HDL Particles Research Articles

Lipoprotein subclasses are associated with Hepatic steatosis: insights from the prospective multicenter imaging study for the evaluation of chest pain (PROMISE) clinical trial

ObjectivesTo determine the relationship between lipoprotein particle size/number with hepatic steatosis (HS), given its association with traditional lipoproteins and coronary atherosclerosis. MethodsIndividuals with available CT data and blood samples enrolled in the PROMISE trial were studied. HS was defined based on CT attenuation. Lipoprotein particle size/number were measured by nuclear magnetic resonance spectroscopy. Principal components analysis (PCA) was used for dimensionality reduction. The association of PCA factors and individual lipoprotein particle size/number with HS were assessed in multivariable regression models. Associations were validated in an independent cohort of 59 individuals with histopathology defined HS. ResultsIndividuals with HS (n=410/1,509) vs those without (n=1,099/1,509), were younger (59±8 vs 61±8 years) and less often females (47.6 % vs 55.9 %). All PCA factors were associated with HS: factor 1 (OR:1.36, 95 %CI:1.21–1.53), factor 3 (OR:1.75, 95 %CI:1.53–2.02) and factor 4 (OR:1.49; 95 %CI:1.32–1.68) were weighted heavily with small low density lipoprotein (LDL) and triglyceride-rich (TRL) particles, while factor 2 (OR:0.86, 95 %CI:0.77–0.97) and factor 5 (OR:0.74, 95 %CI:0.65–0.84) were heavily loaded with high density lipoprotein (HDL) and larger LDL particles. These observations were confirmed with the analysis of individual lipoprotein particles in PROMISE. In the validation cohort, association between HS and large TRL (OR: 8.16, 95 %CI:1.82–61.98), and mean sizes of TRL- (OR: 2.82, 95 %CI:1.14–9.29) and HDL (OR:0.35, 95 %CI:0.13–0.72) were confirmed. ConclusionsLarge TRL, mean sizes of TRL-, and HDL were associated with radiographic and histopathologic HS. The use of lipoprotein particle size/number could improve cardiovascular risk assessment in HS.

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 114: Inhibition Of Lecithin Cholesterol Acyl Transferase By A Novel Anti-apolipoprotein A1 Antibody Fragment

Apolipoprotein A1 (APOA1), the most abundant protein in high-density lipoproteins (HDL), is the primary activator of lecithin cholesterol acyl transferase (LCAT). LCAT’s cholesteryl esterification activity is key for maturing nascent HDL discs into the spherical forms commonly found in plasma. However, the molecular mechanism for APOA1 activation of LCAT is poorly understood. Using phage display selection against nanodiscs (lipid complexes stabilized by an APOA1 variant commonly used in transmembrane protein structural biology), we have identified, isolated, and expressed a novel Fab fragment (Fab16). Size exclusion chromatography elution shift experiments showed that Fab16 readily bound reconstituted HDL (rHDL) particles containing human purified plasma APOA1 with nearly quantitative binding at a 1:1 molar ratio of Fab16 to APOA1. Negative stain electron microscopy (NSEM), confirmed that 1-2 Fab16 bound to each rHDL particle in a specific pattern around the disc periphery. Additionally, Fab16 effectively bound both large and small spherical HDL particles isolated from human plasma. Chemical cross-linking / mass spectrometry experiments indicated that Fab16 binds an APOA1 epitope between residues 94 and 118 (i.e., within amphipathic helix 4). As our previous work has shown that APOA1 helix 4 is important for LCAT activation, we hypothesized that Fab16 would inhibit LCAT activity. Using a novel gas chromatography cholesterol esterification assay, we found that Fab16 applied at a 1.5:1 molar ratio to APOA1 inhibited LCAT cholesterol esterification activity by 56±7%. The symmetrical nature of both discoidal and spherical HDL particles has hampered the application of cryogenic electron microscopy (cryo EM) for understanding HDL structure. Fab16 may provide a valuable ‘landmark’ to assist in deriving a high-resolution structure of the complex. Work to optimize conditions for collecting high quality cryo EM datasets of discoidal and spherical HDL in the presence and absence of LCAT is ongoing. Deriving a high-resolution understanding of HDL structure and its interaction with remodeling factors such LCAT has been a long-standing problem but is crucial for deriving new strategies to manipulate HDL function for therapeutic benefit.

