High-density Apolipoprotein Research Articles

Relationship of high-density lipoprotein subfractions and apolipoprotein A-I with fat in the pancreas.

To investigate the associations of high-density lipoprotein (HDL) subfractions and apolipoprotein A-I (apo A-I) with fat in the pancreas. A total of 170 individuals were studied. All participants underwent magnetic resonance imaging on a single 3.0-Tesla scanner to determine the presence/absence of fatty pancreas. HDL subfractions were measured using a commercially available lipoprotein subfractions testing system and classed as large, intermediate and small HDL. Both unadjusted and adjusted (accounting for demographics, anthropometrics, insulin resistance and other covariates) logistic regression models were built. Individuals with fatty pancreas had significantly lower circulating levels of the large HDL class and apo A-I. Every unit decrease in the large HDL class was associated with a 93% increase in the likelihood of fatty pancreas in the most adjusted model (P < .001). Every unit decrease in apo A-I was associated with a 45% increase in the likelihood of fatty pancreas in the most adjusted model (P = .012). The intermediate and small HDL classes were not significantly associated with fatty pancreas. Fat in the pancreas is inversely associated with the circulating levels of large HDL particles and apo A-I. Purposely designed studies are warranted to investigate the potential of fatty pancreas as an indicator of the risk of cardiovascular diseases.

Untargeted Lipidomics Reveals Novel HDL Metabotypes and Lipid-Clinical Correlates

Plasma high-density lipoprotein (HDL), originally studied for its role in lipid transport, is now appreciated to have wide-ranging biological functions that become defective during disease. While >200 lipids have collectively been detected in HDL, published HDL lipidomic analyses in different diseases have commonly been targeted to prespecified subsets of lipids. Here, we report the results of untargeted lipidomic analysis of HDL isolated from 101 subjects referred for computed tomographic coronary imaging for whom multiple additional clinical and lipoprotein metadata were measured. Unsupervised clustering of the total HDL lipidome revealed that the subjects fell into one of two discrete groups, herein referred to as HDL ‘metabotypes’. Subjects in metabotype 1 were likelier to be female and tended to have a less atherogenic lipoprotein profile, higher HDL cholesterol efflux capacity (CEC), and lower-grade non-calcified burden on coronary imaging than metabotype 2 counterparts. Specific lipids were relatively enriched in metabotype 1 HDL. Linear modeling revealed that several of these lipids were positively associated with CEC, statin use, HDL size, and HDL particle number, and positively correlated with HDL apolipoprotein A-1, suggesting that they may be informative HDL biomarkers. Taken together, we posit a novel, clinically relevant categorization for HDL revealed by systems biology.

AIBP promotes cell proliferation and migration through the ERK1/2-MAPK signaling pathway in hepatocellular carcinoma.

As a highly aggressive cancer, hepatocellular carcinoma (HCC) is often found at an advanced stage and has a poor prognosis. Therefore, in addition to the surgical treatment of HCC, the drug therapy for HCC is still under continuous exploration. The primary apolipoprotein of high-density lipoproteins (HDLs) is apolipoprotein A-I binding protein (AIBP), which has a significant impact on cholesterol metabolism, angiogenesis, and a wide range of inflammatory disorders, including cancer. The AIBP function in HCC is, however, yet unknown. This study aims to reveal the underlying mechanisms of AIBP influencing HCC proliferation and migration through mitogen-activated protein kinase (MAPK) pathways. AIBP expression and its clinical prognostic association were investigated using The Cancer Genome Atlas (TCGA) data. The AIBP expression was studied in human HCC tissues using immunohistochemistry (IHC) and western blotting. Colony formation assays (CFAs) and cell counting kit-8 (CCK-8) were used to determine in vitro cell proliferation. Cell migration and invasion were evaluated using wound-healing and transwell assays. A xenograft tumor model was employed to investigate HCC cell proliferation in nude mice. Tissues from HCC patients had much increased AIBP expression compared to nearby normal tissues. The prognosis for patients was bleak when AIBP expression was high. When AIBP was overexpressed in SMMC-7721 cells, the cells may become more proliferative, migrative, and invasive. In contrast, the HCC-LM3 cells' ability to proliferate, migrate, and invade was drastically decreased once AIBP was knocked down in vitro. Furthermore, in vivo research showed that AIBP overexpression may enhance cell proliferation in HCC. Finally, we discovered that AIBP could control the MAPK signaling pathway-involved genes expression, including P-MEK, MEK, c-Myc, P-ERK1/2, and ERK1/2, and that GDC-0994, a specific ERK1/2 inhibitor, could suppress the AIBP overexpression induced cell migration and proliferation abilities. These findings demonstrated that the ERK/MAPK signaling pathway might be stimulated by AIBP in HCC tissues, leading to increased cell invasion, migration, and proliferation. It was hypothesized that AIBP might act as a useful prognostic and diagnostic marker for HCC.

