High-density Lipoprotein Production Research Articles

Increased neurotoxicity of high-density lipoprotein secreted from murine reactive astrocytes deficient in a peroxisomal very-long-chain fatty acid transporter Abcd1.

X-linked adrenoleukodystrophy (X-ALD) is a genetic neurodegenerative disorder caused by pathogenic variants in ABCD1, resulting in the accumulation of very-long-chain fatty acids (VLCFAs) in tissues. The etiology of X-ALD is unclear. Activated astrocytes play a pathological role in X-ALD. Recently, reactive astrocytes have been shown to induce neuronal cell death via saturated lipids in high-density lipoprotein (HDL), although how HDL from reactive astrocytes exhibits neurotoxic effects has yet to be determined. In this study, we obtained astrocytes from wild-type and Abcd1-deficient mice. HDL was purified from the culture supernatant of astrocytes, and the effect of HDL on neurons was evaluated in vitro. To our knowledge, this study shows for the first time that HDL obtained from Abcd1-deficient reactive astrocytes induces a significantly higher level of lactate dehydrogenase (LDH) release, a marker of cell damage, from mouse primary cortical neurons as compared to HDL from wild-type reactive astrocytes. Notably, HDL from Abcd1-deficient astrocytes contained significantly high amounts of VLCFA-containing phosphatidylcholine (PC) and LysoPC. Activation of Abcd1-deficient astrocytes led to the production of HDL containing decreased amounts of PC with arachidonic acid in sn-2 acyl moieties and increased amounts of LysoPC, presumably through cytosolic phospholipase A2 α upregulation. These results suggest that compositional changes in PC and LysoPC in HDL, due to Abcd1 deficiency and astrocyte activation, may contribute to neuronal damage. Our findings provide novel insights into central nervous system pathology in X-ALD.

Vitamin D status affects proteomic profile of HDL-associated proteins and inflammatory mediators in dyslipidemia

Vitamin D deficiency and dyslipidemia have substantial implications for human health globally. Vitamin D is essential for bone metabolism and immune modulation, and its insufficiency is linked to various chronic inflammatory conditions. Dyslipidemia, characterized by low levels of high-density lipoprotein (HDL) and elevated levels of low-density lipoprotein (LDL) and triglycerides, is also prevalent. Previous research has shown a connection between vitamin D deficiency and low HDL, but the precise mechanism by which vitamin D influences HDL production and its anti-inflammatory properties remains unclear. This study aimed to investigate the proteomic profiles of individuals with and without vitamin D deficiency and dyslipidemia, specifically focusing on the effects of vitamin D on HDL production, its anti-inflammatory potential, and the molecular pathways associated with vitamin D deficiency and dyslipidemia, particularly inflammation and cancer pathways. By analyzing the proteomic profiles of 274 participants from the Qatar Biobank database, we identified 1301 proteins. Our findings indicated a decrease in HDL-associated apolipoproteins (ApoM and ApoD) in individuals with both dyslipidemia and vitamin D deficiency. Conversely, participants with these conditions exhibited increased expression of acute-phase proteins (SAA1 and SOD1), which are associated with inflammation. Pathway enrichment analysis revealed heightened inflammatory activity in individuals with vitamin D deficiency and dyslipidemia, with notable enrichments in pathways such as MAPK, JAK-STAT, Ras signaling, cytokine-cytokine receptor interaction, AGE-RAGE, ErbB signaling, and cancer pathways. Overall, cases of vitamin D deficiency showed enrichment in inflammation pathways, while individuals with both vitamin D deficiency and dyslipidemia demonstrated enhanced activation of cancer and inflammation pathways.

Pharmacological Investigation on Unraveling Mechanism of Action of Quisqualis indica Leaves for Predicted Treatment of Peptic Ulcer Disease

