Abstract 14133: Hepatic Deletion of the Cargo Receptor Surf4 Causes Marked Hypocholesterolemia in Mice

Abstract

Introduction: High plasma concentration of low-density lipoprotein (LDL) is a strong risk factor for coronary artery diseases. Circulating LDL level is a balance between the secretion of its precursor, very low-density lipoprotein (VLDL), and LDL uptake by tissues. Central to these processes are the secretion of APOB - a protein component of VLDL, and PCSK9 - a negative regulator of LDL uptake. We previously demonstrated that the cargo receptor SURF4 mediates the secretion of PCSK9 heterologously expressed in HEK293T cells. We now report the generation and characterization of hepatocyte-specific Surf4 knockout ( Surf4 LKO ) mice. Methods and Results: Hepatic deletion of Surf4 results in a marked reduction of plasma cholesterol (5.1 mg/dl vs. 71.3 mg/dl, n=5) and triglycerides (17.6 mg/dl vs. 80.4 mg/dl, n=5) as compared to wild-type (WT) littermate controls. Despite modest increases in liver mass (1.14±0.03 g vs. 0.94±0.03 g, n=5) and liver lipid content (3.54±0.46% vs. 0.80±0.57% liver mass, n=4), Surf4 LKO mice show no signs of liver dysfunction or hepatosteatosis as evaluated by serum liver function markers and histology. Consistent with a role for SURF4 in PCSK9 secretion, plasma PCSK9 levels are reduced in Surf4 LKO mice (17.8±2.6 μg/ml vs. 46.0±7.7 μg/ml, n=6) while liver PCSK9 levels remain unchanged. Given that Pcsk9 -/- mice exhibit an approximately 50% reduction in plasma cholesterol, the magnitude of hypocholesterolemia in Surf4 LKO mice suggests that other cargoes involved in lipoprotein metabolism might also depend on SURF4 for secretion. Indeed, an unbiased secretomic study by mass spectrometry revealed that secretion of several lipoproteins, including APOA1, APOA2, and APOB, is reduced in SURF4 null Huh7 cells. As expected, Surf4 LKO mice show reduced APOB and lipoprotein secretion rate. In contrast to Huh7 cells, which demonstrate broad transcriptional changes in response to SURF4 deletion, the livers from Surf4 LKO mice exhibit few transcriptional changes, including the downregulation of genes involved in fatty acid synthesis. Conclusions: These results indicate that the cargo receptor SURF4 has pleiotropic functions in mammalian lipoprotein regulation and may represent a promising target for therapeutic development.