Plasma monomeric ApoA1 and high-density lipoprotein bound ApoA1 are markedly decreased and associated with low levels of lipophilic antioxidants in sickle cell disease: A potential new pathway for therapy.

Patients with sickle cell disease (SCD) exhibit high levels of reactive oxygen species and low plasma levels of lipophilic antioxidants, which may contribute to end-organ damage and disease sequelae. Apolipoprotein A1, the major apolipoprotein of high-density lipoprotein (HDL), is mainly secreted by the intestine and liver in the form of monomeric ApoA1 (mApoA1) present in plasma. Cholesterol and α-tocopherol are delivered to ApoA1 via the ATP-binding cassette transporter, subfamily A, member 1 (ABCA1). We measured cholesterol, mApoA1, ApoA1, and lipophilic antioxidants in the plasma of 17 patients with SCD and 40 healthy volunteers. Mean HDL cholesterol (-C) levels in SCD patients and healthy subjects were 59.3 and 48.1 mg/dL, respectively, and plasma lutein, zeaxanthin, and α-tocopherol were 64.0%, 68.7%, and 9.1% lower, respectively. To compare SCD to healthy subjects with similar HDL-C, we also performed subgroup analyses of healthy subjects with HDL-C above or below the mean. In SCD, the mApoA1 level was 30.4 μg/mL; 80% lower than 141 μg/mL measured in healthy volunteers with similar HDL-C (56.7 mg/dL). The mApoA1 level was also 38.4% greater in the higher versus lower HDL-C subgroups (p = .002). In the higher HDL-C subgroup, lutein and zeaxanthin transported by HDL were 48.9% (p = .01) and 41.9% (p = .02) higher, respectively, whereas α-tocopherol was 31.7% higher (p = .003), compared to the lower HDL-C subgroup. Plasma mApoA1 may be a marker of the capacity of HDL to capture and deliver liposoluble antioxidants, and treatments which raise HDL may benefit patients with high oxidative stress as exemplified by SCD.

Effects of Recombinant Human Lecithin Cholesterol Acyltransferase on Lipoprotein Metabolism in Humans.

LCAT (lecithin cholesterol acyl transferase) catalyzes the conversion of unesterified, or free cholesterol, to cholesteryl ester, which moves from the surface of HDL (high-density lipoprotein) into the neutral lipid core. As this iterative process continues, nascent lipid-poor HDL is converted to a series of larger, spherical cholesteryl ester-enriched HDL particles that can be cleared by the liver in a process that has been termed reverse cholesterol transport. We conducted a randomized, placebocontrolled, crossover study in 5 volunteers with atherosclerotic cardiovascular disease, to examine the effects of an acute increase of recombinant human (rh) LCAT via intravenous administration (300-mg loading dose followed by 150 mg at 48 hours) on the in vivo metabolism of HDL APO (apolipoprotein)A1 and APOA2, and the APOB100-lipoproteins, very low density, intermediate density, and low-density lipoproteins. As expected, recombinant human LCAT treatment significantly increased HDL-cholesterol (34.9 mg/dL; P≤0.001), and this was mostly due to the increase in cholesteryl ester content (33.0 mg/dL; P=0.014). This change did not affect the fractional clearance or production rates of HDL-APOA1 and HDL-APOA2. There were also no significant changes in the metabolism of APOB100-lipoproteins. Our results suggest that an acute increase in LCAT activity drives greater flux of cholesteryl ester through the reverse cholesterol transport pathway without significantly altering the clearance and production of the main HDL proteins and without affecting the metabolism of APOB100-lipoproteins. Long-term elevations of LCAT might, therefore, have beneficial effects on total body cholesterol balance and atherogenesis.

