Apolipoprotein B Research Articles

High Prevalence of Familial Hypercholesterolemia Due to the Founder Effect of the LDLR c.2271del Variant in Communities of Oaxaca, Mexico

In Mexico, familial hypercholesterolemia (FH) is underdiagnosed, but population screening in small communities where at least one homozygous patient has already been detected results in a useful and inexpensive approach to reduce this problem. Considering that we previously reported nine homozygous cases from the state of Oaxaca, we decided to perform a population screening to identify patients with FH and to describe both their biochemical and genetic characteristics. LDL cholesterol (LDLc) was quantified in 2,093 individuals from 11 communities in Oaxaca; either adults with LDLc levels ≥170 mg/dL or children with LDLc ≥130 mg/dL were classified as suggestive of FH and therefore included in the genetic study. LDLR and APOB (547bp fragment of exon 26) genes were screened by sequencing and MLPA analysis. Two hundred and five individuals had suggestive FH, with a mean LDLc of 223 ± 54 mg/dL (range: 131-383 mg/dL). Two pathogenic variants in the LDLR gene were detected in 149 individuals: c.-139_-130del (n = 1) and c.2271del (n = 148). All patients had a heterozygous genotype. With the cascade screening of their relatives (n = 177), 15 heterozygous individuals for the c.2271del variant were identified, presenting a mean LDLc of 133 ± 35 mg/dL (range: 60-168 mg/dL). The FH frequency in this study was 7.8% (164/2093), the highest reported worldwide. A founder effect combined with inbreeding could be responsible for the high percentage of patients with the LDLR c.2271del variant (99.4%), which allowed us to detect both significant biochemical heterogeneity and incomplete penetrance; hence, we assumed the presence of phenotype-modifying variants.

Substitution of dietary monounsaturated fatty acids from olive oil for saturated fatty acids from lard increases low-density lipoprotein apolipoprotein B-100 fractional catabolic rate in subjects with dyslipidemia associated with insulin resistance: a randomized controlled trial

BackgroundThe substitution of monounsaturated acids (MUFAs) for saturated fatty acids (SFAs) is recommended for cardiovascular disease prevention but its impact on lipoprotein metabolism in subjects with dyslipidemia associated with insulin resistance (IR) remains largely unknown. ObjectivesThis study aimed to evaluate the impact of substituting MUFAs for SFAs on the in vivo kinetics of apolipoprotein (apo)B-containing lipoproteins and on the plasma lipidomic profile in adults with IR-induced dyslipidemia. MethodsMales and females with dyslipidemia associated with IR (n = 18) were recruited for this crossover double-blind randomized controlled trial. Subjects consumed, in random order, a diet rich in SFAs (SFAs: 13.4%E; MUFAs: 14.4%E) and a diet rich in MUFAs (SFAs: 7.1%E; MUFAs: 20.7%E) in fully controlled feeding conditions for periods of 4 wk each, separated by a 4-wk washout. At the end of each diet, fasting plasma samples were taken together with measurements of the in vivo kinetics of apoB-containing lipoproteins. ResultsSubstituting MUFAs for SFAs had no impact on triglyceride-rich lipoprotein apoB-48 fractional catabolic rate (FCR) (Δ = –8.9%, P = 0.4) and production rate (Δ = 0.0%, P = 0.9), although it decreased very low-density lipoprotein apoB-100 pool size (PS) (Δ = −22.5%; P = 0.01). This substitution also reduced low-density lipoprotein cholesterol (LDL-C) (Δ = −7.0%; P = 0.01), non–high-density lipoprotein cholesterol (Δ = −2.5%; P = 0.04), and LDL apoB-100 PS (Δ = −6.0%; P = 0.05). These differences were partially attributed to an increase in LDL apoB-100 FCR (Δ = +1.6%; P = 0.05). The MUFA diet showed reduced sphingolipid concentrations and elevated glycerophospholipid levels compared with the SFA diet. ConclusionsThis study demonstrated that substituting dietary MUFAs for SFAs decreases LDL-C levels and LDL PS by increasing LDL apoB-100 FCR and results in an overall improved plasma lipidomic profile in individuals with IR-induced lipidemia. Trial registrationThis trial was registered as clinicaltrials.gov as NCT03872349.