Background:: With the aid of various ulcer-induced models, the goal of this study was to assess the antiulcer ability of Qusqualis indica (Q. indica) leaf extracts in Wistar rats Method:: The induction of ulcers was done by different models like pylorus ligation method, ethanol-induced and stress-induced models. Group 1 (negative control), Group 2 (standard group) were treated with Sucralfate (8.6 mg/kg), Group 3 was treated with aqueous extract of Q. indica (AEQI,200 mg/kg), Group 4 was treated with aqueous extract of Q. indica (AEQI,400 mg/kg), Group 5 was treated with ethanolic extract of Q. indica (EEQI, 200 mg/kg) and Group 6 was treated with ethanol extract of Q. indica (EEQI, 400 mg/kg). All therapies were given orally twice every day. After the course of treatment was complete, blood and gastrointestinal contents were taken, and biochemical tests were run. The acetylcholine and histamine drug response curves were used to develop the mechanism of the extracts. Results:: The groups treated with extracts experienced a significant decrease in ulcer index. The antiulcer potential of the AEQI and EEQI is dose-dependent. Hematological, hepatic, and cardiac parameters were not significantly affected by the extracts, although high-density lipoprotein production was. Acetylcholine and histamine are blocked by AEQI and EEQI, according to the DRC analysis. The obtained scientific facts are amply supported by histopathological analysis Conclusion:: AEQI and EEQI have antiulcer potential in a dose-dependent manner, but further research must be needed.

HDL functionality is dependent on hepatocyte stress defense factors Nrf1 and Nrf2.

High density lipoproteins (HDL) promote homeostasis and counteract stressful tissue damage that underlie cardiovascular and other diseases by mediating reverse cholesterol transport, reducing inflammation, and abrogating oxidative damage. However, metabolically stressful conditions associated with atherosclerosis can impair these effects. Hepatocytes play a major role in the genesis and maturation of circulating HDL, and liver stress elicits marked regulatory changes to circulating HDL abundance and composition, which affect its functionality. The mechanisms linking liver stress to HDL function are incompletely understood. In this study, we sought to determine whether stress defending transcription factors nuclear factor erythroid 2 related factor-1 (Nrf1) and -2 (Nrf2) promote hepatocyte production of functional HDL. Using genetically engineered mice briefly fed a mild metabolically stressful diet, we investigated the effect of hepatocyte-specific deletion of Nrf1, Nrf2, or both on circulating HDL cholesterol, protein composition, and function. Combined deletion, but not single gene deletion, reduced HDL cholesterol and apolipoprotein A1 levels as well as the capacity of HDL to accept cholesterol undergoing efflux from cultured macrophages and to counteract tumor necrosis factor α-induced inflammatory effect on cultured endothelial cells. This coincided with substantial alteration to the HDL proteome, which correlated with liver gene expression profiles of corresponding proteins. Thus, our findings show complementary actions by hepatocyte Nrf1 and Nrf2 play a role in shaping HDL abundance and composition to promote production of functionally viable HDL. Consequently, our study illuminates the possibility that enhancing stress defense programming in the liver may improve atheroprotective and perhaps other health promoting actions of HDL.

The Influence of Oral Administration of Red Dragon Fruit Peels Extract (Hylocereus polyrhizus) on Increasing High Density Lipoprotein in Male White Rats (Rattus norvegicus) Hypercholesterolemia

Background: Hypercholesterolemia is one of the most common diseases in the world, with cholesterol levels exceeding normal levels. Hypercholesterolemia can cause various systemic disorders in the body. One of the signs is by decreasing HDL (High-Density Lipoprotein) cholesterol levels. Dragon fruit peel contains many ingredients, such as vitamin B3 (niacin), vitamin C, flavonoids, anthocyanins, and other minerals that can affect the increase in HDL production and reduce total cholesterol levels. Purpose: To know the effect of red dragon fruit peel extract (Hylocereus polyrhizus)on increasing levels of High-Density Lipoprotein (HDL) in male rats (Rattus norvegicus) hypercholesterolemia. Methods: Male rats were made hypercholesterolemic using a mixture of lard (3 ml) and egg yolk (1 g) for 14 days orally. 20 hypercholesterolemic male rats were further divided into 5 treatment groups and given dragon fruit peel extract therapy with different treatments, namely T0 negative control (CMC-Na 1% + aquadest), T1 positive control (Simvastatin 0.0013 mg/200 g BW), T2, T3 and T4 (each 100, 150, 200 mg/kg BW red dragon fruit peel extract) for 14 days orally. Blood serum was taken on day 36 and tested in the laboratory using a chemical analyzer machine; then the data were analyzed using the univariant multiple way one-way ANOVA statistical test with a significant difference (p>0.05). Results: The P4 treatment group has an effective dose (200 mg/kg BW) to increase high-density lipoprotein (HDL) levels, while the P3 treatment group (dose 150 mg/kg BW) is less effective but can still have an effect. Conclusion: This research showed that red dragon fruit peel extract could increase HDL (High-Density Lipoprotein) cholesterol levels with an effective 200 mg/kg BW dose.

