A novel role for ABCA1-generated large pre-β migrating nascent HDL in the regulation of hepatic VLDL triglyceride secretion

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

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

In Tangier disease, absence of ATP binding cassette transporter A1 (ABCA1) results in reduced plasma HDL and elevated triglyceride (TG) levels. We hypothesized that hepatocyte ABCA1 regulates VLDL TG secretion through nascent HDL production. Silencing of ABCA1 expression in oleate-stimulated rat hepatoma cells resulted in: 1) decreased large nascent HDL (>10 nm diameter) and increased small nascent HDL (<10 nm) formation, 2) increased large buoyant VLDL1 particle secretion, and 3) decreased phosphatidylinositol-3 (PI3) kinase activation. 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.

Original languageEnglish (US)
Pages (from-to)729-742
Number of pages14
JournalJournal of Lipid Research
Volume51
Issue number4
DOIs
StatePublished - Apr 1 2010

Keywords

  • ABCA1 silencing
  • Hepatic ATP binding cassette transporter A1
  • PI3 kinase signaling
  • Tangier disease
  • VLDL assembly
  • Very low density lipoprotein TG secretion

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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