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Published on: November 17, 2018
Mendelian disorders of high-density lipoprotein metabolism
Federico Oldoni1, Richard J Sinke, Jan Albert Kuivenhoven
1From the Departments of Molecular Genetics (F.O., J.A.K.) and Genetics (R.J.S.), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Insights
High-density lipoproteins (HDL) are diverse and dynamic. Genetic mutations significantly impact HDL cholesterol levels, influencing its metabolism and cellular cholesterol balance.
Area of Science:
- Lipid Metabolism
- Molecular Genetics
- Cardiovascular Research
Background:
- High-density lipoproteins (HDL) are heterogeneous, dynamic particles crucial for cholesterol transport.
- HDL metabolism is intricately linked with triglyceride-rich lipoprotein metabolism and cellular cholesterol homeostasis.
Purpose of the Study:
- To review current molecular insights into HDL metabolism.
- To explore the genetic basis of HDL cholesterol levels, focusing on gene mutations affecting HDL and triglyceride metabolism.
Main Methods:
- Analysis of human and animal studies detailing gene mutations impacting HDL cholesterol.
- Review of literature on HDL production, circulation remodeling, catabolism, and cellular cholesterol transport.
Main Results:
- HDL cholesterol levels are genetically heterogeneous, influenced by approximately 40 genes.
- Gene variants affecting HDL metabolism are typically inherited in an autosomal-dominant manner, with heterozygotes being most common.
Conclusions:
- Understanding HDL metabolism requires integrating knowledge of genetics, lipoprotein interactions, and cellular processes.
- Only three Mendelian disorders of HDL metabolism are currently identified, all inherited in an autosomal-recessive mode.
Abstract:
High-density lipoproteins (HDLs) are a highly heterogeneous and dynamic group of the smallest and densest lipoproteins present in the circulation. This review provides the current molecular insight into HDL metabolism led by articles describing mutations in genes that have a large affect on HDL cholesterol levels through their roles in HDL and triglyceride metabolism. Using this information from both human and animal studies, it is discussed how HDL is produced, remodeled in the circulation, affected by factors that control the metabolism of triglyceride-rich lipoproteins, how it helps maintain cellular cholesterol homeostasis, and, finally, how it is catabolized. It can be concluded that HDL cholesterol as a trait is genetically heterogeneous, with as many as 40 genes involved. In most cases, only heterozygotes of gene variants are known, and HDL cholesterol as a trait is inherited in an autosomal-dominant manner. Only 3 Mendelian disorders of HDL metabolism are currently known, which are inherited in an autosomal-recessive mode.
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