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• ALA (n-3 α- linolenic acid) dietary enrichment during pregnancy-lactation, protects the adult LDLRKO mice offspring from HFD-induced lipid disarray. • ALA prevention of HFD- induced hypercholesterolemia and NAFLD is associated with low SCD1- dependent MUFA production. • ALA enriched perinatal diet might account for the resilience of SCD1 to HFD-induced increase. • ALA early priming of SCD1 might contribute to prevent HFD-induced lipid disease. The present study examined the effects of maternal perinatal dietary ALA enrichment on the high fat diet (HFD)-induced lipid disarray in the adult offspring of low density lipoprotein receptor knock-out (LDLRKO) mice. Female LDLRKO mice received, during pregnancy and lactation, isocaloric diets with either corn oil, RD , or flax oil, ALA. The weaning offspring was given a regular chow diet for a washout period of eight weeks, which was followed by HFD for eight weeks. Plasma and liver lipids and SCD1 activity were then analyzed. The HFD-fed RD adult offspring had substantially higher plasma cholesterol levels than the HFD-fed ALA offspring (15.7 versus 9.7 mmole/l, p <0.00001) and non-alcoholic fatty liver disease (NAFLD) (65.0 versus 23.9 mg/g lipids, p <0.00001). Liver lipids oleic acid (OA) content and monounsaturated to saturated fatty acids (MUFA/SAT) ratio, were two times lower in RD compared to ALA (p <0.0001). The threefold HFD-induced SCD1 raised activity (p <0.00001), and OA produced from SA, observed in RD adult offspring were prevented by perinatal ALA. In conclusion, the resilience of SCD1 to HFD- induced increased activity may account for the beneficial effects of perinatal ALA dietary enrichment in preventing NAFLD and hypercholesterolemia from occurring in adult LDLRKO offspring mice. [ABSTRACT FROM AUTHOR]