摘要:Postnatal overfeeding can lead to persistent increases in hepatic lipid synthesis and the risk of nonalcoholic fatty liver disease (NAFLD) in adulthood. The ω3 polyunsaturated fatty acids (ω3PUFAs) exhibit beneficial effects on NAFLD. Here, we employed a rat model and an in vitro HepG2 cell model to investigate whether fish oil (FO) affects hepatic lipid synthesis due to postnatal overfeeding. Male Sprague‐Dawley were divided into litter sizes of three (small litters, SLs) or 10 (normal litters, NLs) on postnatal day 3 and were fed standard chow or FO diet beginning on postnatal week 3 to generate NL, SL, NL‐FO, and SL‐FO groups. The results indicated that the FO diet reduced the postnatal overfeeding‐induced body weight gain and NAFLD characteristics (such as serum and liver triglyceride (TG) and hepatic steatosis). In addition, FO restored the expression of hepatic lipid metabolism‐related genes (including SCD1, FASN, CPT1, LPL, ACC, and SREBP‐1c) in SL‐FO rats. Specifically, the activity and expression pattern of ACC were consistent with SREBP‐1c. Furthermore, HepG2 cells were treated with oleic acid (OA), followed by eicosapentenoic acid (EPA), with or without SREBP‐1c siRNA. The cellular lipid droplets, TG content, and the expression of ACC (by 75%) and SREBP‐1c (by 45%) were increased by OA stimulation (p .05), which was inhibited by EPA treatment. However, the effect of EPA treatment was abolished when SREBP‐1c was silenced. In conclusion, ω3PUFAs‐rich diet may be an effective way to reverse the developmental programming of hepatic lipid synthesis, at least partially, by inhibiting ACC through modulating SREBP‐1c.