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Expression of ATP binding cassette-transporter ABCG1 prevents cell death by transporting cytotoxic
Thomas Engel1, Frank Kannenberg, Manfred Fobker
1Leibniz-Institute for Arteriosclerosis Research, Westphalian Wilhelms-University, 48149 Muenster, Germany. engeltho@uni-muenster.de <engeltho@uni-muenster.de>
Abstract:
Oxysterols result from cholesterol by enzymatic or oxidative processes. Some exert cytotoxic effects leading to necrosis or apoptosis. Detoxification of these compounds mainly occurs in the liver and requires transport from peripheral tissues towards it. Some ATP-binding cassette transporters are involved in export of cytotoxic compounds. In the current study, we investigated whether ABC transporter family member G1 (ABCG1) may be involved in oxysterol transport, since its gene expression is highly responsive to oxysterol loading. TetOff HeLa cells stably expressing ABCG1 showed decreased mass uptake of 7beta-hydroxycholesterol (7beta-HC) whereas that of other physiologically relevant oxysterols was unaffected. Application of 7beta-HC to ABCG1 expressing cells induced hyperpolarization of mitochondrial membrane potential and production of reactive oxygen species, indicating energy consumption by the ATP-binding cassette transporter when it is activated by its correct substrate. Our study points to detoxification as one of potential cellular functions of ABCG1. We assume that ABCG1 protects against 7beta-HC-induced cell death, an important role in prevention of neurodegenerative and cardiovascular disease.
Insights
ATP-binding cassette transporter G1 (ABCG1) facilitates the detoxification of 7beta-hydroxycholesterol (7beta-HC). This suggests ABCG1 plays a crucial role in preventing cell death and may aid in preventing neurodegenerative and cardiovascular diseases.
Area of Science:
- Cellular biology
- Biochemistry
- Molecular mechanisms of disease
Background:
- Oxysterols, derived from cholesterol, can induce cell death through necrosis or apoptosis.
- Detoxification of oxysterols primarily occurs in the liver, necessitating transport from peripheral tissues.
- ATP-binding cassette (ABC) transporters are known to export cytotoxic compounds.
Purpose of the Study:
- To investigate the potential role of ATP-binding cassette transporter G1 (ABCG1) in oxysterol transport.
- To determine if ABCG1 is involved in the cellular detoxification of oxysterols.
- To explore the functional consequences of ABCG1 activation by oxysterols.
Main Methods:
- Stable expression of ABCG1 in TetOff HeLa cells.
- Measurement of intracellular oxysterol uptake, specifically 7beta-hydroxycholesterol (7beta-HC).
- Assessment of mitochondrial membrane potential and reactive oxygen species production in response to 7beta-HC.
Main Results:
- ABCG1 expression led to decreased uptake of 7beta-hydroxycholesterol (7beta-HC) in HeLa cells.
- Other physiologically relevant oxysterols were not affected in their uptake.
- 7beta-HC exposure in ABCG1-expressing cells triggered mitochondrial hyperpolarization and reactive oxygen species generation, indicating transporter activation and energy consumption.
Conclusions:
- ABCG1 functions in the detoxification of 7beta-hydroxycholesterol (7beta-HC).
- ABCG1 activation by 7beta-HC suggests a protective role against oxysterol-induced cell death.
- This protective mechanism may be significant in preventing neurodegenerative and cardiovascular diseases.
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