Proteomic Analysis of Egg Yolk Proteins During Embryonic Development in Wanxi White Goose.

To investigate the alterations of yolk protein during embryonic development in Wanxi white goose, the egg yolk protein composition at days 0, 4, 7, 14, 18, and 25 of incubation (D0, D4, D7, D14, D18, and D25) was analyzed by two-dimensional gel electrophoresis combined with mass spectrometry. A total of 65 spots representing 11 proteins with significant abundance changes were detected. Apolipoprotein B-100, vitellogenin-1, vitellogenin-2-like, riboflavin-binding protein, and serotransferrin mainly participated in nutrient (lipid, riboflavin, and iron ion) transport, and vitellogenin-2-like showed a lower abundance after D14. Ovomucoid-like were involved in endopeptidase inhibitory activity and immunoglobulin binding and exhibited a higher expression after D18, suggesting a potential role in promoting the absorption of immunoglobulin and providing passive immune protection for goose embryos after D18. Furthermore, myosin-9 and actin (ACTB) were involved in the tight junction pathway, potentially contributing to barrier integrity. Serum albumin mainly participated in cytolysis and toxic substance binding. Therefore, the high expression of serum albumin, myosin-9, and ACTB throughout the incubation might protect the developing embryo. Apolipoprotein B-100, vitellogenin-1, vitellogenin-2-like, riboflavin-binding protein, and serotransferrin might play a crucial role in providing nutrition for embryonic development, and VTG-2-like was preferentially degraded/absorbed.

Dextran sulfate bulk and surface-modified microfiltration membrane for simultaneous blood plasma harvesting and low-density lipoprotein removal during plasmapheresis

Plasmapheresis is currently used for the harvesting of blood plasma in medical labs and plasma donation centers. This is a fast, single-step membrane process for both collection of blood plasma and simultaneous blood cell isolation. This paper presents the development of a novel membrane that can be used to simultaneously harvest blood plasma and isolate low-density lipoprotein (LDL), known as bad cholesterol, from the blood. To achieve this goal, dual surface and bulk modification by dextran sulfate (DS) was performed on a polyethersulfone (PES) membrane containing single wall carbon nanotubes (SWCNT). DS is an anionic ligand that repels negatively charged substances like red blood cells (RBCs) and adsorbs positively charged substances like Apo B100; the apoprotein of LDL. Scanning Electron Microscope (SEM), Energy Dispersive X-Ray (EDX), and Fourier Transform Infrared (FTIR) spectroscopy analyses provided evidence of the grafting of DS on single wall carbon nanotubes (DS-SWCNT). Surface studies including water contact angle, zeta potential analysis, surface morphology, Attenuated Total Reflectance-FTIR (ATR-FTIR), and EDX, confirmed the presence of DS on the PES membrane surface. The SEM cross-section results showed the formation of a two-zone morphology with an open structure on the upside and a dense structure on the downside that provide optimal conditions for efficient separation of blood cells. The complete blood count (CBC) and biochemistry analyses revealed dual bulk and surface-modified membrane, and a specific sample (DM2) showed the best performance for blood cells and LDL separation. The maximum separation of blood cells was 87% RBC, 98% white blood cells (WBCs), and 83% platelets (PLTs). Moreover, DM2 exhibited a sieving ratio for LDL of 0.33. Blood compatibility analyses confirmed that DM2 and other related samples had low hemolysis and prolonged coagulation times.

Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function.

Lipid processing by the retinal pigment epithelium (RPE) is necessary to maintain retinal health and function. Dysregulation of retinal lipid homeostasis due to normal aging or age-related disease triggers lipid accumulation within the RPE, on Bruch's membrane (BrM), and in the subretinal space. In its role as a hub for lipid trafficking into and out of the neural retina, the RPE packages a significant amount of lipid into lipid droplets for storage and into apolipoprotein B (APOB)-containing lipoproteins (Blps) for export. Microsomal triglyceride transfer protein (MTP), encoded by the MTTP gene, is essential for Blp assembly. Herein we test the hypothesis that MTP expression in the RPE is essential to maintain lipid balance and retinal function using the newly generated RPEΔMttp mouse model. Using non-invasive ocular imaging, electroretinography, and histochemical and biochemical analyses we show that genetic depletion of Mttp from the RPE results in intracellular lipid accumulation, increased photoreceptor-associated cholesterol deposits, and photoreceptor cell death, and loss of rod but not cone function. RPE-specific reduction in Mttp had no significant effect on plasma lipids and lipoproteins. While APOB was decreased in the RPE, most ocular retinoids remained unchanged, with the exception of the storage form of retinoid, retinyl ester. Thus suggesting that RPE MTP is critical for Blp synthesis and assembly but is not directly involved in plasma lipoprotein metabolism. These studies demonstrate that RPE-specific MTP expression is necessary to establish and maintain retinal lipid homeostasis and visual function.

