The Influence of Menopause and Cardiorespiratory Fitness on Lipoprotein Particles in Midlife Women

Lipoprotein particles may provide better information about cardiovascular risk than standard cholesterol measures for women. Whether lipoprotein subclasses change with menopausal stage is unclear. Given the high prevalence of low cardiorespiratory fitness in midlife women and benefit to cardiovascular risk, it is also important to understand the effect of fitness on lipoprotein profiles. Purpose: To evaluate the influence of menopausal status and fitness on lipoprotein particles in healthy midlife women. Methods: Lipoprotein particles were measured in high-(HIGH,n=25) and low-fit(LOW,n=13) perimenopausal and late postmenopausal women, and in HIGH premenopausal(n=10), perimenopausal(n=12), and late postmenopausal women(n=13). Results: There were larger low-density lipoprotein particles(LDL-P, 21.7±0.06vs.21.3±0.1nm, p=0.002), more large LDL-P(623.1±32.8vs.500.2±52.6nmol/L, p=0.045), and fewer small LDL-P(145.5±31.4vs. 311.5±44.7nmol/L, p=0.001) in HIGH vs. LOW. High-density lipoprotein particles(HDL-P) were larger(10.1±0.1vs.9.7±0.1nm, p=0.002) in HIGH, with more large(14.8±0.7vs.11.0±0.9μmol/L, p=0.002), medium(12.9±0.8vs. 8.4±0.9μmol/L, p=0.002), and fewer small HDL-P(10.2±1.1vs.15.4±1.6μmol/L, p=0.009) compared to LOW. HIGH postmenopausal women had more large LDL-P(662.9±47.5nmol/L) compared to premenopausal women(479.1±52.6nmol/L, p=0.035), and more HDL-P(40.2±1.1μmol/L) compared to premenopausal(34.9±1.5μmol/L, p=0.023) and perimenopausal women(35.4±1.3μmol/L, p=0.033). Conclusion: High fitness positively influences lipoprotein particles in healthy perimenopausal and late postmenopausal women. In healthy fit women, menopause may not have a large influence on lipoprotein particles. Novelty Bullets: • In highly-fit women, menopause may not have a negative influence on lipoprotein particle subclasses. • High fitness is associated with a less atherogenic lipoprotein profile in perimenopausal and late postmenopausal women.

Advanced Quantitative Lipoprotein Characteristics Do Not Relate to Healthy Dietary Patterns in Adults from a Mediterranean Area

We aimed to assess the potential relationship between dietary patterns (i.e., Mediterranean diet and healthy eating) and the advanced lipoprotein profile (ALP) in a representative cohort of the Mediterranean population. Thus, ALP data from 1142 participants, including 222 with type 1 (19.4%) and 252 type 2 diabetes (22.1%), and 668 subjects without diabetes were used to study cross-sectional associations between quantitative characteristics of lipoproteins and adherence to the Mediterranean diet. The alternate Mediterranean diet score (aMED) and the alternate healthy eating index (aHEI) were calculated. The ALP was determined by nuclear magnetic resonance (NMR) spectrometry. Bivariable and multivariable analyses were performed. Participants in the third tertile of the aMED showed higher levels of low-density lipoprotein triglycerides (LDL-TG) (mean (SD) 17.5 (5.0); p = 0.037), large high-density lipoprotein particles (HDL-P) (0.3 (0.1); p = 0.037), and medium low-density lipoprotein particles (LDL-P) (434.0 (143.0); p = 0.037). In comparison with participants in the second and first tertiles of the aHEI, participants in the third tertile had higher levels of LDL-TG (17.7 (5.0); p = 0.010), and large HDL-P (0.3 (0.1); p = 0.002), IDL-C (11.8 (5.0); p = 0.001), intermediate-density lipoprotein triglycerides (IDL-TG) (13.2 (4.2); p < 0.001), LDL-TG (17.7(5.0); p = 0.010), high-density lipoprotein triglycerides (HDL-TG) (14.5 (4.4); p = 0.029,) large HDL-P (0.3 (0.1); p = 0.002) and very–low-density lipoprotein particles (VLDL-P) size (42.1 (0.2); p = 0.011). The adjusted-multivariable analysis for potential confounding variables did not show any association between the lipoproteins and dietary patterns (i.e., aMED and aHEI). In conclusion, none of the quantitative characteristics of lipoproteins were concomitantly associated with the extent of adherence to the Mediterranean diet measured using the aMED or aHEI scores in the studied population. Our findings also revealed that people with the highest adherence were older, had a higher body mass index (BMI) and more frequently had dyslipidemia, hypertension, or diabetes than those with the lowest adherence to the Mediterranean diet (MDiet). Thus, further research may be needed to assess the potential role of the dietary pattern on the ALP.

