In view of the data showing that the LRP1 NPxY mutant mice were resistant to HFHC diet-induced hypercholesterolemia, yet exhibited impaired hepatic insulin signaling, we compared liver phenotype in wild-type and mutant mice to explore whether the distal NPxY motif participates in LRP1 modulation of liver steatosis and inflammation. This evidence concerns the gene LRP1 and familial hypercholesterolemia.