Abstract 1026: Apolipoprotein A1 On High-density Lipoprotein Interferes With Low-density Lipoprotein Binding To Proteoglycans

Background: The entrapment of apolipoprotein (APO) B-100 containing low density lipoproteins (LDL) by proteoglycans (PGs) in the extracellular matrix (ECM) of the arterial intima is a key initial step in the development of atherosclerotic vascular lesions. High density lipoproteins (HDL) can interfere with this process, but the underlying mechanism is not fully understood and is thought to be due to APOE. The aim of this study was to utilize our recently developed quantitative assay that measures the binding of LDL to PGs in the ECM and to investigate how HDL and other apolipoproteins may influence this process. Methods: An in-cell ELISA was used to measure the binding of LDL to PGs in the ECM synthesized by mouse vascular smooth muscle cells. Fast Protein Liquid Chromatography, immunoprecipitation, and immunoblotting analysis were performed to identify how HDL interacts with LDL to prevent binding to ECM-PGs. Results: LDL binding to PGs was inhibited by HDL and APOA1 in a dose dependent manner. Competition experiments showed that HDL does not compete directly with LDL for ECM-PG binding. Instead, our data revealed an association between LDL with APOA1 that diminishes LDL ability to bind ECM-PGs. Conclusion: HDL inhibits LDL binding to ECM-PG through an interaction with its main apolipoprotein, APOA1 that is different from APOE. Further investigation is warranted to understand the role of this interaction in the atherosclerosis process.

Abstract 2083: Apolipoprotein A-II Increases Cholesterol Efflux Capacity Of HDL Via The Apolipoprotein A-I C-terminus

The ability of high-density lipoprotein (HDL) to promote cellular cholesterol efflux (CEC) is a more robust predictor of cardiovascular disease protection than its plasma quantity. Previously, we found that fully lipidated HDL containing apolipoprotein A-II (APOA2) promotes cholesterol efflux via the ATP binding cassette transporter (ABCA1). This was surprising given that ABCA1 is thought to primarily interact with lipid-poor apolipoproteins. Having previously focused on isolated lipoproteins, we moved into human plasma with the hypothesis APOA2 can enhance ABCA1-mediated CEC in this more complex environment. Human plasma was incubated with increasing amounts of lipid-free APOA2. The samples were assayed for CEC from macrophages +/- cAMP for ABCA1 stimulation. APOA2 dose dependently increased whole plasma CEC - due mostly to HDL as the effect persisted in apoB-depleted plasma. Next, plasma was incubated with lipid-free APOA1 or APOA2, immediately fractionated by size exclusion chromatography and each fraction assayed for CEC. In unmodified plasma, cholesterol effluxed to peaks corresponding to LDL, HDL and lipid-free apolipoproteins with the latter exclusively increased by ABCA1 expression, as expected. When lipid-free APOA1 was added, efflux to LDL and HDL remained largely unchanged. Strikingly, when APOA2 was added, APOA2 increased ABCA1-mediated cholesterol efflux to the fully lipidated HDL fractions. Proteomic analyses indicated that APOA2 increased in HDL though some APOA1 was retained. To explore the mechanism, we reconstituted HDL particles with APOA1 that either contained or lacked its C-terminal lipid binding helix. APOA2 lost the ability to stimulate ABCA1 efflux to HDL when the C-terminal domain of APOA1 was deleted. Our current hypothesis is that APOA2 displaces the C-terminal helix of APOA1 from the HDL surface which can then interact with ABCA1 - much like it does in lipid-poor APOA1. Reconstituted forms of APOA1 are under development as a therapy to rapidly clear cholesterol from coronary arteries in patients with acute coronary syndrome. Our work suggests APOA2 may be a novel target given its dual benefits for cholesterol efflux.

Cholesterol transport and beyond: Illuminating the versatile functions of HDL apolipoproteins through structural insights and functional implications.

