A novel role for ABCA1-generated large pre-beta migrating nascent HDL in the regulationof hepatic VLDL triglyceride secretion

Soonkyu Chung, Abraham K. Gebre, Jeongmin Seo, Gregory S. Shelness, and John S. Parks

Pathology, Wake Forest Univ. Health Sciences, Winston-Salem, NC 27157

Corresponding Author: jparks{at}wfubmc.edu

ATP binding cassette transporter A1 (ABCA1) is required for nascent HDL formation and genetic absence of functional ABCA1 in Tangier disease results in a severe reduction of plasma HDL and a significant elevation in plasma triglyceride (TG) concentrations. Since hepatocytes are important in both HDL and VLDL production, we hypothesized that hepatocyte ABCA1 may regulate VLDL TG secretion through nascent HDL production. To test this hypothesis, we silenced ABCA1 expression using siRNA in oleate-stimulated rat hepatoma cells and found: 1) decreased formation of large nascent HDLs (>10 nm diameter) and increased formation of small nascent HDLs (<10 nm), 2) increased secretion of large buoyant VLDL1 particles, and 3) attenuation of PI3 kinase activation. As inhibition of PI3 kinase activation increases VLDL TG secretion, we examined whether large nascent HDL particles, the products of ABCA1 activity, increase hepatic PI3 kinase activation and decrease VLDL TG secretion. Nascent HDL-containing conditioned medium from rat hepatoma cells or HEK293 cells transfected with ABCA1 was effective in increasing PI3 kinase activation and reducing VLDL TG secretion in ABCA1-silenced hepatoma cells. Addition of isolated large nascent HDL particles to ABCA1-silenced hepatoma cells inhibited VLDL TG secretion to a greater extent than small nascent HDL. Similarly, addition of recombinant HDL, but not human plasma HDL, was effective in attenuating TG secretion and increasing PI3 kinase activation in ABCA1-silenced 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. This pathway may explain the elevated plasma TG concentration that occurs in most Tangier subjects and may also account, in part, for the inverse relationship between plasma HDL and TG concentrations in individuals with compromised ABCA1 function.

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