|Ahead of print publication
Role of high-density lipoprotein cholesterol in health and diseases
Brijesh Yadav1, Narayan Prasad2
1 Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Nephrology and Renal Transplant, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Submission||29-Aug-2020|
|Date of Acceptance||15-Dec-2020|
Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
Primary function of high-density lipoprotein cholesterol is to reverse transport the cholesterol from extrahepatic cell to liver for its metabolism and excretion. Studies have demonstrated the anti-inflammatory, anti-atherogenic, anti-oxidant, and anti-diabetic property of the high-density lipoprotein cholesterol. Although the exact mechanism still remains unelucidated, high-density lipoprotein cholesterol is a complex of lipids and proteins carrying many associated cargo molecules such as enzymes, signaling molecules, miRNA, which imparts overall functionality of high-density lipoprotein cholesterol for its beneficial health effects. However, the protein and lipids components get transform by the enzymes associated with high-density lipoprotein cholesterol, hyperglycemia, oxidative stressor, and free radicals, leading to qualitative and quantitative alterations in high-density lipoprotein cholesterol (HDLc) and diminishes its beneficial effects. In this review, we have discussed the different property of high-density lipoprotein cholesterol, its function and factors influencing HDLc property in light of anti-inflammatory activity in rheumatoid arthritis and the role of cholesterol-lowering statin drug in enhancing the beneficial effect of high-density lipoprotein cholesterol in different cell types.
Keywords: ABCA1, Apo-A1, cholesterol, high-density lipoprotein cholesterol, treg
| High-Density Lipoprotein Cholesterol|| |
High-density lipoprotein cholesterol (HDLc) is a heterogeneous complex of >200 lipids species, >80 proteins and several miRNA, biologically active compounds, enzymes paraoxonase, myeloperoxidase (MPO), haptoglobulin, signaling molecule sphingosine-1-phosphate (S1P), lipopolysaccharides-binding proteins (LBPs), phospholipid transfer protein (PLTP) and other associated cargo molecules, which renders structural and functional hetrogenity to HDLc.,
Depending on decreasing lipids to protein ration, lipoproteins are classified as low-density lipoprotein (LDL), intermediate density lipoprotein (IDL), and high-density lipoprotein (HDL). HDLc have the lowest lipids to protein ration making HDLc most densest particle compare to its others siblings. Further, depending upon the proportions of lipids and protein, lipo-protein complex attain a different packaging volume and density, leading to different buoyant density. The density of HDL fall between 1.06 and 1.21 g/ml and size of 6 and 12.5 nM.
A complex proportions of lipids and protein renders HDLc heterogeneity in terms of size, shape, and functions. Important apoprotein associated with HDLc are apo-A, C, L1, M and E, of these two major apo-protein of HDLc are Apo-AI (70%) and apo-A II (20%). Apolipoprotein-A1 is the most important and abundant protein of HDLc require for executing it's most of the functions. Patients with higher HDLc level experience less likely to develop cardiovascular complications and other inflammatory diseases and witness overall health benefits.,, However, the mechanism, how increased HDLc level mediates the beneficial effect remained unelucidated till recent few year back.
| Formation of High-density Lipoprotein Cholesterol|| |
The major protein components of the HDLc, are apo-protein AI and AII (apo-A), synthesized by the liver hepatocytes and intestinal cell, which are further trans-conjugated with phospholipids and cholesterol moiety, leading to the formation of a discoidal pre-β HDLc apo-lipoprotein molecules. This step is facilitated by ATP binding cassette transporter-A1/G1. ABCA/G1 is a cell membrane-associated efflux transporter (ATP-binding cassette transporter) transfer cellular cholesterol to the apo-A1 protein of HDLc. ABCA/G1 is expressed by the adipocyte, hepatocyte, muscle, and other cells. Further, liver synthesized, plasma enzyme lecithin cholesterol acyltransferase (LCAT), esterify free cholesterol of pre-β HDLc into cholesteryl ester, burying the nonpolar cholesteryl ester and triglyceride residue inside the core, this leads to formation of a mature spherical HDLc particle.