High-density lipoproteins (HDLs) play a vital role in lipid metabolism and cardiovascular health, as they are intricately involved in cholesterol transport and inflammation modulation. The proteome of HDL particles is indeed complex and distinct from other components in the bloodstream. Proteomics studies have identified nearly 285 different proteins associated with HDL; however, this review focuses more on the 15 or so traditionally named "apo" lipoproteins. Important lipid metabolizing enzymes closely working with the apolipoproteins are also discussed. Apolipoproteins stand out for their integral role in HDL stability, structure, function, and metabolism. The unique structure and functions of each apolipoprotein influence important processes such as inflammation regulation and lipid metabolism. These interactions also shape the stability and performance of HDL particles. HDLs apolipoproteins have multifaceted roles beyond cardiovascular diseases (CVDs) and are involved in various physiological processes and disease states. Therefore, a detailed exploration of these apolipoproteins can offer valuable insights into potential diagnostic markers and therapeutic targets. This comprehensive review article aims to provide an in-depth understanding of HDL apolipoproteins, highlighting their distinct structures, functions, and contributions to various physiological processes. Exploiting this knowledge holds great potential for improving HDL function, enhancing cholesterol efflux, and modulating inflammatory processes, ultimately benefiting individuals by limiting the risks associated with CVDs and other inflammation-based pathologies. Understanding the nature of all 15 apolipoproteins expands our knowledge of HDL metabolism, sheds light on their pathological implications, and paves the way for advancements in the diagnosis, prevention, and treatment of lipid and inflammatory-related disorders.

No effect of liraglutide on high density lipoprotein apolipoprotein AI kinetics in patients with type 2 diabetes

AimThe catabolism of high density lipoprotein (HDL) apolipoprotein AI (apoAI) is accelerated in patients with type 2 diabetes (T2D), related to hypertriglyceridemia, insulin resistance and low plasma adiponectin levels. Since liraglutide is likely to partly correct these abnormalities, we hypothesized that it might have a beneficial effect on HDL apoAI kinetics in patients with T2D. MethodsAn in vivo kinetic study of HDL apoAI was performed in 10 patients with T2D before and after 6 months of treatment with 1.2 mg/day of liraglutide, using a bolus of l-[1–13C]leucine followed by a 16-hour constant infusion. ResultsLiraglutide reduced BMI (34.9 ± 4.7 vs 36.6 ± 4.9 kg/m2, P = 0.012), HbA1c (7.1 ± 1.1 vs 9.6 ± 2.6%, P = 0.003), HOMA-IR (5.5 ± 1.9 vs 11.6 ± 11.2, P = 0.003), fasting triglycerides (1.76 ± 0.37 vs 2.48 ± 0.69 mmol/l, P < 0.001) and triglycerides during kinetics (2.34 ± 0.81 vs 2.66 ± 0.65 mmol/l, P = 0.053). Plasma HDL cholesterol and adiponectin concentrations were unchanged (respectively 0.97 ± 0.26 vs 0.97 ± 0.19 mmol/l, P = 1; 3169 ± 1561 vs 2618 ± 1651 µg/l, P = 0.160), similar to triglyceride content in HDL (5.13 ± 1.73 vs 5.39 ± 1.07%, P = 0.386). Liraglutide modified neither HDL apoAI fractional catabolic rate (0.35 ± 0.11 vs 0.38 ± 0.11 pool/day, P = 0.375), nor its production rate (0.44 ± 0.13 vs 0.49 ± 0.15 g/l/day, P = 0.375), nor its plasma concentration (1.26 ± 0.19 vs 1.29 ± 0.14 g/l, P = 0.386). ConclusionSix months of treatment with 1.2 mg/day of liraglutide had no effect on the kinetics of HDL apoAI in patients with T2D. The lack of decrease in triglyceride content in HDL related to an only moderate decrease in triglyceridemia, probably greatly explains these results. Insufficient improvement of insulin sensitivity and adiponectinemia may also be implied.

Type 2 Diabetes and HDL Dysfunction: A Key Contributor to Glycemic Control.

High-density lipoproteins (HDL) have been shown to exert multiple cardioprotective and antidiabetic functions, such as their ability to promote cellular cholesterol efflux and their antioxidant, anti-inflammatory, and antiapoptotic properties. Type 2 diabetes (T2D) is usually associated with low high-density lipoprotein cholesterol (HDL-C) levels as well as with significant alterations in the HDL composition, thereby impairing its main functions. HDL dysfunction also negatively impacts both pancreatic β-cell function and skeletal muscle insulin sensitivity, perpetuating this adverse self-feeding cycle. The impairment of these pathways is partly dependent on cellular ATP-binding cassette transporter (ABC) A1-mediated efflux to lipid-poor apolipoprotein (apo) A-I in the extracellular space. In line with these findings, experimental interventions aimed at improving HDL functions, such as infusions of synthetic HDL or lipid-poor apoA-I, significantly improved glycemic control in T2D patients and experimental models of the disease. Cholesteryl ester transfer protein (CETP) inhibitors are specific drugs designed to increase HDLC and HDL functions. Posthoc analyses of large clinical trials with CETP inhibitors have demonstrated their potential anti-diabetic properties. Research on HDL functionality and HDL-based therapies could be a crucial step toward improved glycemic control in T2D subjects.

