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Published on: January 22, 2019
Cyclosporine A and PSC833 inhibit ABCA1 function via direct binding
Kohjiro Nagao1, Minami Maeda, Noralyn B Mañucat
1Institute for integrated Cell-Material Sciences (iCeMS), Kyoto University, Kyoto 606-8502, Japan.
Biochimica Et Biophysica Acta
|November 17, 2012
Summary
Cyclosporine A and PSC833 directly bind and inhibit ATP-binding cassette protein A1 (ABCA1), a key factor in high-density lipoprotein (HDL) formation. PSC833 is a promising tool for studying HDL biogenesis mechanisms.
Area of Science:
- Biochemistry
- Molecular Biology
- Lipid Metabolism
Background:
- ATP-binding cassette protein A1 (ABCA1) is crucial for high-density lipoprotein (HDL) biogenesis.
- The precise mechanisms governing HDL formation are not fully understood.
- Specific chemical inhibitors are needed to elucidate ABCA1's role in HDL production.
Purpose of the Study:
- To investigate the inhibitory effects of cyclosporine A and related compounds on ABCA1 function.
- To determine if cyclosporine A's inhibition of ABCA1 is mediated through calcineurin.
- To identify novel chemical tools for studying HDL formation.
Main Methods:
- Utilized BHK/ABCA1 cells to assess ABCA1-mediated cholesterol efflux.
- Tested various compounds including cyclosporine A, FK506, pimecrolimus, rapamycin, and PSC833.
- Performed radioligand binding assays using [(3)H] cyclosporine A with purified ABCA1.
Main Results:
- Cyclosporine A, FK506, pimecrolimus, and rapamycin inhibited ABCA1-mediated cholesterol efflux in a dose-dependent manner.
- The effective concentrations for ABCA1 inhibition were higher than those affecting the primary targets of these drugs, suggesting direct ABCA1 interaction.
- Direct binding of [(3)H] cyclosporine A to ABCA1 was observed.
- PSC833, a non-immunosuppressive cyclosporine derivative, potently inhibited ABCA1 and competed for cyclosporine A binding.
Conclusions:
- Cyclosporine A and PSC833 directly bind to ABCA1, inhibiting its function in cholesterol efflux.
- The observed inhibition is likely independent of calcineurin or mTOR pathways.
- PSC833 is a valuable, direct ABCA1 inhibitor for future research into HDL formation mechanisms.
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