Vascular Dysfunction and Inflammation in Liver Transplant Recipients

INTRODUCTION Liver transplant (LT) recipients have an increased risk of developing cardiovascular disease (CVD) after transplant. The physiological mechanisms driving this risk are not fully understood. Vascular endothelial dysfunction is the initial pathophysiological step in the development of atherosclerosis. The objective of this study was to characterize vascular endothelial function in LT recipients. It was hypothesized that compared to matched healthy controls (HC), LT recipients would have impaired vascular function. METHODS. Conduit artery endothelial function was measured by flow-mediated dilation of the brachial artery (FMDBA) with duplex ultrasound in 40 LT patients (18 male, 22 female; mean ± SD: Age, 56±11 years) and 10 age matched HC (4 male, 6 female; Age 51±16 years). Central aortic blood pressures were derived from radial arterial tonometry and the use of the generalized transfer function. A venous blood sample was obtained for nuclear magnetic resonance spectroscopy assessment of the inflammation biomarker GlycA, and high-density lipoprotein (HDL) particle subspecies. A novel metabolic inflammation index was derived from plasma GlycA and HDL subparticle concentrations. RESULTS. LT recipients had higher peripheral (Median [IQR]: HC vs. LT, 119 [111-136] vs. 135 [124-147] mmHg, p=0.01) and central aortic (113 [102-126] vs. 124 [116-139] mmHg, p=0.03) systolic blood pressures. LT recipients had impaired vascular endothelial function (HC vs. LT, FMDBA: 6.08 [5.01-7.61] vs. 4.54 [3.31-6.24] %, p = 0.04). In LT recipients, the inflammation index (55 [45-62] AU) was negatively associated with vascular endothelial function ( r=-0.4, p=0.03). CONCLUSIONS. Despite optimal pharmacological intervention, LT recipients had higher systolic blood pressures and worse vascular endothelial dysfunction compared to HC. In LT recipients, a higher inflammation index was associated with worse endothelial function, suggesting that chronic low-grade inflammation may partly contribute to endothelial dysfunction in this patient population. These findings provide support for the vascular endothelium as a potential therapeutic target to improve cardiovascular health in LT recipients. Supported by CTSA award No. UM1TR004360 from the National Center for Advancing Translational Sciences. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract 3040: Quantitative Proteomic Analysis Of HDL Shows Apolipoprotein M (ApoM) As A Possible Marker For COVID-19 Mortality

Introduction: High-density lipoprotein (HDL) comprises a heterogeneous group of particles that differ in many aspects, such as density, size, composition and function. The use of mass spectrometry-based proteomics to investigate HDL protein composition has brought some new insights into the field. The qualitative and quantitative HDL proteome is remodeled in different disease states, such as diabetes mellitus, hypercholesterolemia and kidney dysfunction. Beyond its established role in inflammatory and cardiovascular diseases, HDL's involvement in infectious diseases, such as COVID-19, has recently come to light. Here, we investigate the remodeling of HDL proteome in hospitalized and non-hospitalized COVID-19 patients. Hypothesis: We hypothesize HDL proteome is remodeled in infectious diseases and may be a marker and perhaps a predictor of a poor prognosis. Methods: We implemented a robust, global label-free quantification proteomic approach to unravel relative changes in HDL protein composition. We analyzed the proteome of COVID-19 subjects from Brazil categorized in two groups, hospitalized (n=30) and non-hospitalized (n=11). Results: Comparative analysis between hospitalized and non-hospitalized patients revealed a more than 50% increase in relative levels of certain proteins in hospitalized patients, including the inflammatory proteins serum amyloid A1 and A2, as well as pulmonary surfactant-associated protein B. We also observed reductions in the lipid-metabolism related apolipoprotein A2 and phospholipid transfer protein. These findings, independent of sex, triglyceride and HDL-cholesterol, suggest an inflammatory remodeling of the HDL particles. Further analysis of surviving (n=35) and deceased patients (n=6) indicated a negative association between ApoM levels and odds of death due to COVID-19 complications (odds ratio per 1-SD increase in ApoM was 0.27 [0.07 to 0.72], P=0.007). Conclusions: Our results point out HDL remodeling is a marker of COVID-19 severity and ApoM-carried sphingosine-1-phosphate signaling pathway may play a pivotal role in the disease outcome.