Apolipoprotein A-1 Accelerated Liver Regeneration Through Regulating Autophagy Via AMPK-ULK1 Pathway

Apolipoprotein A-1 (ApoA-1), the main apolipoprotein of high-density lipoprotein, has been well studied in the area of lipid metabolism and cardiovascular diseases. In this project, we clarify the function and mechanism of ApoA-1 in liver regeneration. Seventy percent of partial hepatectomy was applied in male ApoA-1 knockout mice and wild-type mice to investigate the effects of ApoA-1 on liver regeneration. D-4F (ApoA-1 mimetic peptide), autophagy activator, and AMPK activator were used to explore the mechanism of ApoA-1 on liver regeneration. We demonstrated that ApoA-1 levels were highly expressed during the early stage of liver regeneration. ApoA-1 deficiency greatly impaired liver regeneration after hepatectomy. Meanwhile, we found that ApoA-1 deficiency inhibited autophagy during liver regeneration. The activation of autophagy protected against ApoA-1 deficiency in inhibiting liver regeneration. Furthermore, ApoA-1 deficiency impaired autophagy through AMPK-ULK1 pathway, and AMPK activation significantly improved liver regeneration. The administration of D-4F could accelerated liver regeneration after hepatectomy. These findings suggested that ApoA-1 played an essential role in liver regeneration through promoting autophagy in hepatocytes via AMPK-ULK1 pathway. Our findings enrich the understanding of the underlying mechanism of liver regeneration and provide a potential therapeutic strategy for liver injury.

Antibacterial Activity of Rainbow Trout Plasma: In Vitro Assays and Proteomic Analysis.

The objective of this study was to investigate the bactericidal activity of blood plasma from cultured rainbow trout obtained from two different fish farms. Plasma from trout naturally infected with the bacterial pathogen Flavobacterium psychrophilum was found to inhibit the growth of Aeromonas hydrophila in vitro. Incubation of A. hydrophila in bacteriostatic trout plasma resulted in agglutination and growth retardation, without causing massive damage to the cell membrane. The proteome of the plasma with high antimicrobial activity revealed an abundance of high-density apolipoproteins, some isoforms of immunoglobulins, complement components C1q and C4, coagulation factors, lectins, periostin, and hemoglobin. Analysis of trout proteins retained on A. hydrophila cells revealed the presence of fish immunoglobulins, lectins, and complement components on bacteria whose growth was inhibited, although the native membrane attack complex of immunised trout plasma did not assemble effectively, resulting in a weak bactericidal effect. Furthermore, this study examined the bacterial response to trout plasma and suggested that the protein synthesis pathway was the target of antimicrobial proteins from fish blood. Taken together, these findings illustrate the advantages of the affinity approach for understanding the role of plasma proteins in host defence against pathogens.

Apple Polyphenol Extract Ameliorates Atherosclerosis and Associated Cognitive Impairment through Alleviating Neuroinflammation by Weakening TLR4 Signaling and NLRP3 Inflammasome in High-Fat/Cholesterol Diet-Fed LDLR-/- Male Mice.

Although studies have supported the beneficial effects of the ingredients of apple polyphenol extract (APE), a polyphenol mixture being extracted from whole fresh apples, on neurodegenerative diseases, the role of APE in atherosclerosis-related cognitive impairment remains unclear. To clarify the role of APE in regulating cognitive dysfunction in mice with atherosclerosis and the underlying mechanisms, high-fat/cholesterol diet-fed male LDLR-/- mice were gavaged with 125 or 500 mg/(kg·bw·d) APE solution or sterile double-distilled water for consecutive 8 weeks, and age-matched C57BL/6 male mice were employed as normal control. APE intervention increased the serum concentration of high-density apolipoprotein cholesterol, improved atherosclerosis, and ameliorated cognitive function of mice by inhibiting the phosphorylation of tau protein, supporting with significantly reduced platform latency and obviously increased swimming distance in the target quadrant according to the Morris water maze test. APE intervention alleviated neuroinflammation by attenuating the activation of microglia and astrocytes and inhibiting TLR4 signaling with reduced protein expression of NF-κB, MyD88, TRIF, and IKKβ. Meanwhile, APE intervention inactivated NLRP3 inflammasome with downregulated protein expression of caspase-1, IL-18, and IL-1β. Additionally, APE intervention improved the damaged brain barrier structure by upregulating the protein expression of ZO-1 and occludin. Therefore, our research supplemented new data, supporting the potential of APE as an effective dietary bioactive ingredient to improve atherosclerosis and associated cognitive impairment.

