Abstract 5480: A Novel Role for Abca1-Generated Large Nascent HDL in the Regulation of VLDLTriglyceride Secretion
Metabolic syndrome is associated with low plasma HDL and elevated triglyceride (TG) concentrations. ATP binding cassette transporter A1 (ABCA1) is required for nascent HDL formation and is critical for maintaining plasma HDL levels. We have observed that hepatocyte-specific deletion of ABCA1 in mice leads to a severe reduction in plasma HDL and a 2-fold increase in liver TG secretion. Since hepatocytes are important in both HDL and VLDL production, we hypothesized that hepatocyte ABCA1 indirectly regulates VLDL assembly and TG secretion through nascent HDL formation. To test this hypothesis, we silenced ABCA1 expression by ~70% using siRNA in oleate-stimulated rat hepatoma cells and found:
increased secretion of large buoyant VLDL1 particles,
preferential loss of large nascent HDLs (>10 nm diameter) and accumulation of small nascent HDLs (<10nm), and
attenuation of PI3 kinase activation.
As chemical inhibition of PI3 kinase activation also increased VLDL TG secretion, we examined whether nascent HDL particles, the products of ABCA1 activity, can stimulate hepatic PI3 kinase activation and decrease VLDL TG secretion. Nascent HDL-containing conditioned media from rat hepatoma cells or HEK293 cells transfected with ABCA1 increased PI3 kinase activation and attenuated VLDL TG secretion in ABCA1-silenced hepatoma cells. Addition of 2 μg protein/ml of isolated large, but not small, nascent HDL particles also inhibited VLDL TG secretion in ABCA1-silenced hepatoma cells. Collectively, these data suggest that large nascent HDL particles assembled by hepatic ABCA1 generate a PI3 kinase-mediated autocrine signal that attenuates VLDL maturation and TG secretion. These data provide a mechanistic explanation for the elevated plasma TG concentrations in Tangier subjects and may partially explain the inverse relationship between plasma HDL and TG concentrations, one of the phenotypic characteristics of metabolic syndrome.
This research has received full or partial funding support from the American Heart Association, AHA Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia & Washington, DC).