ATP Binding Cassette A1 Paul Rushton

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ATP Binding Cassette A-1 Paul Rushton
Camilla Lyon Dean
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Genetics

• Chromosome 9q31
• Ubiquitously expressed - especially in the liver,
  small intestine, adrenal glands, lungs, placenta
  and foetal tissues.
• Localised in plasma membrane and golgi of
  lysosomes.
• Complicated transcription regulation but
  importantly oxysterols and retinoids upregulate
  ABCA1 via LXR/RXR.

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Structure

• 2261aa
• 240kDa
• Difficult to determine precise topography but
  presently
• 2 transmembrane domains for translocation,
  composed of 6 alpha helices each
• 2 intracellular NBDs for ATP
• Amino terminus orientated into cytosol
• 2 large extracellular loops

Image adapted from www.genomenewsnetwork.org/.../a
bca_SNP_lg.jpg
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Triglyceride and Cholesterol Transport
DIET DERIVED
ENDOGENOUS
CM TG rich
VLDL TG rich
TISSUE
IDL
CMR TG rich
Pre ß HDL
Reverse cholesterol transport
a HDL
LIVER
LDL Cholesterol rich
LIVER

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Cholesterol uptake

• Most cells in the body can limit their
  cholesterol uptake by altering gene expression.
• Macrophages are unable to limit cholesterol
  uptake, mediated by uncontrolled scavenger
  receptors.
• Macrophage lipid level largely depends on
• EFFLUX

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Cholesterol Efflux
Image adapted from Cavelier C et al. 2006
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HDL Cholesterol (HDL-C)

• Phospholipids (PL) and cholesterol are effluxed
  from the cell onto lipid-poor pre-ß-HDL,
  containing Apolipoprotein A-I (ApoA-1).
• Cholesterol is esterified and moves to the core
  of the HDL particle, generating the large lipid
  rich a-HDL.
• Preß and a HDL Cholesterol can be differentiated
  by electrophoresis.
• a-HDL may exchange some cholesterol esters and
  ApoE for TG with VLDL before returning the
  remaining cholesterol esters and PL to the liver.

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Atherosclerosis

• Cholesterol influx gt Cholesterol efflux
• Excess cellular cholesterol is toxic, thus
  cholesterol is esterified by the macrophage and
  stored.
• Macrophages become activated foam cells,
  producing various growth factors, cytokines and
  proteases.
• This leads to atherosclerosis.

Image from www.brown.edu
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The Plasma Membrane

• Asymmetrical distribution of phospholipids
• External choline-containing phospholipids
• Phosphatidylcholine (PC)
• Sphingomyelin (SM)
• Internal amine-containing phospholipids
• Phosphatidylserine (PS)
• Phosphatidylethanolamine (PE)

Floppase e.g. ABCA1
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Tangier Disease (TD)

• Cause a variety of mutations in ABCA1 gene
• Very rare
• TD patients show
• extremely low level of HDL total lack of a-HDL,
  some preß-HDL
• reduced total cholesterol, raised triglycerides
• peripheral neuropathy
• accumulation of cholesterol esters in macrophage
  foam cells causing enlargement of the liver,
  spleen and tonsils.

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• Macrophage and fibroblast efflux of cholesterol
  and PL in TD is massively reduced.
• It has been concluded that ABCA1 transports both
  cholesterol and PL across the membrane,

Image from Nofer J.R and Remaley A.T. 2005
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BUT

• Recent research suggests that this is not the
  case.
• Fielding (2000) and others showed inhibition of
  cholesterol transport independent of ABCA1
  mediated phospholipid transport. Leading to a 2
  step model for HDL loading
• (1) Interaction of ApoA-1 with ABCA1, ABCA1
  DEPENDENT PL efflux and lipidation of ApoA-1 and
  conversion to a cholesterol accepting molecule.
• (2) ABCA1 INDEPENDENT cholesterol loading onto
  ApoA-1-PL complex.

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Image from Fielding et al., 2000
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Synergism with ABCG1?
Image adapted from Cavelier C et al. 2006
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Conclusion

• ABCA1 is essential for the lipidation of
  apolipoproteins (A1) and thus the formation of
  HDL-C, the key 1st step in reverse cholesterol
  transport.

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The FuturePPARs?

• Activated LXRs upregulate ABCA1 expression.
• Transcription of the LXRs is modulated by
  agonists of peroxisome proliferator-activated
  receptors (PPARa, ? and d).
• PPAR agonists have been shown to increase
  cholesterol efflux and reduce atherosclerosis in
  mice and chinese bama minipigs through increasing
  levels of both ABCA1 and ABCG1.

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References

• Fielding P, Nagao K, Hakamata H, Chimini G and
  Fielding C. 2000. A Two-Step Mechanism for Free
  Cholesterol and Phospholipid Efflux from Human
  Vascular Cells to Apolipoprotein A-1.
  Biochemistry 2000, 39, 14113-14120
• Cavelier C, Lorenzi I, Rohrer L and Von
  Eckardstein A. 2006. Lipid efflux by the
  ATP-binding cassette transporters ABCA1 and
  ABCG1. Biochimica et Biophysica Acta 1761 (2006)
  655666
• Nofer J.R and Remaley A.T. 2005. Tangier disease
  still more questions than answers. CMLS, Cell.
  Mol. Life Sci. 62 (2005) 21502160
• Paulusma C, Oude Elferink RPJ. 2006. Minireview
  Diseases of intramembranous lipid transport. FEBS
  Letters 580 (2006) 55005509
• ABC proteins from bacteria to man, pp479-481.
  (2003). Holland I.B., Cole S.P.C, Kuckler K. and
  Higgins, C.F., Eds. 2003. Academic Press, New
  York.  
• Medical Biochemistry, pp 207-210. Baynes J.
  Dominiczak, M.H. (2003) Elsevier Mosby,
  Philadelphia USA.