Kupffer cells dictate hepatic responses to the atherogenic dyslipidemic insult

Apolipoprotein-B (APOB)-containing lipoproteins cause atherosclerosis. Whether the vasculature is the initially responding site or if atherogenic dyslipidemia affects other organs simultaneously is unknown. Here we show that the liver responds to a dyslipidemic insult based on inducible models of familial hypercholesterolemia and APOB tracing. An acute transition to atherogenic APOB lipoprotein levels resulted in uptake by Kupffer cells and rapid accumulation of triglycerides and cholesterol in the liver. Bulk and single-cell RNA sequencing revealed a Kupffer-cell-specific transcriptional program that was not activated by a high-fat diet alone or detected in standard liver function or pathological assays, even in the presence of fulminant atherosclerosis. Depletion of Kupffer cells altered the dynamic of plasma and liver lipid concentrations, indicating that these liver macrophages help restrain and buffer atherogenic lipoproteins while simultaneously secreting atherosclerosis-modulating factors into plasma. Our results place Kupffer cells as key sentinels in organizing systemic responses to lipoproteins at the initiation of atherosclerosis.

Potential association of genetically predicted lipid and lipid-modifying drugs with rheumatoid arthritis: A Mendelian randomization study.

Past studies have demonstrated that patients diagnosed with rheumatoid arthritis (RA) often exhibit abnormal levels of lipids. Furthermore, certain lipid-modifying medications have shown effectiveness in alleviating clinical symptoms associated with RA. However, the current understanding of the causal relationship between lipids, lipid-modifying medications, and the risk of developing RA remains inconclusive. This study employed Mendelian randomization (MR) to investigate the causal connection between lipids, lipid-modifying drugs, and the occurrence of RA. We obtained genetic variation for lipid traits and drug targets related to lipid modification from three sources: the Global Lipids Genetics Consortium (GLGC), UK Biobank, and Nightingale Health 2020. The genetic data for RA were acquired from two comprehensive meta-analyses and the R8 of FINNGEN, respectively. These variants were employed in drug-target MR analyses to establish a causal relationship between genetically predicted lipid-modifying drug targets and the risk of RA. For suggestive lipid-modified drug targets, we conducted Summary-data-based Mendelian Randomization (SMR) analyses and using expression quantitative trait loci (eQTL) data in relevant tissues. In addition, we performed co-localization analyses to assess genetic confounders. Our analysis revealed no significant causal relationship between lipid and RA. We observed that the genetically predicted 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) -mediated low density lipoprotein cholesterol (LDL-C) (OR 0.704; 95% CI 0.56, 0.89; P = 3.43×10-3), Apolipoprotein C-III (APOC3) -mediated triglyceride (TG) (OR 0.844; 95% CI 0.77, 0.92; P = 1.50×10-4) and low density lipoprotein receptor (LDLR) -mediated LDL-C (OR 0.835; 95% CI 0.73, 0.95; P = 8.81×10-3) were significantly associated with a lowered risk of RA. while Apolipoprotein B-100 (APOB) -mediated LDL-C (OR 1.212; 95%CI 1.05,1.40; P = 9.66×10-3) was significantly associated with an increased risk of RA. Our study did not find any supporting evidence to suggest that lipids are a risk factor for RA. However, we observed significant associations between HMGCR, APOC3, LDLR, and APOB with the risk of RA.