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.

Abstract 3045: Dietary Whole-grain Rice Differentially Regulates HDL-associated MicroRNAs And Hepatic Lipase In Healthy Japanese Volunteers.

Background: The Japanese population consumes a diet high in rice. Dietary whole-grain (brown) rice has advantageous health benefits over white rice, largely predicted to be conferred by brown rice bran, germ, and fiber. We have previously reported that high-density lipoproteins (HDL) transport microRNAs (miRNA) and deliver functional RNA to recipient hepatocytes. Here, we hypothesize that dietary brown rice reorganizes functional small RNA (sRNA) cargo on circulating HDL and regulates systemic lipid metabolism through hepatic HDL-miRNA uptake. Methods: Healthy subjects (n=13, 20-65 y.o., 38.5% male) consumed 150 g/serving for all 3 meals of (1) white rice, (2) brown rice, and (3) white rice for 3 days with intervals of 4 to 7 days. At day 4, plasma HDL-cholesterol (HDL-C) and total plasma lipids were measured by direct and enzymatic methods. Total RNA was isolated HDL purified by size-exclusion chromatography from human plasma. HDL-sRNA sequencing was completed using NovaSeq6000 (Illumina). HTGL protein levels were measured by ELISA (IBL). Results: Plasma cholesterol, HDL-C, and non-HDL-C levels were not immediately affected by dietary brown rice; however, HDL-C levels were increased after a delay of 10 days. Nevertheless, HDL-associated miR-203-3p and miR-205-5p were found to be significantly decreased in subjects with brown rice consumption compared to white rice. miR-203-3p is predicted to target and suppress hepatic lipase ( LIPC , HTGL). Plasma levels of HTGL were not altered by brown rice, but HTGL protein levels were found to be significantly decreased when the brown rice diet was switched back to white rice, and miR-203-3p levels returned to HDL particles. Conclusions: Dietary brown rice reduces HDL-associated miR-203-3p and miR-205-5p after 3 days and differentially regulates the systemic level of a putative miR-203-3p target gene. These results support that HDL-miR-203-3p functionality may be responsive to brown rice diets and post-transcriptionally regulate LIPC gene expression in recipient hepatocytes. These observations can potentially be used to design dietary supplements to regulate HDL-miRNA function in the liver to control systemic lipid metabolism.

Defective HDL particles functionality in patients with ST-segment elevation acute myocardial infarction

Defective HDL particles functionality in patients with ST-segment elevation acute myocardial infarction

Contributions of Lipid-Related Metabolites and Complement Proteins to Early and Intermediate Age-Related Macular Degeneration