Effect of citrus-coconut electrolyte blend on growth performance, haemato-biochemical status, organs development and intestinal morphology of broiler chickens

In a bid to mitigate growing concerns regarding the use of antibiotics in food animals OBJECTIVES: This study determined the growth performance, haemato-biochemical status, organ development and intestinal morphology of Arbor Acre broiler chicken strain on oral administration of citrus-coconut electrolyte blend (CCEB) for 26 days. One-hundred ninety-two chicks were brooded for 2 weeks and thereafter divided on a weight equalization basis into four groups (0, 5, 10 and 15 ml CCEB per litre of water) of six replicates each and eight birds per replicate. Phytochemical screening of CCEB was determined, while data collected for growth performance, organ proportions and intestinal morphology were subjected to a one-way analysis of variance. Phytochemical composition revealed the abundance of phenols (128.40 mg/100g) and tannins (78.10 mg/100g) in CCEB. All productive performance parameters measured were not significantly (p < 0.05) different across treatment means. However, significantly (p < 0.05) highest concentrations (134.47 and 66.48 mg/dl, respectively) for total cholesterol and high-density lipoprotein (HDL) and the lowest concentration (38.34 mg/dl) for low-density lipoprotein (LDL) were recorded in birds on 15 ml of CCEB/litre of water. Furthermore, a progressive reduction (p < 0.05) in the bursa of Fabricius was observed with increasing CCEB/litre of water. The supplementation of CCEB did not influence (p > 0.05) duodenal morphological parameters. The study concluded that 15 ml of CCEB/litre of water enhanced the production of HDL, reduced LDL, and improved immunity via the reduction of the bursa of Fabricius in broiler chickens.

ABCA1 is an extracellular phospholipid translocase

Production of high density lipoprotein (HDL) requires ATP-binding cassette transporter A1 (ABCA1) to drive phospholipid (PL) from the plasma membrane into extracellular apolipoprotein A-I. Here, we use simulations to show that domains of ABCA1 within the plasma membrane remove PL from the membrane’s outer leaflet. In our simulations, after the lipid diffuses into the interior of ABCA1’s outward-open cavity, PL extracted by the gateway passes through a ring-shaped domain, the annulus orifice, which forms the base of an elongated hydrophobic tunnel in the transporter’s extracellular domain. Engineered mutations in the gateway and annulus strongly inhibit lipid export by ABCA1 without affecting cell-surface expression levels. Our finding that ABCA1 extracts lipid from the outer face of the plasma membrane and forces it through its gateway and annulus into an elongated hydrophobic tunnel contrasts with the alternating access model, which proposes that ABCA1 flops PL substrate from the inner leaflet to the outer leaflet of the membrane. Consistent with our model, ABCA1 lacks the charged amino acid residues in the transmembrane domain found in the floppase members of the ABC transporter family.

A high-fat/high-cholesterol diet, but not high-cholesterol alone, increases free cholesterol and apoE-rich HDL serum levels in rats and upregulates hepatic ABCA1 expression

A high-fat/high-cholesterol (HFC) diet, but not a high-cholesterol (HC) diet, is known to induce elevated serum apolipoprotein E (apoE)-rich high-density lipoprotein (HDL) levels in animal models. However, the exact mechanisms by which the combination of dietary fat and cholesterol induces apoE-rich HDL production is not well understood. Here, we investigated the effects of dietary fat and cholesterol on serum lipoprotein profiles and hepatic mRNA expression that are associated with HDL production, cholesterol transport, and bile acid metabolism. Male Sprague-Dawley rats were fed HFC, HC, high-fat, or control diets and then evaluated. The HFC diet induced significant increases in hepatic free-cholesterol accumulation (1.4-fold, p < 0.01) and serum apoE-rich HDL cholesterol (8.7-fold, p < 0.001) levels compared with the HC diet. The apoE-rich HDL induced by the HFC diet was remarkably rich in free cholesterol. Liver gene-expression was mostly similar between the HC and HFC diet groups. However, there was a significant increase of ATP-binding cassette transporter A1 (ABCA1) levels in the HFC group compared to the HC group for both mRNA (1.9-fold, p < 0.001) and protein (6.6-fold, p < 0.01). These results suggest that an increase in apoE-rich HDL induced by dietary fat and cholesterol may be involved in cholesterol efflux from the liver through increased ABCA1-mediated free-cholesterol efflux.