Mendelian randomization reveals apolipoprotein B shortens healthspan and possibly increases risk for Alzheimer’s disease

Apolipoprotein B-100 (APOB) is a component of fat- and cholesterol-transporting molecules in the bloodstream. It is the main lipoprotein in low-density lipoprotein cholesterol (LDL) and has been implicated in conditions that end healthspan (the interval between birth and onset of chronic disease). However, APOB’s direct relationship with healthspan remains uncertain. With Mendelian randomization, we show that higher levels of APOB and LDL shorten healthspan in humans. Multivariable Mendelian randomization of APOB and LDL on healthspan suggests that the predominant trait accounting for the relationship is APOB. In addition, we provide preliminary evidence that APOB increases risk for Alzheimer’s disease, a condition that ends healthspan. If these relationships are causal, they suggest that interventions to improve healthspan in aging populations could include strategies targeting APOB. Ultimately, given that more than 44 million people currently suffer from Alzheimer’s disease worldwide, such interventions are needed.

Targeting Lipoprotein(a): Can RNA Therapeutics Provide the Next Step in the Prevention of Cardiovascular Disease?

Numerous genetic and epidemiologic studies have demonstrated an association between elevated levels of lipoprotein(a) (Lp[a]) and cardiovascular disease. As a result, lowering Lp(a) levels is widely recognized as a promising strategy for reducing the risk of new-onset coronary heart disease, stroke, and heart failure. Lp(a) consists of a low-density lipoprotein-like particle with covalently linked apolipoprotein A(apo[a]) and apolipoprotein B-100, which explains its pro-thrombotic, pro-inflammatory, and pro-atherogenic properties. Lp(a) serum concentrations are genetically determined by the apo(a) isoform, with shorter isoforms having a higher rate of particle synthesis. To date, there are no approved pharmacological therapies that effectively reduce Lp(a) levels. Promising treatment approaches targeting apo(a) expression include RNA-based drugs such as pelacarsen, olpasiran, SLN360, and lepodisiran, which are currently in clinical trials. In this comprehensive review, we provide a detailed overview of RNA-based therapeutic approaches and discuss the recent advances and challenges of RNA therapeutics specifically designed to reduce Lp(a) levels and thus the risk of cardiovascular disease.

Tetrahydroberberine alleviates high-fat diet-induced hyperlipidemia in mice via augmenting lipoprotein assembly-induced clearance of low-density lipoprotein and intermediate-density lipoprotein

The promotion of excess low-density lipoprotein (LDL) clearance stands as an effective clinical approach for treating hyperlipidemia. Tetrahydroberberine, a metabolite of berberine, exhibits superior bioavailability compared to berberine and demonstrates a pronounced hypolipidemic effect. Despite these characteristics, the impact of tetrahydroberberine on improving excessive LDL clearance in hyperlipidemia has remained unexplored. Thus, this study investigates the potential effects of tetrahydroberberine on high-fat diet-induced hyperlipidemia in mice. The findings reveal that tetrahydroberberine exerts a more potent lipid-lowering effect than berberine, particularly concerning LDL-cholesterol in hyperlipidemic mice. Notably, tetrahydroberberine significantly reduces serum levels of upstream lipoproteins, including intermediate-density lipoprotein (IDL) and very low-density lipoprotein, by promoting their conversion to LDL. This reduction is further facilitated by the upregulation of hepatic LDL receptor expression induced by tetrahydroberberine. Intriguingly, tetrahydroberberine enhances the apolipoprotein E (ApoE)/apolipoprotein B100 (ApoB100) ratio, influencing lipoprotein assembly in the serum. This effect is achieved through the activation of the efflux of ApoE-containing cholesterol in the liver. The ApoE/ApoB100 ratio exhibits a robust negative correlation with serum levels of LDL and IDL, indicating its potential as a diagnostic indicator for hyperlipidemia. Moreover, tetrahydroberberine enhances hepatic lipid clearance without inducing lipid accumulation in the liver and alleviates existing liver lipid content. Importantly, no apparent hepatorenal toxicity is observed following tetrahydroberberine treatment for hyperlipidemia. In summary, tetrahydroberberine demonstrates a positive impact against hyperlipidemia by modulating lipoprotein assembly-induced clearance of LDL and IDL. The ApoE/ApoB100 ratio emerges as a promising diagnostic indicator for hyperlipidemia, showcasing the potential clinical significance of tetrahydroberberine in lipid management.

