonic acid, an n-6 PUFA that promotes inflammation, increased. Further analysis showed that supplementing EPA (100 mg/kg), which was reduced during short-term HFD intake, significantly mitigated the worsening of Con A-induced liver injury, primarily owing to its anti-inflammatory and anticoagulant effects. These findings in mice suggest that early EPA supplementation may effectively prevent liver injury and reduce the risk of MASLD progression, even before the emergence of clinical symptoms.