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Cholesterol Homeostasis: An In Silico Investigation into How Aging Disrupts Its Key Hepatic Regulatory Mechanisms.
Amy Elizabeth Morgan1, Mark Tomás Mc Auley1
1Faculty of Science and Engineering, University of Chester, Thornton Science Park, Chester CH2 4NU, UK.
Biology
|October 3, 2020
Summary
Aging significantly impacts liver cholesterol balance. A computational model shows reduced ACAT2 activity, not increased HMGCR, most affects cholesterol levels, with implications for age-related diseases like NAFLD and CVD.
Area of Science:
- Biochemistry
- Computational Biology
- Gerontology
Background:
- Intracellular cholesterol homeostasis is crucial for preventing age-related diseases, particularly cardiovascular disease (CVD).
- Computational modeling aids in understanding complex regulatory systems like cholesterol homeostasis, including enzymatic reactions and feedback loops.
- Existing models have not specifically addressed the impact of aging on hepatic cholesterol regulation.
Purpose of the Study:
- To develop and utilize a computational model to investigate the effects of aging on hepatic intracellular cholesterol homeostasis.
- To explore the influence of reactive oxygen species on 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity in the context of aging.
- To examine the impact of age-related decreases in hepatic acetyl-CoA acetyltransferase 2 (ACAT2) activity.
Main Methods:
- Development of a computational model simulating hepatic intracellular cholesterol homeostasis.
- Investigation of HMG-CoA reductase activation by reactive oxygen species using the model.
- Analysis of the effects of decreased hepatic ACAT2 activity on cholesterol metabolism.
Main Results:
- The model indicates that a decrease in hepatic ACAT2 activity has a more significant impact on cholesterol homeostasis than increased HMGCR activity.
- Reduced ACAT2 activity leads to increased free cholesterol (FC) and decreased low-density lipoprotein cholesterol (LDL-C) levels.
- Increased acetyl-CoA synthesis results in reduced hepatic LDL receptors, elevated LDL-C, FC, and cholesterol esters, with FC accumulation partially restricting LDL-C rise.
Conclusions:
- Age-related changes in hepatic ACAT2 activity play a critical role in cholesterol dysregulation.
- Findings suggest a link between hepatic FC accumulation, non-alcoholic fatty liver disease (NAFLD), and increased CVD risk in aging populations.
- The model's results may help explain increased mortality in the oldest old associated with low LDL-C levels.
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