Uncovering the dual role of hepatocyte-derived Apolipoprotein E in lipoprotein metabolism

Abstract

Background and aims: Apolipoprotein E (ApoE) is a key regulator of lipid metabolism, controlling transport and clearance of triglyceride rich lipoproteins. Although ApoE is produced in several tissues, the liver, especially hepatocytes, is the main source of circulating ApoE. Whole body ApoE knockout mice develop severe dyslipidemia, whereas mice lacking ApoE only in hepatocytes (ApoEΔHep) display only mild alterations on a standard diet, suggesting compensation from extrahepatic sources and raising questions about the specific contribution of hepatic ApoE. This work investigated the distinct role of hepatocyte derived ApoE in hepatic lipid handling.
Methods: ApoEΔHep mice were generated by crossing ApoE flox/flox mice with Albumin Cre mice. Animals were kept on a standard chow diet for 12 weeks. Lipid metabolism was assessed by FPLC, Western blotting, hepatic gene expression analysis and functional assays of lipoprotein production and clearance.
Results: Plasma WB confirmed that hepatocyte-derived ApoE is the main circulating source of the protein, which was absent in ApoEΔHep mice. Total plasma cholesterol was similar to controls under both standard diet (76,199,99 vs. 85,6415,20 mg/dL) and high cholesterol diet (154,726,45 vs. 151,414,35 mg/dL). However, lipoprotein profiling revealed a shift toward LDL enriched cholesterol in ApoEΔHep mice, in contrast to the VLDL dominant pattern of global ApoE KO mice. ApoEΔHep animals showed delayed clearance of triglycerides, consistent with impaired removal of triglyceride rich lipoproteins, and a 46% reduction (p < 0.0001) in VLDL production, indicating a role for hepatocyte ApoE in the synthesis and secretion of these particles. Hepatic transcript analysis pointed to deregulated lipid metabolic pathways.
Conclusions: This work highlights a dual role of hepatocyte-derived ApoE in both the production and clearance of TG-rich lipoproteins, pointing to distinct function of ApoE at systemic versus hepatocellular level. Ongoing molecular analyses aim to further dissect the intracellular mechanisms of lipoprotein synthesis and clarify the hepatocyte-specific contributions of ApoE to lipid metabolism and dyslipidemia.