title: Selective reduction of bis(monoacylglycero)phosphate ameliorates the storage burden in a THP-1 macrophage model of Gaucher disease.
abstract: Bis(monoacylglycero)phosphate (BMP) assists lysosomal function by facilitating interaction of hydrolases and activator proteins with sphingolipid substrates. Impaired lysosomal degradation of the sphingolipid glucosylceramide (GC) occurs in Gaucher disease due to an inherited deficiency of acid β-glucosidase, with secondary BMP alterations. We investigated the nature of BMP accumulation and whether its correction reduced the storage burden in a THP-1 macrophage model of Gaucher disease. Using sucrose gradients and detergent solubility, 98% of BMP resided in the detergent-soluble membranes (DSM) rather than in the detergent-resistant membranes (DRM) where 73% of GC predominated. There was a 2-fold widespread elevation in BMP, including the saturated, mono- and polyunsaturated species. Linoleic acid in the culture media selectively reduced BMP from 4.2 nmol/mg to 0.49 nmol/mg (except 18:1/18:2) and prevented up to one third of GC, dihexosylceramide (DHC), and trihexosylceramide (THC) from accumulating. The 2-fold reduction in these sphingolipids occurred only in the DRM and did not reduce 18:1/16:0. However, once GC had accumulated, linoleic acid could not reverse it, DHC, or THC, despite effectively reducing BMP. These results imply a causative link for BMP in the pathobiology of Gaucher disease and demonstrate that linoleic acid can shield the cell from excessive substrate accumulation.
authors.affiliation: Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital, North Adelaide, South Australia, Australia; and.
authors.forename: Leanne K
authors.initials: LK
authors.lastname: Hein
authors.affiliation: Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital, North Adelaide, South Australia, Australia; and.
authors.forename: Stephen
authors.initials: S
authors.lastname: Duplock
authors.affiliation: Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital, North Adelaide, South Australia, Australia; and; Department of Pediatrics, University of Adelaide, Adelaide, South Australia, Australia. Electronic address: maria.fuller@adelaide.edu.au.
authors.forename: Maria
authors.initials: M
authors.lastname: Fuller
mesh_terms: D045744:Cell Line, Tumor; D002518:Ceramides / Q000235:genetics / Q000378:metabolism; D005776:Gaucher Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019787:Linoleic Acid / Q000235:genetics / Q000378:metabolism; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D050178:Monoglycerides / Q000235:genetics / Q000378:metabolism*; D013107:Sphingolipids / Q000235:genetics / Q000378:metabolism
chemical_list: D002518:Ceramides; D008246:Lysophospholipids; D050178:Monoglycerides; D013107:Sphingolipids; C012786:bis(monoacylglyceryl)phosphate; D019787:Linoleic Acid; D005962:Glucosylceramidase
keywords: detergent-resistant membranes; fatty acids; glucosylceramide; lysosomal disease; lysosomal dysfunction; lysosomal storage disorder; mass spectrometry; membrane microdomains
references.citation: Mol Genet Metab. 2008 Apr;93(4):437-43
references.pmid: 18162427
references.citation: Mol Genet Metab. 2007 Dec;92(4):336-45
references.pmid: 17881272
references.citation: Can J Biochem Physiol. 1959 Aug;37(8):911-7
references.pmid: 13671378
references.citation: J Lipid Res. 2008 Aug;49(8):1725-34
references.pmid: 18427156
references.citation: J Biol Chem. 2002 Aug 30;277(35):32157-64
references.pmid: 12065580
references.citation: Nat Rev Mol Cell Biol. 2004 Jul;5(7):554-65
references.pmid: 15232573
references.citation: Biochim Biophys Acta. 2009 Apr;1793(4):674-83
references.pmid: 19014978
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2009 Nov-Dec;81(5-6):313-24
references.pmid: 19857945
references.citation: J Lipid Res. 1977 May;18(3):379-88
references.pmid: 864326
references.citation: Mol Genet Metab. 2007 Feb;90(2):148-56
references.pmid: 17079175
references.citation: J Biol Chem. 1951 Nov;193(1):265-75
references.pmid: 14907713
references.citation: Biochim Biophys Acta. 2009 Jan;1788(1):24-32
references.pmid: 19014904
references.citation: Methods Enzymol. 1995;250:655-68
references.pmid: 7651184
references.citation: J Biol Chem. 2002 Nov 15;277(46):43674-81
references.pmid: 12223468
references.citation: J Biol Chem. 1998 Nov 13;273(46):30271-8
references.pmid: 9804787
references.citation: J Biol Chem. 1957 May;226(1):497-509
references.pmid: 13428781
references.citation: J Biol Chem. 2008 Oct 10;283(41):27871-27880
references.pmid: 18644787
references.citation: Lipids. 1976 Jul;11(7):539-44
references.pmid: 948249
references.citation: Biochem J. 2008 Apr 1;411(1):71-8
references.pmid: 18052935
references.citation: J Lipid Res. 2007 Sep;48(9):1997-2008
references.pmid: 17558022
references.citation: Science. 2004 Jan 23;303(5657):531-4
references.pmid: 14739459
references.citation: Blood. 1969 Feb;33(2):379-90
references.pmid: 5250471
references.citation: Biochim Biophys Acta. 1999 Mar 25;1437(3):277-86
references.pmid: 10101262
references.citation: Biochemistry. 1996 Nov 5;35(44):13995-4002
references.pmid: 8909297
references.citation: Biochim Biophys Acta. 1986 Apr 15;876(2):318-26
references.pmid: 2937457
references.citation: PLoS One. 2007 Apr 25;2(4):e391
references.pmid: 17460758
references.citation: Nat Rev Mol Cell Biol. 2001 Oct;2(10):721-30
references.pmid: 11584299