LDLR (low density lipoprotein receptor) is the building block of the LDLR family proteins. Members of this receptor family (i.e. LDLR, VLDLR, ApoER2, LRP1, LRP2, and LRP6) share common structural motifs with N-terminal cysteine rich type A repeats (class A LDLR domain), which are responsible for ligand binding. Following the class A LDLR are two epidermal growth factor (EGF)-like domains known to be involved in pH-dependent release of ligands in endosomes. The cytoplasmic tail of LDLR is responsible for clustering the receptors into a clathrin coated pit and binds to select adaptor proteins. Elevated LDL levels are a prevalent risk factor for coronary artery disease and other atherosclerotic diseases, which constitute the largest cause of mortality in the United States. LDLRs localized on hepatocytes play an important role in removing cholesterol-transporting LDL from the plasma by receptor-mediated endocytosis. LDLR is constitutively expressed and binds ApoB of LDL and ApoE of VLDL and is responsible for clearing 70% of plasma LDL in the liver. Although, members of the family were originally thought to be endocytic receptors, it is now clear that some members interact with adjacent cell surface molecules, expanding their range of activities. Mouse LDLR shares a 78% amino acid homology with its human counterpart. Mutations in the LDLR gene have been shown to cause familial hypercholesterolemia, inherited in an autosomal dominant pattern. It was shown that targeted disruption of LDLR causes hypercholesterolemia and atherosclerosis. In addition, LDLR-/- mice developed sustained hepatic inflammation and liver damage upon long term high cholesterol diet, due to increased sensitivity for oxidized LDL uptake. This finding indicates that the LDLR-/- mice are a promising physiological model to investigate the onset of hepatic inflammation in non-alcoholic steatohepatitis.