ObjectiveOur objective was to determine the effects of lipids and complement proteins on early and intermediate age-related macular degeneration (AMD) stages using machine learning models by integrating metabolomics and proteomic data. DesignNested case-control study. Subjects, Participants, and/or ControlsThe analyses were performed in a subset of the Singapore Indian Chinese Cohort (SICC) Eye Study. Among the 6,753 participants, we randomly selected 155 AMD Indian and 155 Chinese cases and matched them with 310 controls on age, sex and ethnicity. MethodsWe measured 35 complement proteins and 56 lipid-related metabolites using Mass Spectrometry and Nuclear Magnetic Resonance, respectively. We first selected the most contributing lipids and complement proteins to early and intermediate AMD using random forest models. Then we estimated their effects using a multinomial model adjusted for potential confounders. Main Outcome MeasuresAMD was classified using the Beckman classification system. ResultsAmong the 310 individuals with AMD, 166 (53.5%) had early and 144 (46.5%) intermediate AMD. Firstly, high-density lipoprotein (HDL) particle diameter was positively associated with both early and intermediate AMD (ORearly=1.69 [1.11, 2.55] and ORintermediate=1.72 [1.11, 2.66] per 1-SD increase in HDL diameter). Secondly, five complement proteins: complement protein 2 (C2), complement C1 inhibitor (ICI1), complement protein 6 (C6), complement protein 1QC (C1QC) and complement factor H-related protein 1 (FHR1), were associated with AMD. C2 was positively associated with both early and intermediate AMD (ORearly=1.58 [1.08, 2.30] and ORintermediate=1.56 [1.04, 2.34]). C6 was positively (ORearly=1.41 [1.03, 1.93]) associated with early AMD. However, IC1 was negatively associated with early AMD (ORearly=0.62 [0.38, 0.99]), while C1QC (ORintermediate=0.63 [0.42, 0.93]) and FHR1 (ORintermediate=0.73 [0.54, 0.98) were both negatively associated with intermediate AMD. ConclusionsWhile both HDL diameter and C2 levels show associations with both early and intermediate AMD, dysregulations of IC1, C6, C1QC, and FHR1 are only observed at specific stages of AMD. These findings underscore the complexity of complement system dysregulation in AMD, which appears to vary depending on the disease severity.

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.

Structural studies of a serum amyloid A octamer that is primed to scaffold lipid nanodiscs.

Serum amyloid A (SAA) is a highly conserved acute-phase protein that plays roles in activating multiple pro-inflammatory pathways during the acute inflammatory response and is commonly used as a biomarker of inflammation. It has been linked to beneficial roles in tissue repair through improved clearance of lipids and cholesterol from sites of damage. In patients with chronic inflammatory diseases, elevated levels of SAA may contribute to increased severity of the underlying condition. The majority of circulating SAA is bound to lipoproteins, primarily high-density lipoprotein (HDL). Interaction with HDL not only stabilizes SAA but also alters its functional properties, likely through altered accessibility of protein-protein interaction sites on SAA. While high-resolution structures for lipid-free, or apo-, forms of SAA have been reported, their relationship with the HDL-bound form of the protein, and with other possible mechanisms of SAA binding to lipids, has not been established. Here, we have used multiple biophysical techniques, including SAXS, TEM, SEC-MALS, native gel electrophoresis, glutaraldehyde crosslinking, and trypsin digestion to characterize the lipid-free and lipid-bound forms of SAA. The SAXS and TEM data show the presence of soluble octamers of SAA with structural similarity to the ring-like structures reported for lipid-free ApoA-I. These SAA octamers represent a previously uncharacterized structure for lipid-free SAA and are capable of scaffolding lipid nanodiscs with similar morphology to those formed by ApoA-I. The SAA-lipid nanodiscs contain four SAA molecules and have similar exterior dimensions as the lipid-free SAA octamer, suggesting that relatively few conformational rearrangements may be required to allow SAA interactions with lipid-containing particles such as HDL. This study suggests a new model for SAA-lipid interactions and provides new insight into how SAA might stabilize protein-lipid nanodiscs or even replace ApoA-I as a scaffold for HDL particles during inflammation.

Effect of Empagliflozin with or without the Addition of Evolocumab on HDL Subspecies in Individuals with Type 2 Diabetes Mellitus: A Post Hoc Analysis of the EXCEED-BHS3 Trial.