Plasma Membrane Lipids: An Important Binding Site for All Lipoprotein Classes

Cholesterol is one of the main constituents of plasma membranes; thus, its supply is of utmost importance. This review covers the known mechanisms of cholesterol transfer from circulating lipoprotein particles to the plasma membrane, and vice versa. To achieve homeostasis, the human body utilizes cellular de novo synthesis and extracellular transport particles for supply of cholesterol and other lipids via the blood stream. These lipoprotein particles can be classified according to their density: chylomicrons, very low, low, and high-density lipoprotein (VLDL, LDL, and HDL, respectively). They deliver and receive their lipid loads, most importantly cholesterol, to and from cells by several redundant routes. Defects in one of these pathways (e.g., due to mutations in receptors) usually are not immediately fatal. Several redundant pathways, at least temporarily, compensate for the loss of one or more of them, but the defects trigger systemic diseases, such as atherosclerosis later on. Recently, intracellular membrane–membrane contact sites were shown to be involved in intracellular cholesterol transfer and the plasma membrane itself has been proposed to act as a binding site for lipoprotein-mediated cargo unloading.

Human Fecal Metabolome Reflects Differences in Body Mass Index, Physical Fitness, and Blood Lipoproteins in Healthy Older Adults

This study investigated how body mass index (BMI), physical fitness, and blood plasma lipoprotein levels are related to the fecal metabolome in older adults. The fecal metabolome data were acquired using proton nuclear magnetic resonance spectroscopy and gas chromatography–mass spectrometry on 163 healthy older adults (65–80 years old, 80 females and 83 males). Overweight and obese subjects (BMI ≥ 27) showed higher levels of fecal amino acids (AAs) (valine, alanine, and phenylalanine) compared to normal-weight subjects (BMI ≤ 23.5). Adults classified in the high-fitness group displayed slightly lower concentrations of fecal short-chain fatty acids, propionic acid, and AAs (methionine, leucine, glutamic acid, and threonine) compared to the low-fitness group. Subjects with lower levels of cholesterol in low-density lipoprotein particles (LDLchol, ≤2.6 mmol/L) displayed higher fecal levels of valine, glutamic acid, phenylalanine, and lactic acid, while subjects with a higher level of cholesterol in high-density lipoprotein particles (HDLchol, ≥2.1 mmol/L) showed lower fecal concentration of isovaleric acid. The results from this study suggest that the human fecal metabolome, which primarily represents undigested food waste and metabolites produced by the gut microbiome, carries important information about human health and should be closely integrated to other omics data for a better understanding of the role of the gut microbiome and diet on human health and metabolism.

Meal-Related Changes in Apolipoprotein Particles After Treatment With an Antisense Oligonucleotide to Apolipoprotein CIII

Background: Lipodystrophy (LD) is defined by partial or complete absence of adipose tissue causing metabolic complications such as high triglycerides (TG). Apolipoprotein CIII (ApoCIII) contributes to high TG by inhibiting lipoprotein lipase (LPL). Measurement of lipoprotein particles using NMR can offer insights into lipid metabolism. Hypothesis: We hypothesized that during a mixed meal test (MMT), clearance of TG-rich lipoprotein particles (TRLP) measured by NMR would increase in LD patients given an antisense oligonucleotide (ASO) to lower ApoCIII. Experimental Design: Five adults with partial LD underwent an MMT (with 18g fat) at week 0 and after 16 weeks (wk) of the ApoCIII ASO. Blood samples were obtained at 0, 30, 60, 120, 180, 240, 300, and 360 minutes (min) and assessed using NMR with the LP4 deconvolution algorithm, which separates TRLPs into 5 size categories: very large (VL), large (L), medium (M), small (S), and very small (VS), all expressed as nmol/L. Major Results: At wk 0, patients had high fasting TG (median 523 mg/dL, IQR 335–1060 mg/dL, normal &lt;150), which decreased after 16wk of ASO[BR([1] (196 mg/dL) Mean TRLP over the 360 min of the MMT was lower after ASO (181.6±14.1 at wk 0, 80.4±2.2 at wk 16). At wk 0, mean L_TRLP during the MMT was 26.8 ± 6.9 and decreased to 9.3±1.3 at wk 16. At wk 0, L_TRLP rose during the MMT to a peak at 180min; at wk 16 there was no rise in L_TRLP during the MMT. Mean S_TRLP during the MMT increased from wk 0 (5.4±3.9) to wk 16 (13.4±10.4). At wk 0, S_TRLP increased minimally during the MMT from 5.2±11.7 at 0 min to 10.9±15.2 at 360 min. At wk 16 there was a more notable rise in S_TRLP in the last 3 hrs of the MMT, from 12.2±15.1 at 0 min to 37.6±28.6 at 360 min. Interpretation of Results and Conclusions: As expected, an ApoCIII ASO lowered fasting and postprandial TG and TRLP. There was minimal rise or fall in any subclass of TRLP during the MMT, either before or after ASO, likely due to the small fat load, which was chosen due to concern for triggering pancreatitis in this at-risk group. The greater post-prandial fluctuation of L_TRLP prior to ASO may represent appearance and disappearance of chylomicron remnants; at wk 16 this was not seen, perhaps due to more rapid clearance of chylomicron remnants by LPL. The larger increase in S_TRLP at the end of the MMT at wk 16 may reflect more rapid lipolysis of L_TRLP by LPL during ASO treatment, thus generating S_TRLP. Next steps include measuring apoB48 and apoB100 during the MMT to distinguish VLDL from chylomicrons, accruing a larger sample size, and collecting MMT data in healthy controls.

