Targeted Deletion of Hepatocyte Abca1 Increases Plasma HDL (High-Density Lipoprotein) Reverse Cholesterol Transport via the LDL (Low-Density Lipoprotein) Receptor

Abstract

Objective: The role of hepatocyte Abca1 (ATP binding cassette transporter A1) in trafficking hepatic free cholesterol (FC) into plasma versus bile for reverse cholesterol transport (RCT) is poorly understood. We hypothesized that hepatocyte Abca1 recycles plasma HDL-C (high-density lipoprotein cholesterol) taken up by the liver back into plasma, maintaining the plasma HDL-C pool, and decreasing HDL-mediated RCT into feces. Approach and Results: Chow-fed hepatocyte-specific Abca1 knockout (HSKO) and control mice were injected with human HDL radiolabeled with 125 I-tyramine cellobiose ( 125 I-TC; protein) and 3 H-cholesteryl oleate ( 3 H-CO). 125 I-TC and 3 H-CO plasma decay, plasma HDL 3 H-CO selective clearance (ie, 3 H- 125 I fractional catabolic rate), liver radiolabel uptake, and fecal 3 H-sterol were significantly greater in HSKO versus control mice, supporting increased plasma HDL RCT. Twenty-four hours after 3 H-CO-HDL injection, HSKO mice had reduced total hepatic 3 H-FC (ie, 3 H-CO hydrolyzed to 3 H-FC in liver) resecretion into plasma, demonstrating Abca1 recycled HDL-derived hepatic 3 H-FC back into plasma. Despite similar liver LDLr (low-density lipoprotein receptor) expression between genotypes, HSKO mice treated with LDLr-targeting versus control antisense oligonucleotide had slower plasma 3 H-CO-HDL decay, reduced selective 3 H-CO clearance, and decreased fecal 3 H-sterol excretion that was indistinguishable from control mice. Increased RCT in HSKO mice was selective for 3 H-CO-HDL, since macrophage RCT was similar between genotypes. Conclusions: Hepatocyte Abca1 deletion unmasks a novel and selective FC trafficking pathway that requires LDLr expression, accelerating plasma HDL-selective CE uptake by the liver and promoting HDL RCT into feces, consequently reducing HDL-derived hepatic FC recycling into plasma.