Evolocumab and empagliflozin yield a modest rise in plasma high-density lipoprotein cholesterol (HDL-C) through unknown mechanisms. This study aims to assess the effect of evolocumab plus empagliflozin vs. empagliflozin alone on HDL subspecies isolated from individuals with type 2 diabetes mellitus (T2D). This post hoc prespecified analysis of the EXCEED-BHS3 trial compared the effects of a 16-week therapy with empagliflozin (E) alone or in combination with evolocumab (EE) on the lipid profile and cholesterol content in HDL subspecies in individuals with T2D divided equally into two groups of 55 patients. Both treatments modestly increased HDL-C. The cholesterol content in HDL subspecies 2a (7.3%), 3a (7.2%) and 3c (15%) increased from baseline in the E group, while the EE group presented an increase from baseline in 3a (9.3%), 3b (16%) and 3c (25%). The increase in HDL 3b and 3c was higher in the EE group when compared to the E group (p < 0.05). No significant interactive association was observed between changes in hematocrit and HDL-C levels after treatment. Over a 16-week period, empagliflozin with or without the addition of evolocumab led to a modest but significant increase in HDL-C. The rise in smaller-sized HDL particles was heterogeneous amongst the treatment combinations.

Lipoprotein Insulin Resistance Score and Mortality Risk Stratification in Heart Failure

BackgroundHigher total serum cholesterol is associated with lower mortality in heart failure. Evaluating associations between lipoprotein subfractions and mortality among people with heart failure may provide insights into this observation. MethodsWe prospectively enrolled a community cohort of people with heart failure from 2003 to 2012 and assessed vital status through 2021. Plasma collected at enrollment was used to measure lipoprotein subfractions via nuclear magnetic resonance spectroscopy. A composite score of 6 lipoprotein subfractions was generated using the lipoprotein insulin resistance index (LP-IR) algorithm. Using covariate-adjusted proportional hazards regression models, we evaluated associations between LP-IR score and all-cause mortality. ResultsAmong 1382 patients with heart failure (median follow-up 13.9 years), a one-standard-deviation (SD) increment in LP-IR score was associated with lower mortality (hazard ratio [HR] 0.93; 95% confidence interval [CI], 0.97-0.99). Among LP-IR parameters, mean high-density lipoprotein (HDL) particle size was significantly associated with lower mortality (HR per 1-SD decrement in mean HDL particle size = 0.83; 95% CI, 0.78-0.89), suggesting that the inverse association between LP-IR score and mortality may be driven by smaller mean HDL particle size. ConclusionsLP-IR score was inversely associated with mortality among patients with heart failure and may be driven by smaller HDL particle size.

Impaired Cholesterol Uptake Capacity in Patients with Hypertriglyceridemia and Diabetes Mellitus.

Although low high-density lipoprotein cholesterol (HDL-C) levels are a common metabolic abnormality associated with insulin resistance, their role in cardiovascular risk stratification remains controversial. Recently, we developed a simple, high-throughput, cell-free assay system to evaluate the "cholesterol uptake capacity (CUC)" as a novel concept for HDL functionality. In this study, we assessed the CUC in patients with hypertriglyceridemia and diabetes mellitus. The CUC was measured using cryopreserved serum samples from 285 patients who underwent coronary angiography or percutaneous coronary intervention between December 2014 and May 2019 at Kobe University Hospital. The CUC was significantly lower in diabetic patients (n = 125) than in nondiabetic patients (93.0 vs 100.7 arbitrary units (A.U.), P = 0.002). Patients with serum triglyceride (TG) levels >150 mg/dL (n = 94) also had a significantly lower CUC (91.8 vs 100.0 A.U., P = 0.004). Furthermore, the CUC showed a significant inverse correlation with TG, hemoglobin A1c (Hb A1c), homeostasis model assessment of insulin resistance (HOMA-IR), and body mass index (BMI). Finally, the HDL-C/Apolipoprotein A1 (ApoA1) ratio, calculated as a surrogate index of HDL particle size, was significantly positively correlated with the CUC (r2 = 0.49, P < 0.001), but inversely correlated with TG levels (r2 = -0.30, P < 0.001). The CUC decreased in patients with hypertriglyceridemia and diabetes mellitus, and HDL particle size was a factor defining the CUC and inversely correlated with TG levels, suggesting that impaired CUC in insulin-resistant states was partially due to the shift in HDL towards smaller particles. These findings provide a better understanding of the mechanisms underlying impaired HDL functionality.