Atherosclerosis and thrombosis

Atherosclerosis is the main underlying cause of heart disease. The continuous exposure to cardiovascular risk factors induces endothelial activation/dysfunction which enhances the permeability of the endothelial layer and the expression of cytokines/chemokines and adhesion molecules. This results in the accumulation of lipids (low-density lipoprotein particles) in the intimal layer and the triggering of an inflammatory response. Accumulated low-density lipoprotein particles attached to the extracellular matrix suffer modifications and become pro-atherogenic, enhancing leucocyte recruitment and further transmigration across the endothelium into the intima. Infiltrated pro-atherogenic monocytes (mainly Mon2) differentiate into macrophages which acquire a specialized phenotypic polarization (protective/M1 or harmful/M2), depending on the stage of the atherosclerosis progression. Once differentiated, macrophages upregulate pattern recognition receptors capable of engulfing modified low-density lipoprotein, leading to foam cell formation. Foam cells release growth factors and cytokines that promote vascular smooth muscle cell migration into the intima, which then internalize low-density lipoproteins via low-density lipoprotein receptor-related protein-1 receptors becoming foam cells. As the plaque evolves, the number of vascular smooth muscle cells decline, whereas the presence of fragile/haemorrhagic neovessels and calcium deposits increases, promoting plaque destabilization. Disruption of this atherosclerotic lesion exposes thrombogenic surfaces rich in tissue factor that initiate platelet adhesion, activation, and aggregation, as well as thrombin generation. Platelets also participate in leucocyte and progenitor cell recruitment are likely to mediate atherosclerosis progression. Recent data attribute to extracellular vesicles (mainly microvesicles) a role in all stages of atherosclerosis development and evidence their potential use as systemic biomarkers of thrombus growth. This chapter reviews our current understanding of the pathophysiological mechanisms involved in atherogenesis, highlights platelet contribution to thrombosis and atherosclerosis progression, and provides new insights into how atherothrombosis may be prevented and modulated.

Effect of PCSK9 inhibitor on lipoprotein particles in patients with acute coronary syndromes

Background To assess the effects of proprotein convertase subtilisin/kexin type 9 inhibitor (evolocumab) on lipoprotein particles subfractions with Nuclear Magnetic Resonance spectroscopy in patients with acute coronary syndromes. Methods A total of 99 consecutive patients with ACS were enrolled and assigned to either the experimental group (n = 54) or the control group (n = 45). The combination therapy of PCSK9 inhibitor (Repatha®, 140 mg, q2w) and moderate statin (Rosuvastatin, 10 mg, qn) was administered in the experimental group, with statin monotherapy (Rosuvastatin, 10 mg, qn) in the control group. The therapeutic effects on lipoprotein particle subfractions were assessed with NMR spectroscopy after 8 weeks treatment, and the achievement of LDL-C therapeutic target in both groups were analyzed. Results In the experimental group, after 8 weeks of evolocumab combination treatment, the concentrations of blood lipids (TC, LDL-C and its subfractions [LDL-1 to 6], VLDL-C and its subfractions [VLDL-1 to 5], IDL-C, and HDL-C), lipoprotein particles, and their subfractions [VLDL-P, IDL-P, LDL-P, and its subfractions [LDL-P1 to 6], apoB, and LP(a)] demonstrated therapeutic benefits with statistical significance (P < 0.05). The decrease in total LDL-P concentrations was mainly due to a decreased concentration of small-sized LDL particles (LDL-P 5 + 6), which was significantly more prominent than the decrease in medium-sized LDL-P (LDL-P3 + 4) and large-sized LDL-P (LDL-P1 + 2) (P < 0.001). According to lipid control target recommended by the latest China Cholesterol Education Program Expert Consensus in 2019, after 8 weeks treatment, 96.3% patients in the experimental group and 13.3% in the control group had achieved the LDL-C therapeutic target (P < 0.01). Conclusions Evolocumab combination treatment for 8 weeks significantly improves the plasma lipid profiles in ACS patients, and significantly decrease the concentration of lipoprotein particles which might contribute to the pathonesis of atherosclerosis.

Circulating Hedgehog: a fresh view of a classic morphogen

ABSTRACTMembers of the Hedgehog family of morphogens mediate the intercellular communication necessary for the organisation and development of many animal tissues. They are modified by various lipid adducts, rendering them insoluble in hydrophilic environments and leading to the contentious question of how these molecules travel in the aqueous extracellular space. Seminal work carried out by Suzanne Eaton and her colleagues has shed light on how these morphogens can spread over long distances through their association with lipoprotein particles. In this Spotlight article, we discuss Suzanne's pioneering work and her contribution to our understanding of the transport and activity of morphogens, in particular Hedgehog. We also describe two other essential aspects of her work: the discovery and characterisation of endogenously present Hedgehog variants, as well as her proposition that, in addition to its role as a morphogen, Hedgehog acts as an endocrine hormone.