| High-Density Lipoprotein Cholesterol Status in the Indian Population|| |
As per the guideline of Indian Society of the heart, the targeted range of normal HDLc level corresponds to 50–60 mg/dl in the South Asian population. However, HDLc below 40 mg/dl in male and 50 mg/ml in female poses a individual for greater risk of cardiovascular disease. A study shows that approximately 0.75%–1% of the Indian population have rheumatide arthritis (RA) and 38.5% Indian RA patient exhibits dyslipidemia, of which 34.3% had deficiency of HDLc. A multicentric cohort study in the Indian population shows the prevalence of dyslipidemia in 79% of population and HDLc deficiency occurs in 72.3% of the population, of which 13% had hypercholesteremia, 25.9% had hypertriglyceridemia, and 11.8% had high level of LDLc. This dyslipidemia was most prevalent in urban resident compared to rural resident., In the rural population, 1 out of 450 persons had hypercholesterolemia compared to 1 out of 125 persons in the urban population. However, another study shows that there is no difference in dyslipidemia trend between the rural and urban population. Further, this HDLc level was asymmetrically lower in female compared to male., However, the incidence of rheumatoid arthritis is 3–4 time more in female compare to male, suggesting a lower HDLc level may be a major risk factor in female for developing rheumatoid arthritis., An increasing urbanization, change in life-style, and dietary ingredients are the major driver for this dyslipidemia [Figure 1].
|Figure 1: Regeneration and metabolism of high-density lipoprotein cholesterol: In extrahepatic cells such as macrophage, muscle express ABCA1 transporter, which effluxes extra-phospholipids and cholesterol to apo-AI protein and form a discoidal premature pre-β high-density lipoprotein cholesterol. Further, enzyme lecithin: Cholesterol acyltransferase esterify the cholesterol into cholesteryl ester, leading sequestration of hydrophobic residue inside the core and forming a mature globular shape high density lipoprotein cholesterol. Apo-A1 protein binds to scavenger receptor of the hepatocytes and deliver cholesteryl ester into hepatocytes cell, where it is converted into bile acid and get excreted into feces|
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| High-Density Lipoprotein Cholesterol Biogenesis and Recycling|| |
Apolipoprotein-A1 of HDLc binds to scavenger receptor class B type 1 (SR-B1) expressed in hepatocytes and other steroidogenic tissue for receiving cholesterol from HDLc, for its recycling and steroid hormone synthesis. Lipids and cholesterol loaded apo-A1 protein of HDLc interact with the receptor scavenger-B type 1 of hepatocyte and deliver most of the lipids and cholesterol to hepatocyte cell and attains lower lipid cholesterol state. Free cholesterol in the liver is converted into bile acid by the enzyme cholesterol 7-alpha-hydroxylase and get excreted in feces. Furthermore, ABCA1 transporter re-loads HDLc with newer cholesterol and phospholipids molecules and which again get delivered in the liver for recycling, in this way HDLc keep reverse transporting extracholesterol and maintain a optimum level of cholestrol in our body. PLTP also transfer excess membrane triglyceride phospholipid to HDLc to maintain a definite proportion of phospholipids in HDLc particle.
| Immunomodulatory Mechanism of High-Density Lipoprotein Cholesterol|| |
HDLc possesses potent anti-inflammatory property, which is due to the distribution of cholesterol in the lipid raft of the plasma membrane. Lipid raft is tiny micro-domain structure concentrated with lipid and protein complex in the cell membrane. Cholestrol is required for maintaining the fluidity of membrane. ABCA1 transporter in cell membrane transfer cholesterol to apo-A1 of the HDLc and efflux it from cell, resulting re-distribution of the membrane proteins. Many cellular signaling receptors such as TLRs, B-cell receptor, TCRs, MHC, ABCA1 remains interspersed in lipid raft,, thus redistribution of membrane proteins leads modulation of the signaling pathways in immune cells. An reduced cholesterol content decreases the fluidity of the membrane and attenuates the protein to protein interaction resulting diminished signaling. Furthermore, apoA-1 protein strongly binds to bacterial toxins lipopolisaccharides and lipoteichoic acid and help in its clearance in the liver from the serum by binding to SR-B1 of hepatocytes thus preventing endotoxemia and decreasing inflammatory cytokines secretion from the macrophage cell., A study shows that, an increased level of HDLc and apoA1 is associated with decrease leukocytosis, recruitment of monocyte-macrophage and neutrophils cell to endothelial cell in different organs thus prevents inflamation. An apoA-1 knockout mice shows reduced serum corticosteron level and increased inflammatory cytokines level and impaired polymorphonuclear cell recruitment in septicemic mice.