ApoB100 and Atherosclerosis: What's New in the 21st Century?

ApoB is the main protein of triglyceride-rich lipoproteins and is further divided into ApoB48 in the intestine and ApoB100 in the liver. Very low-density lipoprotein (VLDL) is produced by the liver, contains ApoB100, and is metabolized into its remnants, intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL). ApoB100 has been suggested to play a crucial role in the formation of the atherogenic plaque. Apart from being a biomarker of atherosclerosis, ApoB100 seems to be implicated in the inflammatory process of atherosclerosis per se. In this review, we will focus on the structure, the metabolism, and the function of ApoB100, as well as its role as a predictor biomarker of cardiovascular risk. Moreover, we will elaborate upon the molecular mechanisms regarding the pathophysiology of atherosclerosis, and we will discuss the disorders associated with the APOB gene mutations, and the potential role of various drugs as therapeutic targets.

Ipragliflozin and sitagliptin differentially affect lipid and apolipoprotein profiles in type 2 diabetes: the SUCRE study

BackgroundSGLT2 inhibitors and DPP4 inhibitors have been suggested to affect lipid metabolism. However, there are few randomized controlled trials comparing the effects on the lipid metabolism between the two types of antidiabetic drugs. The SUCRE study (UMIN ID: 000018084) was designed to compare the effects of ipragliflozin and sitagliptin on serum lipid and apolipoprotein profiles and other clinical parameters.MethodsThis is a multicenter, open-label, randomized, controlled trial. Patients with type 2 diabetes (20–74 years old) with HbA1c levels of 7.0-10.5% and serum triglyceride levels of 120–399 mg/dL (1.35–4.50 mmol/L) on diet and/or oral hypoglycemic agents were enrolled. Subjects were randomized to treatment with ipragliflozin (50 mg/day, n = 77) or sitagliptin (50 mg/day, n = 83). Laboratory measurements were performed at 0, 1, 3, and 6 months of treatment.ResultsIpragliflozin and sitagliptin reduced fasting plasma glucose, glycoalbumin, and HbA1c almost equally. Ipragliflozin increased HDL-C and decreased apo E. Sitagliptin decreased TG, apo B48, CII, and CIII, but increased LDL-C. The between-treatment differences were significant for HDL-C (P = 0.02) and apo B48 (P = 0.006), and nearly significant for apo A1 (P = 0.06). In addition, ipragliflozin reduced body weight, blood pressure, serum liver enzymes, uric acid, and leptin, and increased serum ketones compared with sitagliptin.ConclusionsWhile ipragliflozin and sitagliptin showed similar effects on glycemic parameters, the effects on serum lipid and apolipoprotein profiles were different. Ipragliflozin may have an anti-atherogenic effect through modulation of HDL-C and apo E compared to sitagliptin through TG and apo B48, CII, and CIII in patients with type 2 diabetes.

Genetic aspects of decreased low-density lipoprotein cholesterol values

Aim. To study genetic causes of decreased low-density lipoprotein cholesterol (LDL-C) in Russian patients.Material and methods. The study included the following Epidemiology of Cardiovascular Diseases and their Risk Factors in Regions of Russian Federation (ESSE-RF) participants: individuals with LDL-C<5th percentile, taking into account sex and age (n=52), who underwent targeted sequencing of protein-coding regions of 6 genes (APOB, PCSK9, MTTP, ANGPTL3, SAR1B, APOC3) and determination of the genetic risk score (GRS) for hypercholesterolemia; and a representative sample of the Ivanovo region population (ESSEIvanovo, n=1667), for which only GRS was determined. Genetic testing was performed using next generation sequencing.Results. In 10 (19,2%) of 52 participants with decreased LDL-C levels, the following rare variants potentially associated with hypocholesterolemia were identified: 8 — leading to a premature termination codon in the APOB gene, 1 — leading to a premature termination codon in the APOC3 gene and 1 missense variant in the PCSK9 gene. Of the 10 identified variants, 6 are described by us for the first time. GRS in the LDL-C group (0,27±0,25) was significantly lower than in the ESSE-Ivanovo population sample (0,43±0,27) (p=4,7×10-06).Conclusion. Genetic reasons explain decreased LDL-C levels (<5th percentile) in 32,7% of patients, of which only monogenic variants were identified in 13,5%, a combination of monogenic and polygenic hypocholesterolemia — in 5,7%, and polygenic hypocholesterolemia — in 13,5%.