Effect of procyanidins on lipid metabolism and inflammation in rats exposed to alcohol and iron

BackgroundLifestyle involving uncontrolled alcohol consumption coupled regularly with red meat and other iron sources has detrimental effects on the liver, which in the long term, results in Alcoholic Liver Disease (ALD). Procyanidin has lately garnered increasing attention and has become the focus of research owing to its antioxidant properties. This study explores the anti-inflammatory effects of procyanidins, in preventing ALD, by analyzing the biological activities of the compound on liver injury caused by excessive alcohol and iron. MethodMale SPF Wistar rats were placed in 4 groups; the control Group A (basic diet); the model Group B (excess alcohol 8–12 mL/kg/d and iron 1000 mg/kg diet); the low dose procyanidin Group C (model group diet plus 60 mg/kg/d of procyanidin); and the high dose procyanidin Group D (model group diet plus 120 mg/kg/d of procyanidin). Serum biochemical markers for liver damage were measured spectrophotometrically. The NFκB and IκB mRNA expression levels were determined using RT-PCR; the NFκB p65 and IκB protein expression levels were assessed via western blotting, while ELISA was used to detect serum inflammatory factors. ResultsThe pathological score of the model Group B, low and high dose procyanidin Groups C and D were 6.58 ± 0.90,4.69 ± 0.70 and 2.00 ± 0.73, respectively (P < 0.05). The results showed that high alcohol and iron contents in the model group led to significant damage of liver structure, increased low-density lipoproteins (LDLs), steatosis, and increased levels of inflammatory cytokines. High amounts of procyanidins led to the preservation of the liver structure, production of high-density lipoproteins, and reduction in serum inflammatory cytokines while also significantly decreasing the expression levels of NFκB p65. ConclusionThe results prove that procyanidins have hepatoprotective potential and could be effective in reversing histopathology, possibly by alleviating inflammation and improving lipid metabolism.

Highly conserved amino acid residues in apolipoprotein A1 discordantly induce high density lipoprotein assembly in vitro and in vivo

ObjectiveApolipoprotein A1 (APOA1) is essential to reverse cholesterol transport, a physiologically important process that protects against atherosclerotic cardiovascular disease. APOA1 is a 28 kDa protein comprising multiple lipid-binding amphiphatic helices initialized by proline residues, which are conserved across multiple species. We tested the hypothesis that the evolutionarily conserved residues are essential to high density lipoprotein (HDL) function. ApproachWe used biophysical and physiological assays of the function of APOA1P➔A variants, i.e., rHDL formation via dimyristoylphosphatidylcholine (DMPC) microsolubilization, activation of lecithin: cholesterol acyltransferase, cholesterol efflux from human monocyte-derived macrophages (THP-1) to each variant, and comparison of the size and composition of HDL from APOA1−/− mice receiving adeno-associated virus delivery of each human variant. ResultsDifferences in microsolubilization were profound and showed that conserved prolines, especially those in the C-terminus of APOA1, are essential to efficient rHDL formation. In contrast, P➔A substitutions produced small changes (−25 to +25%) in rates of cholesterol efflux and no differences in the rates of LCAT activation. The HDL particles formed following ectopic expression of each variant in APOA1−/− mice were smaller and more heterogeneous than those from control animals. ConclusionStudies of DMPC microsolubilization show that proline residues are essential to the optimal interaction of APOA1 with membranes, the initial step in cholesterol efflux and HDL production. In contrast, P➔A substitutions modestly reduce the cholesterol efflux capacity of APOA1, have no effect on LCAT activation, but according to the profound reduction in the size of HDL formed in vivo, P➔A substitutions alter HDL biogenesis, thereby implicating other cellular and in vivo processes as determinants of HDL metabolism and function.

