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Understanding High HDL: Quantity, Quality, and Functionality
HDL Quantity and Cardiovascular Health
High-density lipoproteins (HDL) are often referred to as "good" cholesterol due to their role in transporting cholesterol from the arteries to the liver for excretion. Epidemiological studies have shown an inverse relationship between serum HDL-C concentrations and the risk of coronary heart disease (CHD), even at low levels of low-density lipoprotein cholesterol (LDL-C). However, recent genetic and clinical research challenges the notion that higher HDL-C levels are always beneficial. Instead, HDL functionality, particularly its cholesterol efflux capacity (CEC), is a more critical factor in atheroprotection.
HDL Quality: Composition and Modification
The quality of HDL is determined by its protein and lipid content, extent of oxidation, and glycation. HDL quality can change due to various factors, including infection, disease, and lifestyle choices such as diet and exercise. High HDL-C levels are generally associated with good HDL quality and functionality, but this is not always the case. Dysfunctional HDL, characterized by lower apoA-I content, reduced antioxidant ability, smaller size, and ambiguous shape, is often linked to acute infectious diseases and chronic aging-related diseases.
HDL Functionality: Beyond Cholesterol Transport
HDL functionality encompasses several performance metrics, including antioxidant, anti-inflammatory, and cholesterol efflux activities. HDL's role in cholesterol efflux from macrophages is a key metric of its functionality and is strongly inversely associated with carotid intima-media thickness and coronary artery disease (CAD). HDL also plays a role in reducing atherosclerosis by facilitating cholesterol efflux from foam cells, decreasing oxidized LDL, and increasing nitric oxide synthesis.
HDL and Neurodegenerative Disorders
Emerging evidence suggests that HDL may play a pivotal role in preserving cognitive function and protecting against neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. HDL's anti-inflammatory and antioxidative properties are believed to contribute to its protective effects on the central nervous system. Additionally, HDL functionality has been linked to the removal of β-amyloid plaques and inhibition of α-synuclein aggregation in the brain, potentially attenuating Alzheimer's and Parkinson's diseases.
HDL's Antioxidant and Antiviral Properties
HDL has significant antioxidant properties, primarily due to enzymes like paraoxonase-1 (PON1), which metabolize lipid hydroperoxides and prevent their accumulation on LDL, thus impeding atherogenic modifications. Furthermore, native HDL exhibits potent antiviral activity against SARS-CoV-2, while glycated HDL loses this antiviral activity, highlighting the importance of HDL quality in immune function.
Clinical Implications and Future Directions
The evolving understanding of HDL's role in cardiovascular and overall health suggests that future therapeutic strategies should focus on enhancing HDL functionality rather than merely increasing HDL-C levels. Clinical trials are underway to develop new HDL-raising drugs that could potentially reduce cardiovascular events by improving HDL functionality. Additionally, the identification of specific HDL subspecies associated with either higher or lower risk of CHD could lead to more targeted and effective treatments.
Conclusion
While high HDL-C levels have traditionally been viewed as protective against cardiovascular disease, recent research underscores the importance of HDL quality and functionality. Factors such as HDL composition, antioxidant properties, and cholesterol efflux capacity play crucial roles in determining HDL's protective effects. As our understanding of HDL continues to evolve, future therapies may focus on enhancing HDL functionality to improve cardiovascular and overall health outcomes.
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