Mendelian Disorders of High-Density Lipoprotein Metabolism

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. an overview of the knowledge that has been obtained through mutations (or targeted disruption) of these genes and illustrates the current molecular details of HDL anabolism, conversion, and catabolism. The Table summarizes how mutations in these genes may affect atheroclerosis. TerminologyDefinitions of HDL and HDL-C The mobilization of cellular cholesterol by HDL, the transport of cholesterol by HDL in the circulation, and the hepatic uptake of HDL-C are generally considered as key to the function of this lipoprotein class. However, from a biochemical perspective, HDL-C is a mere figure indicating how much cholesterol is carried by the pool of HDL in blood. Unfortunately, the terms HDL and HDL-C are often used interchangeably. This leads to confusion and sometimes wrong interpretations. In the lay literature, HDL-C is often typed as the good cholesterol, suggesting that cholesterol is beneficial as long as it is in HDL that diverts from the multiple functions that are attributed to HDL that has little if nothing to do with its cholesterol component. In this review, HDL is used when either the particle or the pool of circulating HDL is meant, whereas HDL-C refers to the free cholesterol (FC) and cholesteryl ester (CE) carried by HDL in the circulation. HDL deficiency indicates that HDL and, therefore, HDL-C are (close to) absent. In an attempt to be comprehensive, we have combined genetic insights from both animal and human studies. Finally, the terms hypoalphalipoproteinemia and hyperalphalipoproteinemia are used when HDL-C concentrations are <10th percentile or >90th percentile for age and sex, respectively. Reverse Cholesterol Transport and Cellular Cholesterol HomeostasisReverse cholesterol transport is generally used to describe the transport of cholesterol by HDL from the vascular wall to the liver for excretion into bile as neutral sterol or bile acid. Despite ≈50 years of research, there is, as of yet, little evidence that HDL can transport cholesterol from the vessel...

Depletion in LpA-I:A-II particles enhances HDL-mediated endothelial protection in familial LCAT deficiency

“…HDL quantity and quality and HDL function, because carriers of inherited HDL disorders not only have extremely low or high HDL-C levels, but also have abnormal HDL subclass distributions (29).…”

HDL and atherosclerosis: Insights from inherited HDL disorders

“…More than 60 mutations in the APOA1 gene have been reported to date; more than half of them are associated with low plasma HDL-C levels [46], mostly located in the central region of apoA-I [47]. The apoA-I Milano (A-I M ), characterized by a cysteine for arginine substitution at position 173, has been the first apoA-I mutant described in humans [48,49], and it is the best characterized apoA-I variant.…”

Current Treatment of Dyslipidemia: Evolving Roles of Non-Statin and Newer Drugs

“…with these mutations, despite extremely low levels of HDL-C that led investigators to expect profound atherosclerosis, no consistent premature CHD was apparent [10,11]. Although still incomplete, the lack of genetic evidence argues against the HDL hypothesis.…”