Atherosclerosis and Vine

In light of today's scientific knowledge about the causes and process of atherosclerosis, how to explain and interpret the fact, seemingly very illogical, that the French do not have a high mortality from coronary diseases caused by atherosclerosis, despite the high fat content of everyday nutrition? Such epidemiological ilogenicity, called the French Paradox, has been attributed to daily, moderate consumption of red wines, which proved correct [2]. It has been proven that the beneficial effects of red wine in the process of preventing atherosclerosis can be attributed to the effects of the polyphenols present, likewise, these effects do not only apply to red wine, but also to other drinks, alcoholic and non-alcoholic, containing polyphenols [3]. Studies conducted on beer consumption have produced similar results. [18] It should be noted that the effect of alcohol is described by the J curve, suggesting that moderate alcohol consumption reduces the risk of atherosclerosis, unlike abstinence and excessive alcohol lovers, where this risk is noticeably higher. This effect of red wine is attributed, among other agents, to a significantly increased concentration of high density lipoprotein (HDL) [4]. The paper discusses the effect of HDL particles on nascent chylomicrons in the lymphoma system, which, by entering the circulatory system, affects possible association with atherosclerosis. After such knowledge of the effects of red wine (polyphenols) on the organism, can it be considered that non-consumption of the same and other polyphenols-containing drinks is a certain risk factor? ( In vino veritas).

Lactiplantibacillus plantarum strains KABP011, KABP012, and KABP013 modulate bile acids and cholesterol metabolism in humans.

Probiotics with high bile salt hydrolase (BSH) activity have shown to promote cardiovascular health. However, their mechanism(s) of action remain poorly understood. Here, we performed a pilot exploratory study to investigate effects of a 4-week intervention with escalating doses of a BSH-active formula containing Lactiplantibacillus plantarum strains KABP011, KABP012, and KABP013 on bile acid (BA), lipid profile, and lipoprotein function. Healthy overweight individuals were included in this study. The probiotic intake was associated with a progressive decrease of conjugated BAs in serum, due to the reduction of tauro- and glyco-conjugated forms. Plasma levels of fibroblast growth factor-19 were significantly reduced and correlated with BA changes. The probiotic induced significant changes in serum lipids, with reduction in non-HDL cholesterol (non-HDLc) and LDL cholesterol (LDLc) levels. The largest decrease was evidenced in the subgroup with higher baseline LDLc levels (LDLc > 130 mg/dL). Fasting levels of circulating apolipoprotein(Apo) B100 and ApoB48 were significantly reduced. Importantly, the decrease in non-HDLc levels was associated with a significant reduction in small LDL particles. Functional testing indicated that LDL particles had a significantly lower susceptibility to oxidation, while HDL particles gained antioxidant capacity after the probiotic intake. The microbiota profile in faeces collected at the end of the study was enriched with members of class Desulfovibrio, a taurine-consuming bacteria, likely because of the increase in free taurine in the gut due to the BSH activity of the probiotic. The intervention with L. plantarum strains induces beneficial effects on BA signature and lipoprotein profile. It reduces ApoB and small LDL levels and LDL susceptibility to oxidation and increases HDL antioxidant capacity. These metabolic profile changes suggest increased protection against atherosclerotic disease.

SGLT2 inhibition, high-density lipoprotein, and kidney function: a mendelian randomization study.