Challenges in Drug Development Targeting Anti-atherosclerotic Proteins

Atherosclerosis is a vascular disease responsible for acute heart attacks and stroke, which are leading causes of death not only in industrialized countries but also worldwide, and the number of patients afflicted by this disease has been increasing in Japan. High-density lipoprotein (HDL) is the plasma lipoprotein that carries what is often called your "good cholesterol" through the blood. This good cholesterol moniker is associated with HDL because higher circulating levels of this lipoprotein are associated with a well-known reduction in the risk of arteriosclerosis. Moreover, many protective mechanisms by which HDL could reduce atherosclerosis are described, including reverse cholesterol transport, along with anti-oxidant, anti-inflammatory and anti-thrombosis activities. However, HDL-modulating therapies to lower cardiovascular risk are not yet available. It has recently been proposed that apolipoprotein A-I (apoA-I) binding protein (AIBP) enhances HDL function by accelerating lipid release from cells and reducing associated inflammatory processes. In this context, our research is focused on the function of HDL-related proteins, such as proteins that regulate HDL production (ATP-binding cassette transporters), and HDL-binding proteins. We expect that these studies could eventually help in the development of HDL-related prognostic and therapeutic strategies to reduce the burden of cardiovascular disease in the future.

Lipid-Modulating Effect of Black Lingzhi Medicinal Mushroom, Amauroderma rugosum (Agaricomycetes), on Oleate-Induced Human Hepatocellular Liver Carcinoma Cells.

Dyslipidemia is the key precursor of atherosclerotic cardiovascular disease. The aim of this study was to investigate the lipid-modifying potential of organic solvent-partitioned extracts from fruiting bodies of Amauroderma rugosum in vitro using oleate-induced human hepatocellular liver carcinoma (HepG2) cells. Our results demonstrated that oleate-induced HepG2 cells treated with ethyl acetate (EA) extract greatly decreased intracellular and secreted total triglyceride (TG) and total cholesterol (TC) compared with other extracts. Further investigation of cellular expression of selected apolipoproteins also revealed that oleate-induced HepG2 cells treated with the EA extract best attenuated the apolipoprotein (Apo) profile by downregulating ApoB-100 and ApoE while upregulating ApoA1. Because both ApoB-100 and ApoE are key components of low-density lipoprotein (LDL) and very LDL (VLDL), which are recognized as "bad cholesterol," this result indicates that treatment with the EA extract inhibited LDL and VLDL production in oleate-induced HepG2 cells. On the other hand, increasing ApoA1 evidence shows antiatherogenic benefits to increasing ApoA1, the key component of high-density lipoprotein (HDL), particularly in relation to its role in promoting reverse cholesterol transport and preventing LDL oxidation; this indicates that the EA extract upregulated the production of HDL ("good cholesterol"). Hence, the EA extract is a good source of lipid-ameliorating agents in the management of dyslipidemia.

SEDding Ourselves Up for Problems

SEDding Ourselves Up for Problems

Cholesterol and lipoprotein metabolism: Early Career Committee contribution.

Cholesterol and lipoprotein metabolism: Early Career Committee contribution.

Abstract 671: Beyond Cholesterol Efflux: Defining HDL Function in Atherosclerosis and the Requirement for Procollagen C-Endopeptidase Enhancer Protein 2

Recent studies suggest that assessment of high density lipoprotein (HDL) function provides a more reliable metric of athero-protection than plasma concentration alone. One important function attributed to apolipoprotein A-I (apoA-I), the major protein constituent of HDL, is its ability to accept newly effluxed cholesterol from ATP-binding cassette A-I (ABCA1) to form nascent HDL (nHDL). New studies suggest that the protein, procollagen c-endopeptidase enhancer protein 2 (PCOLCE2; PCPE2), is involved in mediating nHDL particle formation. PCPE2 is a 52 kDa glycoprotein sharing 43% amino acid identity with PCOLCE (PCPE1). Both are secreted into the extracellular matrix where they enhance the catalytic cleavage of the C-terminal propeptides of procollagen catalyzed by bone morphogenetic protein 1 (BMP1). The connection between PCPE2 and HDL was discovered after significant correlations were found between single-nucleotide polymorphisms and plasma HDL-cholesterol concentrations in population studies. Consistent with these findings a recent genome-wide siRNA screening study indicated that PCPE2 was a significant modulator of HDL apoA-I secretion from cells, while other studies in mice lacking PCPE2 showed defective ABCA1-mediated cholesterol efflux, despite elevated plasma HDL. Thus, we began the current studies to determine if the increased plasma HDL, in light of defective cholesterol efflux, would be atheroprotective or atherogenic. PCPE2 null mice were crossed with LDL receptor null mice to obtain double knockout, LDLr -/- , PCPE2 -/- mice. Both LDLr -/- and LDLr -/- , PCPE2 -/- mice were fed an atherogenic diet for 12 wks after which the lipid deposition in the aortic root was evaluated. As expected, LDLr -/- , PCPE2 -/- mice showed elevated levels of enlarged HDL compared to control mice, while LDL levels were similar between the two genotypes. Despite elevations in plasma HDL, LDLr -/- , PCPE2 -/- mice showed significantly more atherosclerosis compared to LDLr -/- mice, similar in extent to that found in mice that lack HDL due to an absence of plasma apoA-I (LDLr -/- , apoA-I -/- ). This outcome suggests that PCPE2 is atheroprotective and likely participates at various levels of HDL metabolism, including HDL production, remodeling and catabolism.