Effects of CaCl2 on the structure of high-density lipoprotein and low-density lipoprotein isolated from rapidly salted separated egg yolk

According to previous research, adding CaCl2 to the salting solution improves the quality of salted separated egg yolk. To further understand the improvement mechanism of CaCl2, this paper investigated the effect of CaCl2 on the structure of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) during the salting process. The results indicated that the addition of CaCl2 can affect the composition of HDL and LDL apolipoproteins, improving the orderliness of the HDL structure and the looseness of the LDL structure. It was discovered by atomic force microscopy (AFM) that adding CaCl2 to the salting solution can weaken the aggregation behavior of HDL. Simultaneously, the addition of CaCl2 decreased the relative content of intermolecular β-sheets in the secondary structure of HDL and LDL, influenced their tertiary conformation, and prevented HDL and LDL from participating in the formation of a three-dimensional gel structure by influencing their hydrogen bonds and hydrophobic interactions.

Apolipoprotein A2 reduces the levels of circulating triglyceride-rich lipoproteins, an effect blocked by apolipoprotein E

Apolipoprotein A2 (APOA2), the second in quantity apolipoprotein of high density lipoprotein (HDL) is synthesized by the liver and much less by the intestine. Studies in humans, failed to establish a clear role for APOA2 in coronary heart disease and overall human physiology. Even though we know that APOA2 plays a key role in the biogenesis and functionality of HDL particles and can interact physically with other apolipoproteins such as apolipoprotein E (APOE), forming dimers, our knowledge on its role in triglyceride-rich lipoprotein (TRL) metabolism remains limited. Here, we investigated how functional interactions between APOA2 and APOE may affect plasma lipoprotein metabolism in the absence of apolipoprotein A1 (APOA1). For this purpose, APOA1 deficient and APOA1xAPOE double deficient mice were fed high fat diet for two weeks and were subsequently infected with either an adenovirus expressing the human APOA2 (AdAPOA2) or a control adenovirus AdGFP. Five days post-infection blood was collected, and plasma and lipoprotein fractions were isolated. After confirmation of human APOA2 expression in vivo by western blot we measured plasma and lipoprotein total cholesterol and triglyceride levels. APOA2 expression increased total cholesterol and triglyceride levels in APOA1 deficient mice. To the contrary, when APOA2 was expressed in APOA1xAPOE double deficient mice, which lack functional APOE a significant reduction in both plasma cholesterol and triglyceride levels associated with a notable reduction in TRL was observed. Overall, our data support that a significant functional interaction between APOA2 and APOE impacts plasma TRL metabolism.

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.

Do blood metals influence lipid profiles? Findings of a cross-sectional population-based survey

Dyslipidemia, an imbalance of lipids and a major risk factor for cardiovascular disease, has been associated with elevated blood and urine levels of several heavy metals. Using data from a Canadian Health Measures Survey (CHMS), we tested associations between blood levels of cadmium, copper, mercury, lead, manganese, molybdenum, nickel, selenium, and zinc, and the lipids triglycerides (TG), total cholesterol (TC), low density lipoproteins (LDL), high density lipoproteins (HDL) and apolipoproteins A1 (APO A1), and B (APO B). All adjusted associations between single metals and lipids were positive and significant, except for APO A1 and HDL. The joint effect of an interquartile range increase in heavy metals was positively associated with percentage increases of TC, LDL and APO B of 8.82% (95%CI: 7.06, 10.57), 7.01% (95%CI: 2.51, 11.51) and 7.15% (95%CI: 0.51, 13.78), respectively. Future studies are warranted to determine if reducing environmental exposure to heavy metals favorably influences lipid profiles and the risk of cardiovascular disease.

