Abstract
Dennd5b plays a pivotal role in intestinal absorption of dietary lipids and is associated with body mass index in humans. This study examined the impact of whole-body Dennd5b deletion on plasma lipid concentrations, atherosclerosis, and hepatic lipid metabolism. Hypercholesterolemia was induced in Dennd5b-/- mice by infection with an adeno-associated viral (AAV) expressing the proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) gain-of-function mutation (PCSK9D377Y) and feeding a Western diet for 12 weeks. Body weight and plasma lipid concentrations were monitored over 12 weeks, then aortic atherosclerosis and hepatic lipid content were quantified. Compared to Dennd5b+/+ mice, Dennd5b-/- mice were resistant to diet-induced weight gain and PCSK9-induced hypercholesterolemia. Atherosclerosis was evaluated by en face analysis and in aortic root sections, which had significantly lower lesion size in Dennd5b-/- compared to wild type. Additionally, Dennd5b-/- mice had significantly less hepatic lipid content (triglyceride and cholesterol) compared to wild type. To gain insight into the basis for reduced hepatic lipids, quantitative PCR was used to measure mRNA abundance of genes involved in hepatic lipid metabolism. 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.