The Effect of Nutritional Supplements on Serum High-Density Lipoprotein Cholesterol and Apolipoprotein A-I

One of the factors contributing to the increased risk of developing premature atherosclerosis is low plasma concentrations of high-density lipoprotein (HDL) cholesterol. Multiple potential mechanisms account for the cardioprotective effects of HDL and its main protein apolipoprotein A-I (apo A-I). Diet has an important role in modulating HDL cholesterol level. The widespread use of nutritional supplements may also alter the biology of HDL. In this review, we discuss the effect of select nutritional supplements on serum HDL cholesterol and apo A-I levels. Some nutritional supplements, such as phytosterols, soy proteins, and black seed extracts, may increase HDL cholesterol levels, while others such as cholic acid and high doses of commonly used antioxidant vitamins may downregulate HDL cholesterol levels and reduce its cardioprotection. Multiple mechanisms are involved in the regulation of HDL levels, so changes in production and clearance of HDL may have different clinical implications. The clinical relevance of the changes in HDL and apo A-I caused by nutrient supplementation needs to be tested in controlled clinical trials.

Abstract 19434: The Novel PPARalpha-Selective Agonist K-877 Improves Dyslipidemia, Enhances Reverse Cholesterol Transport and Decreases Inflammation and Atherosclerosis

Background: Atherosclerosis is characterized by lipid accumulation and chronic inflammation in the arterial wall. Elevated levels of apolipoprotein (apo) B-containing lipoproteins are a risk factor for cardiovascular disease (CVD). By contrast, plasma levels of high-density lipoprotein (HDL) and apoA-I are protective against CVD by enhancing HDL functionality and reverse cholesterol transport (RCT). Activation of peroxisome proliferator-activated receptor-alpha (PPARalpha), a ligand-activated transcription factor, controls plasma lipid metabolism, macrophage cholesterol handling as well as the inflammatory response. Objective: To study whether pharmacological activation of PPARalpha with the highly potent PPARalpha ligand, K-877, improves lipid metabolism, macrophage cholesterol efflux, inflammation and consequently atherosclerosis development in human apoA-I transgenic mice and in the human apolipoprotein E2 knock-in mouse (apo E2KI) model of mixed dyslipidemia and atherosclerosis. Methods and results: In polarized Caco-2/TC7 human intestinal epithelium cells, K-877 treatment decreased apoB secretion and increased the expression of PPARalpha target genes involved in fatty acid oxidation and intestinal HDL production. Moreover, K-877 induced secretion of apoA-I in HDL particles. In primary human macrophages, K-877 promoted macrophage cholesterol efflux to HDL. K-877 treatment of human apoA-I transgenic mice induced plasma HDL cholesterol and apoA-I levels. Moreover, K-877 stimulated in vivo RCT in these mice. In addition, K-877 treatment exerted anti-inflammatory properties in murine and human macrophages. K-877 treatment not only improved the lipid profile, but also reduced inflammatory and macrophage marker gene expression in the aortic crosses as well as aortic atherosclerotic lesion burden in western diet-fed apo E2KI mice. Conclusion: These results demonstrate that the novel PPARalpha agonist K-877 exerts beneficial effects on lipid metabolism, RCT and inflammation resulting in anti-atherogenic properties.

