Early-onset PUFA deficiency exacerbates lean MAFLD-like hepatic injury in FADS2 knockout mice

• Early-onset PUFA deficiency in FADS2 KO mice gene knockout induced lean MAFLD-like features • Marked hepatic accumulation of cholesterol and oxysterols under early-onset PUFA deficiency • Early-onset PUFA deficiency was associated with inflammation and fibrosis. • Reduced Cyp7b1 expression under PUFA deficiency likely contributed to oxysterol accumulation. • Preventing PUFA deficiency in infancy is essential for maintaining liver health. Polyunsaturated fatty acids (PUFAs) are vital for maintaining health, particularly during infancy and early childhood. In this study, we examined PUFA deficiency in FADS2 knockout (KO) mice, which lack endogenous synthesis of PUFAs with ≥20 carbons, by feeding a PUFA-deficient diet to assess the effects of early- and adult-onset deficiency. Both groups showed reduced body weight and increased hepatic triacylglycerol (TAG) accumulation, whereas liver enlargement was more pronounced in the early-onset mice. Moreover, early-onset KO mice exhibited additional pathological signs, including elevated plasma ALT and AST levels, upregulation of inflammatory and fibrogenic genes, and distinct histological alterations such as inflammation and fibrosis, which are characteristic features of lean metabolic dysfunction-associated fatty liver disease (MAFLD). They also accumulated higher hepatic levels of cholesterol and the hepatotoxic oxysterols 25-hydroxycholesterol and 27-hydroxycholesterol relative to adult-onset mice. Although direct causality was not established, these sterol changes may contribute to the exacerbated hepatic injury observed under early-onset deficiency. Overall, our findings highlight the importance of preventing PUFA deficiency during infancy and early life to protect against MAFLD-like hepatic injury.