Sodium-glucose cotransporter 2 (SGLT2) inhibition is recognized for its evident renoprotective benefits in diabetic renal disease. Recent data suggest that SGLT2 inhibition also slows down kidney disease progression and reduces the risk of acute kidney injury, regardless of whether the patient has diabetes or not, but the mechanism behind these observed effects remains elusive. The objective of this study is to utilize a mendelian randomization (MR) methodology to comprehensively examine the influence of metabolites in circulation regarding the impact of SGLT2 inhibition on kidney function. We used a MR study to obtain associations between genetic proxies for SGLT2 inhibition and kidney function. We retrieved the most recent and comprehensive summary statistics from genome-wide association studies (GWAS) that have been previously published and involved kidney function parameters such as estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), and albuminuria. Additionally, we included blood metabolite data from 249 biomarkers in the UK Biobank for a more comprehensive analysis. We performed MR analyses to explore the causal relationships between SGLT2 inhibition and kidney function and two-step MR to discover potential mediating metabolites. The study found that a decrease in HbA1c levels by one standard deviation, which is genetically expected to result in SGLT2 inhibition, was linked to a decreased likelihood of developing type 2 diabetes mellitus (T2DM) (odds ratio [OR] = 0.55 [95% CI 0.35, 0.85], P = 0.007). Meanwhile, SGLT2 inhibition also protects eGFR (β = 0.05 [95% CI 0.03, 0.08], P = 2.45 × 10- 5) and decreased UACR (-0.18 [95% CI -0.33, -0.02], P = 0.025) and albuminuria (-1.07 [95% CI -1.58, -0.57], P = 3.60 × 10- 5). Furthermore, the study found that of the 249 metabolites present in the blood, only one metabolite, specifically the concentration of small high-density lipoprotein (HDL) particles, was significantly correlated with both SGLT2 inhibition and kidney function. This metabolite was found to play a crucial role in mediating the improvement of renal function through the use of SGLT2 inhibition (β = 0.01 [95% CI 0.005, 0.018], P = 0.001), with a mediated proportion of 13.33% (95% CI [5.71%, 26.67%], P = 0.020). The findings of this investigation provide evidence in favor of a genetically anticipated biological linkage between the inhibition of SGLT2, the presence of circulating metabolites, and renal function. The findings demonstrate that the protective effect of SGLT2 inhibition on renal function is mostly mediated by HDL particle concentrations in circulating metabolites. These results offer significant theoretical support for both the preservation of renal function and a better comprehension of the mechanisms underlying SGLT2 inhibition.

Abstract P182: Ratio of Cholesterol to Triglycerides Within High-Density Lipoprotein (HDL) as a Novel Marker of Risk for Myocardial Infarction (MI)

Background: HDL cholesterol, together with LDL-c and triglycerides, are biomarkers widely used to assess risk of myocardial infarction (MI). Thereafter, apoA1 and HDL particle number (HDL-P) were identified as biomarkers inversely associated with risk of MI. State-of-the-art nuclear magnetic resonance spectroscopy allows for profiling of lipidomic markers within HDL, providing an unprecedented opportunity to identify novel biomarkers of MI. Methods: We examined associations between HDL lipid components and risk of MI in the UK Biobank. We leveraged the most up to date lipidomic data measured by NMR. A total of 8229 MI incidents were documented among 249,140 participants over a median 17.7 years of follow-up. Results: Independent of existing risk factors including LDL-c, triglycerides, apo-A1, HDL-P, the percentage of cholesterol over total lipids in HDL was inversely associated with the risk of MI with Hazard Ratio (HR) of 0.85 (0.76, 0.95), when comparing the highest quintile to the lowest. The percentage of triglycerides in HDL was positively associated with 1.13 (1.01, 1.26). We created the ratio of cholesterol to triglyceride within HDL and found it to be inversely associated with risk of MI (HR=0.89 [0.79, 0.99]). This finding is robust and consistently supported across subclasses of HDL. Conclusions: The ratio of cholesterol to triglycerides within HDL particles may be a new marker of risk for MI, independent of existing biomarkers. Table 1 . Hazard Ratios for Myocardial Infarction (MI) across Percentages of Lipids in HDL. Model 1: Cox model adjusted for conventional covariates: Age, Sex, Race, Body Mass Index, Hypertension status, Statin Use, Type 2 Diabetes status, Smoking, Education, Alcohol intake, and Townsend Deprivation Index, LDL-C, and TriglyceridesModel 2: Cox model adjusted for Model 1 covariates plus Apolipoprotein A1 and HDL particle number.