APOB is a potential prognostic biomarker in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is significantly associated with adverse prognostic outcomes. The development and progression of different types of human tumors are significantly influenced by APOB. Nevertheless, the significance and pathomechanisms of APOB in HCC have not been conclusively determined. We assessed APOB expression levels in HCC using three publicly available databases of TIMER2.0, UALCAN and Human Protein Atlas. To identify the biological function of APOB, we conducted enrichment analysis via LinkedOmics. Moreover, UALCAN was employed to assess the relationship between APOB expression and clinicopathological features among HCC patients. Additionally, the Kaplan–Meier plotter was utilized to investigate the prognostic relevance of APOB in HCC. To explore potential regulatory ncRNAs that could bind to APOB, we utilized StarBase and GEPIA. Furthermore, the correlation between APOB expression and immune cell infiltration, as well as immune checkpoint genes, was investigated using Spearman's correlation analysis in TISIDB, GEPIA, and TIMER2.0. The findings of our investigation showed a notable decrease in the expression levels of APOB among individuals diagnosed with HCC. Moreover, a noteworthy correlation was observed between the expression of APOB and immune checkpoint genes, alongside the occurrence of immune cell infiltration. The levels of APOB expression in HCC tissues also showed correlations with various clinicopathological features. According to Cox regression analysis, decreased APOB expression emerged as a potential autonomous predictor for OS, RFS, DSS, and PFS among HCC patients. Furthermore, we identified six potential pathways associated with non-coding RNA (ncRNA) as the most promising pathway for APOB in HCC. Our results illuminate the possible involvement of APOB in HCC and offer understanding into its governing mechanisms and medical importance.

Gene associations of lipid traits, lipid-lowering drug-target genes and endometriosis

Research QuestionDoes the observed correlation between dyslipidemia and endometriosis indicate bidirectional causal associations? Furthermore, is the prospect of utilizing lipid-lowering drugs to manage endometriosis a viable strategy? DesignBidirectional Mendelian Randomization (MR) is employed to investigate the causal association between lipid traits and endometriosis. Drug-target MR is utilized to explore potential drug-target genes for managing endometriosis. In cases where lipid-mediated effects via specific drug targets are significant, aggregate analyses, such as Summary-data-based Mendelian Randomization (SMR) and Colocalization methods, are introduced to validate the outcomes. Mediation analyses supplement these evaluations. ResultsBidirectional MR results suggested that genetically predicted triglycerides (TG) (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.08-1.23), high-density lipoprotein cholesterol (HDL-C) (OR 0.87, 95% CI 0.81-0.94), low-density lipoprotein cholesterol (LDL-C) (OR 1.20, 95% CI 1.06-1.34) and apolipoprotein A (APOA) (OR 0.90, 95% CI 0.83-0.96) were causally associated with endometriosis. Reverse MR results revealed that genetically proxied endometriosis was causally associated with TG level (OR 1.02, 95% CI 1.01-1.02). In drug-target MR, genetic mimicry in proprotein convertase subtilisin/kexin type 9 (PCSK9) (OR1.40, 95% CI 1.13-1.72), apolipoprotein B (APOB) (OR 1.49, 95% CI 1.21-1.86) and Angiopoietin-related protein 3 (ANGPTL3) (OR 1.57, 95% CI 1.14-2.16) were significantly associated with the risk of endometriosis stages 1-2. ConclusionOur findings suggest a potential bidirectional causal association between endometriosis and dyslipidemia. Genetic mimicry of PCSK9, APOB, and ANGPTL3 is associated with the risk of early-stage endometriosis. The development of lipid-lowering drugs for treating endometriosis holds potential clinical interest.

Lifestyle and Lipoprotein(a) Levels: Does a Specific Counseling Make Sense?

