Epidemiological and clinical studies a role for flavanones (predominately found in citrus fruits) in the prevention of cardiovascular disease. Previously, we have shown that a nutritional dose of naringin exerts anti-atherogenic properties together with non HDL-cholesterol lowering effect in a murin model of dietary-induced hypercholesterolemia . The goal of the present study was to explore possible molecular mechanisms of naringin at the hepatic level. To this end, we analyzed the hepatic transcriptome using a microarray approach in response to naringin supplementation (0.02%) in mice fed a high-fat high-cholesterol diet. Naringin was observed to increase hepatic lipid content (triglyceride and cholesterol) without significant liver dysfunction (ALAT and ASAT activities) or histopathological alterations. Naringin supplementation also significantly improved insulin sensitivity as evaluated by the HOMA index and nutrigenomics revealed that naringin modulated the expression of 1,766 genes. These genes encode proteins involved in different cellular processes, such as lipid metabolism, inflammation and insulin signaling. In conclusion, this study revealed that the hypolipemic and anti-atherogenic effects induced by a nutritional-level naringin supplementation in high-fat high-cholesterol diet could be related to changes in hepatic lipid metabolism and inflammatory response, revealing new in vivo targets of this flavanone.