Abstract P185: Plasma Lipidome Signature of Visceral Fat Reveals Heterogenous Cardiometabolic Risk Profiles

Background: Excessive visceral fat is associated with metabolic alterations and is a causal risk factor for CVD. The plasma lipidome is altered in obesity and lipidome signatures of BMI and obesity have been identified. However, few studies have examined the plasma lipidome in relation to visceral fat. Methods: Plasma lipids were measured using the C8-positive LC-MS method in 671 participants from the HERITAGE Family Study (56% Female, 35% Black, 35 yrs). Visceral fat was measured using CT scans. Linear mixed models were used to test the associations of 193 known plasma lipids with visceral fat adjusting for age, sex, race, and BMI. A FDR&lt;5% was used to determine significance. Results: In individual models, 156 lipid species were significantly associated with visceral fat, with 109 species associated after additional adjustment for BMI ( Fig 1 ). The top positively associated lipids were triglycerides, while cholesterol esters showed the strongest inverse associations with visceral fat. A LASSO regression model retained 73 lipids and explained 78.5% of the variance in visceral fat. Delta visceral fat was calculated as the difference between predicted (from LASSO) and measured visceral fat. Examining quartiles of delta visceral fat showed that discordance between predicted and actual visceral fat was associated with differing cardiometabolic profiles independent of age, sex, race, visceral fat, and BMI. Individuals with higher delta visceral fat (Q4, overpredicted) had significantly (p&lt;1.0x10 -04 ) higher levels of TG, apoB, total cholesterol, LDL-C, and fasting insulin and lower levels of large HDL particles and LPL activity compared to those with lower delta visceral fat (Q1, underpredicted). Conclusions: The plasma lipidome is widely associated with visceral fat levels. A lipidome-based visceral fat score may provide additional information over measured visceral fat for assessment of cardiometabolic health. Further studies are needed to test and validate the clinical utility of such lipidome-based scores.

Hepatic insulin resistance and muscle insulin resistance are characterized by distinct postprandial plasma metabolite profiles: a cross-sectional study

BackgroundTissue-specific insulin resistance (IR) predominantly in muscle (muscle IR) or liver (liver IR) has previously been linked to distinct fasting metabolite profiles, but postprandial metabolite profiles have not been investigated in tissue-specific IR yet. Given the importance of postprandial metabolic impairments in the pathophysiology of cardiometabolic diseases, we compared postprandial plasma metabolite profiles in response to a high-fat mixed meal between individuals with predominant muscle IR or liver IR.MethodsThis cross-sectional study included data from 214 women and men with BMI 25–40 kg/m2, aged 40–75 years, and with predominant muscle IR or liver IR. Tissue-specific IR was assessed using the muscle insulin sensitivity index (MISI) and hepatic insulin resistance index (HIRI), which were calculated from the glucose and insulin responses during a 7-point oral glucose tolerance test. Plasma samples were collected before (T = 0) and after (T = 30, 60, 120, 240 min) consumption of a high-fat mixed meal and 247 metabolite measures, including lipoproteins, cholesterol, triacylglycerol (TAG), ketone bodies, and amino acids, were quantified using nuclear magnetic resonance spectroscopy. Differences in postprandial plasma metabolite iAUCs between muscle and liver IR were tested using ANCOVA with adjustment for age, sex, center, BMI, and waist-to-hip ratio. P-values were adjusted for a false discovery rate (FDR) of 0.05 using the Benjamini–Hochberg method.ResultsSixty-eight postprandial metabolite iAUCs were significantly different between liver and muscle IR. Liver IR was characterized by greater plasma iAUCs of large VLDL (p = 0.004), very large VLDL (p = 0.002), and medium-sized LDL particles (p = 0.026), and by greater iAUCs of TAG in small VLDL (p = 0.025), large VLDL (p = 0.003), very large VLDL (p = 0.002), all LDL subclasses (all p < 0.05), and small HDL particles (p = 0.011), compared to muscle IR. In liver IR, the postprandial plasma fatty acid (FA) profile consisted of a higher percentage of saturated FA (p = 0.013), and a lower percentage of polyunsaturated FA (p = 0.008), compared to muscle IR.ConclusionPeople with muscle IR or liver IR have distinct postprandial plasma metabolite profiles, with more unfavorable postprandial metabolite responses in those with liver IR compared to muscle IR.