Furthermore, cholestrol is required for the corticosteron hormone synthesis, a reduced HDLc level in septicemia patients hampers corticosteron synthesis, consequently, corticosteron mediated regulation of innate immune response remains diminish leading to septicemia. This further suggesting that, a reduced level of HDLc is associated with increased inflammation and disease activity in RA patient. It has been observed that the frequency and functionality of Treg get increased after the treatment with the cholesterol lowering drug simvastatin in patient with acute coronary syndrome, both in-vivo in plaques and in vitro in PBMCs culture, this was further confirmed by Perea et al. that both lovastatin and atorvastatin treatment in healthy volunteer lead increased Treg cell frequency and Treg-associated signature molecule FoxP3, TGF-β expression. They also shown, a circulating HDLc level was positively correlated with Treg cell frequency. Since statin drug also partially increases the HDLc level, which is selectively endocytosed by the Treg for metabolism and longer survival, suggesting that it may be actually the Treg playing a role in all the beneficial effects of serum HDLc meditated by statin drug. However, data on HDLc-mediated Treg immune function are scanty.
Furthermore, treatment with apo-A1 in hypercholesteremic mice leads to increased Treg cell proliferation and decreased T-cell activation in skin and lymph node in autoimmune disease mouse model of systemic lupus erythematous (SLE) and RA. Similarly, an deficiency of scavenger receptor-B type 1 lead 3–4 fold increase in T- and B-cell proliferation, monocyte, macrophage proliferation and inflammatory cytokines interleukin (IL)-6, interferon-gamma (IFN-γ) secretion. Suggesting apo-A1 and its receptors SR-B1 are important for mediating anti-inflammatory property of HDLc.
| High-density Lipoprotein Cholesterol Diminishes Inflammatory Cell Response|| |
One of the important functions of HDLs is the regulation of exaggerated immune response in different diseases. A decrease in HDLc level was frequently occurs in patient with septicemia and associated with poor prognosis. HDLc inhibits the maturation of dendritic cell and Myd88 transcription and co-stimulatroy molecule expression. Myd88 is crucial for the NF-kb mediated cytokine secretion for maturation of helper Th17 and Th1 cell function and cytokine secretion. HDLc further diminishes the inflammatory cytokines IL-12, IL-6, and IL-1β expression from the macrophage. In vitro studies show that recombinant HDLc decreases activation of bone marrow-derived dendritic cell consequently diminished the activation and proliferation of T-helper cell and inflammatory cytokines IFN-γ, IL-17 secretion from Th1 and Th17 cell in rheumatoid arthritis mouse model. In addition, IL-17A together with increased cholesterol level mediates IL-8, CCL20 secretion from the keratinocyte cell in psoriasis mouse model.
Furthermore, HDLc-associated protein S1P signaling further induces tight junctional protein Zonula occludens-1, claudin expression in endothelial cell, which seals the intercellular space between the endothelial cell and prevents the leakage of inflammatory molecules and cells from the capillaries to extracellular space. In addition, S1P signaling also induces motility of endothelial cell to repair injured tissue. Sphinogosin-1-phosphate binds to S1P2 receptor of macrophage cell and inhibits its recruitment at inflammation site, further S1P is a strong signaling molecules, attenuates TLR2 dependent inflammatory cytokine secretion from the macrophage cell.