Liver-Specific Phospholipid Transfer Protein Deficiency Reduces High-Density Lipoprotein and Non–High-Density Lipoprotein Production in Mice

The liver is one of the critical organs for lipoprotein metabolism and a major source for phospholipid transfer protein (PLTP) expression. The effect of liver-specific PLTP deficiency on plasma lipoprotein production and metabolism in mice was investigated. We created a liver-specific PLTP-deficient mouse model. We measured plasma high-density lipoprotein (HDL) and apolipoprotein B (apoB)-containing lipoprotein (or non-HDL) levels and their production rates. We found that hepatic ablation of PLTP leads to a significant decrease in plasma PLTP activity, HDL lipids, non-HDL lipids, apoAI, and apoB levels. In addition, nuclear magnetic resonance examination of lipoproteins showed that the deficiency decreases HDL and apoB-containing lipoprotein particle numbers, as well as very low-density lipoprotein particle size, which was confirmed by electron microscopy. Moreover, HDL particles from the deficient mice are lipid-poor ones. To unravel the mechanism, we evaluated the apoB and triglyceride production rates. We found that hepatic PLTP deficiency significantly decreases apoB and triglyceride secretion rates. To investigate the role of liver PLTP on HDL production, we set up primary hepatocyte culture studies and found that the PLTP-deficient hepatocytes produce less nascent HDL. Furthermore, we found that exogenous PLTP promotes nascent HDL production through an ATP-binding cassette A 1-mediated pathway. Liver-specific PLTP deficiency significantly reduces plasma HDL and apoB-containing lipoprotein levels. Reduction of production rates of both particles is one of the mechanisms.

Inflammation impairs eNOS activation by HDL in patients with acute coronary syndrome

The aim of the present study was to evaluate the high-density lipoprotein (HDL) structure and endothelial NO synthase (eNOS) activation capacity in ST-elevation myocardial infarction (STEMI) patients with different acute-phase inflammatory response (APR). Forty-five STEMI patients were stratified in quartiles according to the delta CRP level, calculated by subtracting the CRP value at admission from the CRP peak value (APR peak). The HDL structure and HDL capacity to stimulate NO production were evaluated at admission and at APR peak. STEMI patients with a low APR had a completely preserved HDL structure and HDL ability to activate eNOS and promote NO production, which did not change during STEMI. On the contrary, HDL from STEMI patients developing a significant APR had compromised ability to stimulate eNOS and promote NO production, and underwent a significant particle remodelling during STEMI. The defective capacity to stimulate NO production of HDL isolated from STEMI patients with high APR was explained, at least in part, by the reduced PON-1 and S1P content. The HDL ability to promote cell cholesterol efflux through different pathways was preserved in ACS patients independently of the inflammatory response. The present results extend previous studies reporting an impaired eNOS-activating capacity of HDL from ACS patients, showing that only a subset of patients undergoing STEMI, and in particular those developing an important inflammatory response, have circulating HDL defective in stimulating endothelial eNOS and NO production.

Factors controlling nascent high‐density lipoprotein particle heterogeneity: ATP‐binding cassette transporter A1 activity and cell lipid and apolipoprotein AI availability

Nascent high-density lipoprotein (HDL) particles arise in different sizes. We have sought to uncover factors that control this size heterogeneity. Gel filtration, native PAGE, and protein cross-linking were used to analyze the size heterogeneity of nascent HDL produced by BHK-ABCA1, RAW 264.7, J774, and HepG2 cells under different levels of two factors considered as a ratio, the availability of apolipoprotein AI (apoAI) -accessible cell lipid, and concentration of extracellular lipid-free apoAI. Increases in the available cell lipid:apoAI ratio due to either elevated ATP-binding cassette transporter A1 (ABCA1) expression and activity or raised cell density (i.e., increasing numerator) shifted the production of nascent HDL from smaller particles with fewer apoAI molecules per particle and fewer molecules of choline-phospholipid and cholesterol per apoAI molecule to larger particles that contained more apoAI and more lipid per molecule of apoAI. A further shift to larger particles was observed in BHK-ABCA1 cells when the available cell lipid:apoAI ratio was raised still higher by decreasing the apoAI concentration (i.e., the denominator). These changes in nascent HDL biogenesis were reminiscent of the transition that occurs in the size composition of reconstituted HDL in response to an increasing initial lipid:apoAI molar ratio. Thus, the ratio of available cell lipid:apoAI is a fundamental cause of nascent HDL size heterogeneity, and rHDL formation is a good model of nascent HDL biogenesis.—Lyssenko, N. N., Nickel, M., Tang, C., Phillips, M. C. Factors controlling nascent high-density lipoprotein particle heterogeneity: ATP-binding cassette transporter A1 activity and cell lipid and apolipoprotein AI availability.