Key genes involved in hepatic lipid metabolism and lipid storage were differentially expressed in Dennd5b−/− liver including Pparg, Cd36, and Pnpla3. These findings demonstrate a significant impact of Dennd5b on plasma and hepatic lipid concentrations and resistance to PCSK9-induced hypercholesterolemia in the absence of Dennd5b. Here, DENND5B is linked to Hypercholesterolemia.