The Mechanism of Probiotics in Preventing the Risk of Hypercholesterolemia

Probiotics are beneficial live microorganisms because they provide health benefits to the host after being consumed in sufficient amounts, primarily by increasing the proliferation of native digestive microflora. Hypercholesterolemia is a condition in which cholesterol serum concentration is elevated significantly (exceeds 200 mg/dL). Hypercholesterolemia is characterized by high plasma levels of low-density lipoprotein (LDL) and low plasma concentration of high-density lipoprotein (HDL). This review aims to examine the mechanism of action of probiotics in preventing the risk of hypercholesterolemia and reducing LDL cholesterol levels in the human body. The mechanism of cholesterol-lowering effect of probiotic bacteria can be classified into four basic principles such as 1) the conversion of cholesterol to coprostanol, 2) the deconjugation of cholesterol by probiotics’ bile salt hydrolase enzyme, 3) the alteration of protein expression related to cholesterol synthesis, and 4) the production of Short Chain Fatty Acids (SCFA) by probiotics. Cholesterol converted to coprostanol is not absorbed by the small intestine and is directly excreted with the feces. The deconjugated cholesterol is easily precipitated and thus not absorbed by the small intestine. It also induces the assimilation of cholesterol into the probiotic membrane. Finally, the SCFAs, produced by probiotics fermentation within host digestive tract, can upregulate the synthesis of HDL apolipoprotein.

Apolipoprotein A-1 protected hepatic ischaemia-reperfusion injury through suppressing macrophage pyroptosis via TLR4-NF-κB pathway.

Apolipoprotein A-1 (ApoA-1), the major apolipoprotein of high-density lipoprotein, plays anti-atherogenic role in cardiovascular diseases and exerts anti-inflammation effect in various inflammatory and infectious diseases. However, the role and mechanism of ApoA-1 in hepatic ischaemia-reperfusion (I/R) injury is unknown. In this study, we measured ApoA-1 expression in human liver grafts after transplantation. Mice partial hepatic I/R injury model was made in ApoA-1 knockout mice, ApoA-1 mimetic peptide D-4F treatment mice and corresponding control mice to examine the effect of ApoA-1 on liver damage, inflammation response and cell death. Primary hepatocytes and macrophages were isolated for in vitro study. The results showed that ApoA-1 expression was down-regulated in human liver grafts after transplantation and mice livers subjected to hepatic I/R injury. ApoA-1 deficiency aggravated liver damage and inflammation response induced by hepatic I/R injury. Interestingly, we found that ApoA-1 deficiency increased pyroptosis instead of apoptosis during acute phase of hepatic I/R injury, which mainly occurred in macrophages rather than hepatocytes. The inhibition of pyroptosis compensated for the adverse impact of ApoA-1 deficiency. Furthermore, the up-regulated pyroptosis process was testified to be mediated by ApoA-1 through TLR4-NF-κB pathway and TLR4 inhibition significantly improved hepatic I/R injury. In addition, we confirmed that D-4F ameliorated hepatic I/R injury. Our study has identified the protective role of ApoA-1 in hepatic I/R injury through inhibiting pyroptosis in macrophages via TLR4-NF-κB pathway. The effect of ApoA-1 may provide a novel therapeutic approach for hepatic I/R injury.

Early time-restricted feeding improves high-density lipoprotein amount and function in nonhuman primates, without effects on body composition.

Time-restricted feeding (TRF), whereby caloric intake is limited to a <12-hour window, is a potential regimen to ameliorate metabolic syndrome and cardiovascular disease (CVD) risk co-occurring with aging and with obesity. Early TRF (eTRF; early morning feeding followed by overnight fasting) times calorie consumption with hepatic circadian gene expression rhythms. Brief TRF trials demonstrate that high-density lipoprotein (HDL) cholesterol increases similar to diet/exercise interventions, which may impart beneficial CVD effects. Using a nonhuman primate (NHP) model, the efficacy of eTRF to raise HDL and increase plasma cholesterol efflux capacity (CEC) (primarily mediated by cholesterol efflux to HDL particles, a process that is inversely associated with CVD risk) was examined. Adult (8-16 years old, n=25) and geriatric (≥17 years old) NHPs were randomized to ad libitum feeding or eTRF for 12 months, and relevant body composition, glycemic control, and plasma HDL cholesterol levels and CEC were measured. Impaired CEC was found in geriatric NHPs. eTRF induced larger-sized HDL particles, increased HDL apolipoprotein A-1 content, lowered triglyceride concentrations, and increased plasma CEC (primarily to HDL particles) in both adult and geriatric NHPs without changes in glycemic control or body composition. A beneficial effect of eTRF on increasing HDL CEC in NHPs was demonstrated.