Abnormal sterols in cholesterol-deficiency diseases cause secretory granule malformation and decreased membrane curvature

Marjorie C. Gondré-Lewis, Horia I. Petrache, Christopher A. Wassif, Daniel Harries, Adrian Parsegian, Forbes D. Porter, Y. Peng Loh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

Cholesterol is an abundant lipid in eukaryotic membranes, implicated in numerous structural and functional capacities. Here, we have investigated the mechanism by which cholesterol affects secretory granule biogenesis in vivo using Dhcr7-/- and Sc5d-/- mouse models of the human diseases, Smith-Lemli-Opitz syndrome (SLOS) and lathosterolosis. These homozygous-recessive multiple-malformation disorders are characterized by the functional absence of one of the last two enzymes in the cholesterol biosynthetic pathway, resulting in the accumulation of precursors. Cholesterol-deficient mice exhibit a significant decrease in the numbers of secretory granules in the pancreas, pituitary and adrenal glands. Moreover, there was an increase in morphologically aberrant granules in the exocrine pancreas of Dhcr7-/- acinar cells. Regulated. secretory pathway function was also severely diminished in these cells, but could be restored with exogenous cholesterol. Sterol precursors incorporated in artificial membranes resulted in decreased bending rigidity and intrinsic curvature compared with cholesterol, thus providing a cholesterol-mediated mechanism for normal granule budding, and an explanation for granule malformation in SLOS and lathosterolosis.

Original languageAmerican English
Pages (from-to)1876-1885
Number of pages10
JournalJournal of Cell Science
Volume119
Issue number9
DOIs
StatePublished - 1 May 2006
Externally publishedYes

Keywords

  • Cholesterol
  • Granule biogenesis
  • Lathosterolosis
  • Membrane curvature
  • Regulated secretory pathway
  • Smith-Lemli-Opitz syndrome (SLOS)

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