Lipoprotein(Lp)(a) is a variant of low-density lipoprotein (LDL), bound to apolipoprotein B100, whose levels are associated with a significant increase in the risk of atherosclerosis-related cardiovascular events, but also to aortic stenosis and atrial fibrillation. Since plasma levels of Lp(a) are commonly considered resistant to lifestyle changes, we critically reviewed the available evidence on the effect of weight loss, dietary supplements, and physical activity on this risk factor. In our review, we observed that relevant body weight loss, a relatively high intake of saturated fatty acids, the consumption of red wine, and intense physical exercise seems to be associated with significantly lower plasma Lp(a) levels. On the contrary, foods rich in trans-unsaturated fatty acids are associated with increased Lp(a) levels. With regard to dietary supplements, coenzyme Q10, L-Carnitine, and flaxseed exert a mild but significant lowering effect on plasma Lp(a).

Discordance between LDL-C and apolipoprotein B is associated with large-artery-atherosclerosis ischemic stroke in patients ⩽70 years of age.

Low density lipoprotein (LDL-C) and other atherogenic lipoproteins are coated by apolipoprotein B100 (apoB). The correlation between LDL-C and apoB is usually thight, but in some cases LDL-C underestimates apoB levels and residual cardiovascular risk. We aimed to assess if a discordance of LDL-C-levels with apoB levels is associated with LAA stroke. We included patients with an acute ischemic stroke from two prospective studies enrolled at the University Hospital Bern, Basel and Zurich, Switzerland. LDL-C and apoB were measured within 24 h of symptom onset. By linear regression, for each LDL-C, we computed the expected apoB level assuming a perfect correlation. Higher-than-expected apoB was defined as apoB level being in the upper residual tertile. Overall, we included 1783 patients, of which 260 had a LAA stroke (15%). In the overall cohort, higher-than-expected apoB values were not associated with LAA. However, a significant interaction with age was present. Among the 738 patients ⩽70 years of age, a higher-than-expected apoB was more frequent in patients with LAA- versus non LAA-stroke (48% vs 36%, p = 0.02). In multivariate analysis, a higher-than-expected apoB was associated with LAA stroke (aOR = aOR 2.48, 95%CI 1.14-5.38). Among those aged ⩽70 years and with LAA, 11.7% had higher than guideline-recommended apoB despite LDL-C ⩽ 1.8 mmol/L (<70 mg/dl), compared to 5.9% among patients with other stroke etiologies (p = 0.04). A triglyceride cut-off of ⩾0.95 mmol/L had, in external validation, a sensitivity of 71% and specificity of 52% for apoB ⩾ 0.65 g/L among patients with LDL-C <1.8 mmol/L. Among patients aged ⩽70 years, a higher-than-expected apoB was independently associated with LAA stroke. Measuring apoB may help identify younger stroke patients potentially benefiting from intensified lipid-lowering therapy.

Traditional Chinese Medicine formula Dai-Zong-Fang alleviating hepatic steatosis in db/db mice via gut microbiota modulation.