| High-Density Lipoprotein Cholesterol Promotes T-Regulatory Cell|| |
Treg is anti-inflammatory subset of T-cell counter the malicious effect of inflammatory immune cell. Recently, a study published in the Journal of Lipid Research, where CM Reuda et al. has explored the mechanism of HDL action in Treg cell in details, they demonstrated that T-reg cell preferably rely on HDL for their metabolic energy source. To achieve it, Treg selectively expressed two-fold higher level of SR-B1, through which HDLc was selectively in taken by Treg. Treg cell treated with HDLc showed an increase oxidative phosphorylation activity, increased ATP synthesis and respiration rate, which was diminished by blocking SR-B1 with antibody. Similarly, they mimic the HDLc with albumin loaded with oleate, which still could promote the Treg survival, suggesting a selective dependence of Treg on fatty acid metabolism and providing an opportunity to manipulate dietary fat for Treg enhancement. Although earlier study also suggested that T-cell prefer fatty acid for their metabolism. Similarly, they also found that low-density lipoprotein cholesterol (LDL)-receptor expression was quite lower in Treg compared to their naive counterpart. A diminish Treg cell frequency and functionality has been seen in many inflammatory diseases.,, However, systematic monitoring of HDLc level and Treg cell frequency in the inflammatory disease largely remained obscure in previous studies., A monitoring and restoring of optimum level of HDLc may have beneficial effect in stabilizing the inflammatory immune response.
| Modification of High-Density Lipoprotein Cholesterol and Functional Alteration|| |
The qualitative and quantitative alteration in lipid and protein constituents lead to functional alteration in HDLc. A modification in apolipoprotein leads to changes in the proportions and nature of lipid and protein, thus changes the overall property of HDLc. This might be the reason for despite of having optimum level of HDLc could not prevent the cardiovascular complexities in many studies., PLTP is exclusively expressed in macrophage cell and transfer phospholipid from triglyceride rich lipoprotein such as VLDL, chylomicron to HDLc to maintain the phospholipid proportions in HDLc. An increased PLTP activity is linked with sever sepsis. The activity of PLTP increases with the age and an increase PLTP activity is associated with an increase in pro-inflamatory cytokines secretion from the fibroblast like synoviocytes in RA patients, this might be due to overloading of triglycerides in HDLc may increase the size of HDLc particle make it functionally dysfunctional. PLTP is also required for maintaining the sphingosinephosphate-1 level in HDLc.
HDLc is associated with MPO enzyme-secreted by the activated neutrophils, macrophages monocytes and get cross-linked with HDLc, MPO catalyze the chlorination and nitration of tyrosin residue of apo-A1 protein and oxidizes apo-A1 protein, thus inactivates HDLc (pro-inflammatory cholesterol) to remove cholesterol from the cell to liver leading cholesterol accumulation inside dendritic cell, which in turn promotes inflammatory cell (Th1, Th17) formation leading to arthritis and other inflammatory disease development., Furthermore, a deficiency of ABCA1 transporter also leads to accumulation of cholesterol in Dendritic cell leading to secretion of pro-inflammatory cytokines IL-12, IL-6 and IL-23, which promotes Th1, Th17, and B cell, antibody secretion leading to onset of glomerulonephritis. An increase in IL-6, IL-23 level is well appreciated to be linked with RA pathophysisology.,
| High Density Lipoprotein Cholestrol in Preventing Infectious Associated Arthritis|| |
Microbial infection is one of the important etiopathogenic factor for the infection-associated arthritis. Human HDLc carry LPS binding protein (LBP) binds to LPS, lipoteichoic acid and transfer it to CD14 + monocyte cell and activates immune system to prevent infection spread. Bacterial, fungal infection spreads in the joint and surrounding tissue cause joint inflammation and pain. Mice studies shows a HDLc treatment prevent endotoxemia and inhibits the elevation of aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, creatinine, lactate dehydrogenase, creatine phosphokinase, reactive nitric oxide free radical production and tumor necrosis factor alpha secretion, decrease leukocytopenia to prevent organ damage. Further, apo-L1 and haptoglobin-related protein, which form a complex, trypanosome lytic factors (TLF) that kills trypanosoma, a protozoan causing sleeping sickness. TLF is also reported to kill Leishmania. Leishmaniasis is a disease of skin causes skin sore and ulcers. RA patients treated with methotrexate usually get infected with Leishmania in tropic and subtropic countries.,
