The metabolism of high-density lipoproteins (HDL), which are inversely related to risk of atherosclerotic cardiovascular disease, involves a complex interplay of factors regulating HDL synthesis, intravascular remodeling, and catabolism. The individual lipid and apolipoprotein components of HDL are mostly assembled after secretion, are frequently exchanged with or transferred to other lipoproteins, are actively remodeled within the plasma compartment, and are often cleared separately from one another. HDL is believed to play a key role in the process of reverse cholesterol transport (RCT), in which it promotes the efflux of excess cholesterol from peripheral tissues and returns it to the liver for biliary excretion. This review will emphasize 3 major evolving themes regarding HDL metabolism and RCT. The first theme is that HDL is a universal plasma acceptor lipoprotein for cholesterol efflux from not only peripheral tissues but also hepatocytes, which are a major source of cholesterol efflux to HDL. Furthermore, although efflux of cholesterol from macrophages represents only a tiny fraction of overall cellular cholesterol efflux, it is the most important with regard to atherosclerosis, suggesting that it be specifically termed macrophage RCT. The second theme is the critical role that intravascular remodeling of HDL by lipid transfer factors, lipases, cell surface receptors, and non-HDL lipoproteins play in determining the ultimate metabolic fate of HDL and plasma HDL-c concentrations. The third theme is the growing appreciation that insulin resistance underlies the majority of cases of low HDL-c in humans and the mechanisms by which insulin resistance influences HDL metabolism. Progress in our understanding of HDL metabolism and macrophage reverse cholesterol transport will increase the likelihood of developing novel therapies to raise plasma HDL concentrations and promote macrophage RCT and in proving that these new therapeutic interventions prevent or cause regression of atherosclerosis in humans.

New insights into the regulation of HDL metabolism and reverse cholesterol transport.

High-density lipoprotein (HDL) has been proposed to have several antiatherosclerotic properties, including the ability to mediate macrophage cholesterol efflux, antioxidant capacity, antiinflammatory properties, nitric oxide–promoting activity, and ability to transport proteins with their own intrinsic biological activities.1 HDL particles are critical acceptors of cholesterol from lipid-laden macrophages and thereby participate in the maintenance of net cholesterol balance in the arterial wall and in the reduction of proinflammatory responses by arterial cholesterol-loaded macrophages. The pathways that regulate HDL-mediated macrophage cholesterol efflux and disposition of cholesterol involve cell membrane–bound transporters, plasma lipid acceptors, plasma proteins and enzymes, and hepatic cellular receptors (Figure 1). From the earliest proposed concept for HDL-mediated cholesterol efflux,2,3 the concentration of the cholesterol content in HDL particles has been considered a surrogate measurement for the efficiency of the “reverse cholesterol transport” (RCT) process; however, macrophage-derived cholesterol represents a minor component of the cholesterol transported by HDL particles.4–7 One important pathway for cholesterol-mediated efflux from macrophage foam cells involves interaction between the ATP-binding cassette transporter A1 (ABCA1) and cholesterol-deficient and phospholipid-depleted apolipoprotein (apo) A-I complexes (pre-β migrating HDL or very small HDL [HDL-VS]; Figure 2).1,8 Subsequently, the ATP-binding cassette transporter G1 (ABCG1) mediates macrophage cholesterol efflux through interactions (Figure 3) with spherical, cholesterol-containing α-HDL particles (small HDL [HDL-S], medium HDL [HDL-M], large HDL [HDL-L], and very large (HDL-VL).1 In contrast, the scavenger receptor class B type I (SR-BI) is a multifunctional receptor that mediates bidirectional lipid transport in the macrophage, which is dependent on the content of cholesterol in lipid-laden macrophages. A more established role for SR-BI in cholesterol trafficking involves selective uptake of cholesteryl esters from mature HDL by the liver. Recent studies suggest that polymorphisms in SR-BI contribute to the functional capacity of this cholesterol …

Cholesterol Efflux and Atheroprotection Advancing the Concept of Reverse Cholesterol Transport

High-density lipoproteins (HDL) possess key atheroprotective biological properties, including cellular cholesterol efflux capacity, and anti-oxidative and anti-inflammatory activities. Plasma HDL particles are highly heterogeneous in physicochemical properties, metabolism, and biological activity. Within the circulating HDL particle population, small, dense HDL particles display elevated cellular cholesterol efflux capacity, afford potent protection of atherogenic low-density lipoprotein against oxidative stress and attenuate inflammation. The antiatherogenic properties of HDL can, however be compromised in metabolic diseases associated with accelerated atherosclerosis. Indeed, metabolic syndrome and type 2 diabetes are characterized not only by elevated cardiovascular risk and by low HDL-cholesterol (HDL-C) levels but also by defective HDL function. Functional HDL deficiency is intimately associated with alterations in intravascular HDL metabolism and structure. Indeed, formation of HDL particles with attenuated antiatherogenic activity is mechanistically related to core lipid enrichment in triglycerides and cholesteryl ester depletion, altered apolipoprotein A-I (apoA-I) conformation, replacement of apoA-I by serum amyloid A, and covalent modification of HDL protein components by oxidation and glycation. Deficient HDL function and subnormal HDL-C levels may act synergistically to accelerate atherosclerosis in metabolic disease. Therapeutic normalization of attenuated antiatherogenic HDL function in terms of both particle number and quality of HDL particles is the target of innovative pharmacological approaches to HDL raising, including inhibition of cholesteryl ester transfer protein, enhanced lipidation of apoA-I with nicotinic acid and infusion of reconstituted HDL or apoA-I mimetics. A preferential increase in circulating concentrations of HDL particles possessing normalized antiatherogenic activity is therefore a promising therapeutic strategy for the treatment of common metabolic diseases featuring dyslipidemia, inflammation, and premature atherosclerosis.

Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis

Arguably the most critical advancement in the elucidation of factors affecting atherogenesis has been the development of mouse models of atherosclerosis. Among available models, the apolipoprotein E–deficient (apoE−/−) mouse is particularly popular because of its propensity to spontaneously develop atherosclerotic lesions on a standard chow diet. A Medline search reveals over 645 articles dedicated to studies using this reliable and convenient “super” animal model since its inception (Piedrahita JA et al, Proc Natl Acad Sci U S A 1992;89:4471–4475; Plump AS et al, Cell 1992;71:343–353) with a more or less steady increase from year to year. This review will examine our present understanding of the pathology and progression of plaques in this animal and highlight some of the nutritional, pharmacological, and genetic studies that have enhanced this understanding.

Atherosclerosis in the apolipoprotein-E-deficient mouse: a decade of progress.

Blood high-density lipoprotein (HDL) levels are inversely related to risk for cardiovascular disease, implying that factors associated with HDL metabolism are atheroprotective. One of these factors is ATP-binding cassette transporter A1 (ABCA1), a cell membrane protein that mediates the transport of cholesterol, phospholipids, and other metabolites from cells to lipid-depleted HDL apolipoproteins. ABCA1 transcription is highly induced by sterols, a major substrate for cellular export, and its expression and activity are regulated posttranscriptionally by diverse processes. Liver ABCA1 initiates formation of HDL particles, and macrophage ABCA1 protects arteries from developing atherosclerotic lesions. ABCA1 mutations can cause a severe HDL deficiency syndrome characterized by cholesterol deposition in tissue macrophages and prevalent atherosclerosis. Genetic manipulations of ABCA1 expression in mice also affect plasma HDL levels and atherogenesis. Metabolites elevated in individuals with the metabolic syndrome and diabetes destabilize ABCA1 protein and decrease cholesterol export from macrophages. Moreover, oxidative modifications of HDL found in patients with cardiovascular disease reduce the ability of apolipoproteins to remove cellular cholesterol by the ABCA1 pathway. These observations raise the possibility that an impaired ABCA1 pathway contributes to the enhanced atherogenesis associated with common inflammatory and metabolic disorders. The ABCA1 pathway has therefore become an important new therapeutic target for treating cardiovascular disease.

https://www.physiology.org/doi/pdf/10.1152/physrev.00005.2005

ATP-Binding Cassette Transporter A1: A Cell Cholesterol Exporter That Protects Against Cardiovascular Disease

The role of hepatic lipase as a multifunctional protein that modulates lipoprotein metabolism and atherosclerosis has been extensively documented over the last decade. Hepatic lipase functions as a lipolytic enzyme that hydrolyzes triglycerides and phospholipids present in circulating plasma lipoproteins. Hepatic lipase also serves as a ligand that facilitates lipoprotein uptake by cell surface receptors and proteoglycans, thereby directly affecting cellular lipid delivery. Recently, another process by which hepatic lipase modulates atherogenic risk has been identified. Bone marrow transplantation studies demonstrate that hepatic lipase present in aortic lesions markedly alters aortic lesion formation even in the absence of changes in plasma lipids. These multiple functions of hepatic lipase, which facilitate not only plasma lipid metabolism but also cellular lipid uptake, can be anticipated to have a major and complex impact on atherogenesis. Consistently, human and animal studies support proatherogenic and antiatherogenic roles for hepatic lipase. The concept of hepatic lipase as mainly a lipolytic enzyme that reduces atherogenic risk has evolved into that of a complex protein with multiple functions that, depending on genetic background and sites of expression, can have a variable effect on atherosclerosis.

Hepatic Lipase, Lipoprotein Metabolism, and Atherogenesis

Hepatic lipase (HL) has a well-established role in lipoprotein metabolism. However, its role in atherosclerosis is poorly understood. Here we demonstrate that HL deficiency raises the proatherogenic apoB-containing lipoprotein levels in plasma but reduces atherosclerosis in lecithin cholesterol acyltransferase (LCAT) transgenic (Tg) mice, similar to results previously observed with HL-deficient apoE-KO mice. These findings suggest that HL has functions that modify atherogenic risk that are separate from its role in lipoprotein metabolism. We used bone marrow transplantation (BMT) to generate apoE-KO and apoE-KO × HL-KO mice, as well as LCAT-Tg and LCAT-Tg × HL-KO mice, chimeric for macrophage HL gene expression. Using in situ RNA hybridization, we demonstrated localized production of HL by donor macrophages in the artery wall. We found that expression of HL by macrophages enhances early aortic lesion formation in both apoE-KO and LCAT-Tg mice, without changing the plasma lipid profile, lipoprotein lipid composition, or HL and lipoprotein lipase activities. HL does, however, enhance oxidized LDL uptake by peritoneal macrophages. These combined data demonstrate that macrophage-derived HL significantly contributes to early aortic lesion formation in two independent mouse models and identify a novel mechanism, separable from the role of HL in plasma lipoprotein metabolism, by which HL modulates atherogenic risk in vivo.

https://dm5migu4zj3pb.cloudfront.net/manuscripts/16000/16484/JCI0316484.pdf

Zengxuan Nong

Papers

Hepatic Lipase, Lipoprotein Metabolism, and Atherogenesis

Hepatic lipase expression in macrophages contributes to atherosclerosis in apoE-deficient and LCAT-transgenic mice

Identification of mouse and human macrophages as a site of synthesis of hepatic lipase

The Ligand-binding Function of Hepatic Lipase Modulates the Development of Atherosclerosis in Transgenic Mice