Introduction: Hepatic steatosis is a hepatic pathological change closely associated with metabolic disorders, commonly observed in various metabolic diseases such as metabolic syndrome (MetS), with a high global prevalence. Dai-Zong-Fang (DZF), a traditional Chinese herbal formula, is widely used in clinical treatment for MetS, exhibiting multifaceted effects in reducing obesity and regulating blood glucose and lipids. This study aims to explore the mechanism by which DZF modulates the gut microbiota and reduces hepatic steatosis based on the gut-liver axis. Methods: This study utilized db/db mice as a disease model for drug intervention. Body weight and fasting blood glucose were monitored. Serum lipid and transaminase levels were measured. Insulin tolerance test was conducted to assess insulin sensitivity. Hematoxylin and eosin (HE) staining was employed to observe morphological changes in the liver and intestine. The degree of hepatic steatosis was evaluated through Oil Red O staining and hepatic lipid determination. Changes in gut microbiota were assessed using 16S rRNA gene sequencing. Serum lipopolysaccharide (LPS) levels were measured by ELISA. The expression levels of intestinal tight junction proteins, intestinal lipid absorption-related proteins, and key proteins in hepatic lipid metabolism were examined through Western blot and RT-qPCR. Results: After DZF intervention, there was a decrease in body weight, alleviation of glucose and lipid metabolism disorders, reduction in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and mitigation of insulin resistance in mice. DZF significantly modulated the diversity of the gut microbiota, with a notable increase in the abundance of the Bacteroidetes phylum. PICRUSt indicated that DZF influenced various functions in gut microbiota, including carbohydrate and amino acid metabolism. Following DZF intervention, serum LPS levels decreased, intestinal pathological damage was reduced, and the expression of intestinal tight junction protein occludin was increased, while the expression of intestinal lipid absorption-related proteins cluster of differentiation 36 (CD36) and apolipoprotein B48 (ApoB48) were decreased. In the liver, DZF intervention resulted in a reduction in hepatic steatosis and lipid droplets, accompanied by a decrease fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1) and fatty acid transport protein 2 (FATP2). Conversely, there was an increase in the expression of the fatty acid oxidation-related enzyme carnitine palmitoyltransferase-1𝛂 (CPT-1𝛂). Conclusion: DZF can regulate the structure and function of the intestinal microbiota in db/db mice. This ameliorates intestinal barrier damage and the detrimental effects of endotoxemia on hepatic metabolism. DZF not only inhibits intestinal lipid absorption but also improves hepatic lipid metabolism from various aspects, including de novo lipogenesis, fatty acid uptake, and fatty acid oxidation. This suggests that DZF may act on the liver and intestine as target organs, exerting its effects by improving the intestinal microbiota and related barrier and lipid absorption functions, ultimately ameliorating hepatic steatosis and enhancing overall glucose and lipid metabolism.

APOB100 transgenic mice exemplify how the systemic circulation content may affect the retina without altering retinal cholesterol input.

Apolipoprotein B (APOB) is a constituent of unique lipoprotein particles (LPPs) produced in the retinal pigment epithelium (RPE), which separates the neural retina from Bruch's membrane (BrM) and choroidal circulation. These LPPs accumulate with age in BrM and contribute to the development of age-related macular degeneration, a major blinding disease. The APOB100 transgenic expression in mice, which unlike humans lack the full-length APOB100, leads to lipid deposits in BrM. Herein, we further characterized APOB100 transgenic mice. We imaged mouse retina in vivo and assessed chorioretinal lipid distribution, retinal sterol levels, retinal cholesterol input, and serum content as well as tracked indocyanine green-bound LPPs in mouse plasma and retina after an intraperitoneal injection. Retinal function and differentially expressed proteins were also investigated. APOB100 transgenic mice had increased serum LDL content and an additional higher density HDL subpopulation; their retinal cholesterol levels (initially decreased) became normal with age. The LPP cycling between the RPE and choroidal circulation was increased. Yet, LPP trafficking from the RPE to the neural retina was limited, and total retinal cholesterol input did not change. There were lipid deposits in the RPE and BrM, and retinal function was impaired. Retinal proteomics provided mechanistic insights. Collectively, our data suggested that the serum LDL/HDL ratio may not affect retinal pathways of cholesterol input as serum LPP load is mainly handled by the RPE, which offloads LPP excess to the choroidal circulation rather than neural retina. Different HDL subpopulations should be considered in studies linking serum LPPs and age-related macular degeneration.

Cholesterol associated genetic risk score and acute coronary syndrome in Czech males.

Despite a general decline in mean levels across populations, LDL-cholesterol levels remain a major risk factor for acute coronary syndrome (ACS). The APOB, LDL-R, CILP, and SORT-1 genes have been shown to contain variants that have significant effects on plasma cholesterol levels. We examined polymorphisms within these genes in 1191 controls and 929 patients with ACS. Only rs646776 within SORT-1 was significantly associated with a risk of ACS (P < 0.05, AA vs. + G comparison; OR 1.21; 95% CI 1.01-1.45). With regard to genetic risk score (GRS), the presence of at least 7 alleles associated with elevated cholesterol levels was connected with increased risk (P < 0.01) of ACS (OR 1.26; 95% CI 1.06-1.52). Neither total mortality nor CVD mortality in ACS subjects (follow up-9.84 ± 3.82years) was associated with the SNPs analysed or cholesterol-associated GRS. We conclude that, based on only a few potent SNPs known to affect plasma cholesterol, GRS has the potential to predict ACS risk, but not ACS associated mortality.