| Statin Drug in Raising High-Density Lipoprotein Cholestrol|| |
Cholesterol lowering drug, statin is widely used for the treatment of cardiovascular complications in patients with chronic kidney disease, rheumatoid arthritis, SLE, nonalcoholic fatty liver disease, diabetic retinopathy; Alzheimer, dementia and mild cognitive impairment,, Statin drug inhibits the rate limiting enzymes hydroxymethyl-glutaryl-coenzyme A reductase required for the cholesterol synthesis and up-regulates the LDL receptor expression in hepatocytes for LDLc clearance by the liver, thus statin inhibits and reduce the LDL synthesis and its over accumulation in intra and extravascular space. Statin therapy also lead to increased HDLc synthesis. Statin drugs such as rosuvastatin, atorvastatin, simvastatin, and pravastatin very mildly increases the HDLc level by 5%–12% and moderately decrease the LDLc level by 8%–26%., A mild increasing effects of statin drug on HDLc level may be due to the inhibition of cholesteryl ester transfer protein (CETP). Cholesteryl ester protein transport cholesteryl from HDLc to LDLc, VLDL and decrease the HDLc level. CETP inhibitors drug torcetrapib and dalcetrapib increased the HDLc level by 30%–35%. However, due to their off target effects, they could not prevent the cardiovascular-associated death and subsequently declined for the clinical use.,
Further, statin therapy have been shown to increase the endothelial cell function, atherosclerotic plaques stabilization, inflammation reduction, enhancing insulin sensitivity by decreasing inflammatory response. This anti-inflammatory activity of Statin therapy may be attributed due to expression of peroxisome-proliferator-activated receptor-α, γ (PPAR-α, γ) in monocyte, macrophage and Treg cell., PPAR-γ is specifically expressed by the FoxP3+ Treg cell resident in the visceral adipose tissue (VAT). PPAR-γ is a nuclear receptor protein interacts with the transcription factor FoxP3 for the regulation of inflammation in the adipose tissue. Thiazolidinediones drug such as pioglitazone enhances PPAR-γ expression in VAT-specific Treg cell and increases the sensitivity of adipose tissue for insulin in obesity associated diabetes, by inhibiting the local inflammatory response. In addition, PPAR-γ lead conversion of inflammatory M1-macrophage in alternative anti-inflammatory M-2 macrophage, which together with Treg cell suppresses, inflammation and increases sensitivity to insulin in diabetic patient. PPAR-Y further induces paraoxonase-1 expression in the liver. Many other studies shown the overall beneficial effects of statin therapy., However, it is not clear whether statin drug directly mediates all these beneficial effects or indirectly through HDLc-Treg cell axis and whether statin sustains the long-term survival and functionality of Treg. Studies show that under inflammatory condition survival and adequate functionality of Treg cell remain diminished., Treg get converted into inflammatory Th17 cell and found to be associated with sustaining inflammation., A close monitoring of HDLc level and immune cell profile in patients may further help in delineating the HDLc role in disease.
| How to Increase High-Density Lipoprotein Cholestrol|| |
HDLc level can be increased by increasing the physical activities, losing overweight, quitting smoking, eating more mono and polyunsaturated fats, such as olive oil, canola oil, peanuts butter, whole grain food, fish meat, vegetables, avoiding snacks, fried, processed food, sweetened drink, cakes, refined carbohydrates, avoiding medication such as anabolic steroids, benzodiazepines, and birth control pills. The maintenance of healthy range of HDLc may have multiple benefits. Therefore, a regular monitoring of HDL level would be of great health benefits.
In conclusion, HDLc has pleiotropic beneficial effects in different cell. HDLc regulates many functions in different cell of our body. The anti-inflammatory effect of HDLc may be mediated by the Treg and M2 macrophage cell. Maintenance of optimum level of HDLc may be a good choice for the overall good health.
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