Blood Lipids, Lipoproteins, and Apolipoproteins With Risk of Coronary Heart Disease: A Prospective Study Among Racially Diverse Populations.

BACKGROUND: Comprehensive blood lipoprotein profiles and their association with incident coronary heart disease (CHD) among racially and geographically diverse populations remain understudied. METHODS AND RESULTS: We conducted nested case-control studies of CHD among 3438 individuals (1719 pairs), including 1084 White Americans (542 pairs), 1244 Black Americans (622 pairs), and 1110 Chinese adults (555 pairs). We examined 36 plasma lipids, lipoproteins, and apolipoproteins, measured by nuclear magnetic resonance spectroscopy, with incident CHD among all participants and subgroups by demographics, lifestyle, and metabolic health status using conditional or unconditional logistic regression adjusted for potential confounders. Conventionally measured blood lipids, that is, total cholesterol, triglycerides, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol, were each associated with incident CHD, with odds ratios (ORs) being 1.33, 1.32, 1.24, and 0.79 per 1-SD increase among all participants. Seventeen lipoprotein biomarkers showed numerically stronger associations than conventional lipids, with ORs per 1-SD among all participants ranging from 1.35 to 1.57 and a negative OR of 0.78 (all false discovery rate <0.05), including apolipoprotein B100 to apolipoprotein A1 ratio (OR, 1.57 [95% CI, 1.45-1.7]), low-density lipoprotein-triglycerides (OR, 1.55 [95% CI, 1.43-1.69]), and apolipoprotein B (OR, 1.49 [95% CI, 1.37-1.62]). All these associations were significant and consistent across racial groups and other subgroups defined by age, sex, smoking, obesity, and metabolic health status, including individuals with normal levels of conventionally measured lipids. CONCLUSIONS: Our study highlighted several lipoprotein biomarkers, including apolipoprotein B/ apolipoprotein A1 ratio, apolipoprotein B, and low-density lipoprotein-triglycerides, strongly and consistently associated with incident CHD. Our results suggest that comprehensive lipoprotein measures may complement the standard lipid panel to inform CHD risk among diverse populations.

Clinical practice recommendations on lipoprotein apheresis for children with homozygous familial hypercholesterolaemia: An expert consensus statement from ERKNet and ESPN.

Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is used for decades, lowering serum LDL-C levels by more than 70% directly after the treatment. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.

Change of serum lipoproteins and its potential use in stratifying patients with sepsis among neonates.

BACKGROUND: Changes of serum lipoprotein concentration during bacteremia or sepsis are observed and lipoproteins concentration facilitate the evaluation severity of sepsis in adults, but its clinical usage is still unclear. Here, we analyzed the lipoprotein concentration in neonates with sepsis and discussed its use in stratifying patients. METHODS: This is a retrospective study involved 88 culture-proven septic patients. Clinical and microbiology data of involved patients were collected via inquiring databases of our institute. Patients were grouped according to blood culture results or procalcitonin level; the difference between groups were analyzed. RESULTS: Compared with uninfected group, there is no change of triglyceride (TG) concentrations and significant decrease of Total cholesterol (TC) concentration in septic patients. There is no significant difference between Gram-positive and Gram-negative-related septic patients in terms of serum TG and TC concentration. Other than group with procalcitonin level of 0.5-2 ng/ml, both serum TG and TC concentration were decreased while serum procalcitonin level increasing. CONCLUSIONS: Our results indicated that serum lipoprotein concentration may be recommended to help diagnosis of bacteria and to evaluate the severity of sepsis.

Type 2 Diabetes mellitus alters the cargo of (poly)phenol metabolome and the oxidative status in circulating lipoproteins.

The incidence of diabetes on the worldwide population has tripled in the past 5 decades. While drug-based therapies are valuable strategies to treat and ease the socio-economic burden of diabetes, nutritional strategies offer valuable alternatives to prevent and manage diabetes onset and contribute to the sustainability of health budgets. Whilst, intervention studies have shown that (poly)phenol-rich diets improve fasting glucose levels and other blood parameters, very little is known about the distribution of ingested polyphenols in circulation and the impact of diabetes on its cargo. In this study we investigate the impact of type 2 diabetes on the cargo of plasma (poly)phenols. Our results show that phenolic compounds are heterogeneously distributed in circulation though mainly transported by lipoprotein populations. We also found that diabetes has a marked effect on the phenolic content transported by VLDL resulting in the decrease in the content of flavonoids and consequently a decrease in the antioxidant capacity. In addition to the reduced bioavailability of (poly)phenol metabolites and increase of oxidative status in LDL and HDL populations in diabetes, cell-based assays show that sub-micromolar amounts of microbial (poly)phenol metabolites are able to counteract the pro-inflammatory status in glucose-challenged endothelial cells. Our findings highlight the relevance of triglyceride-rich lipoproteins in the transport and delivery of bioactive plant-based compounds to the endothelium in T2DM supporting the adoption of nutritional guidelines as an alternative strategy to drug-based therapeutic approaches.

Remnant cholesterol levels are associated with severity and death in COVID-19 patients.

Coronavirus disease-19 (COVID-19) patients with severe complications present comorbidities like cardiovascular-disease, hypertension and type-2 diabetes mellitus (DM), sharing metabolic alterations like insulin resistance (IR) and dyslipidemia. Our objective was to evaluate the association among different components of the lipid-lipoprotein profile, such as remnant lipoprotein (RLP)-cholesterol, in patients with COVID-19, and to analyze their associations with the severity of the disease and death. We studied 193 patients (68 (29-96) years; 49.7% male) hospitalized for COVID-19 and 200 controls (46 (18-79) years; 52.5% male). Lipoprotein profile, glucose and procalcitonin were assessed. Patients presented higher glucose, TG, TG/HDL-cholesterol and RLP-cholesterol levels, but lower total, LDL, HDL and no-HDL-cholesterol levels (p < 0.001). When a binary logistic regression was performed, age, non-HDL-cholesterol, and RLP-cholesterol were associated with death (p = 0.005). As the COVID-19 condition worsened, according to procalcitonin tertiles, a decrease in all the cholesterol fractions (p < 0.03) was observed with no differences in TG, while levels of RLP-cholesterol and TG/HDL-cholesterol increased (p < 0.001). Lower levels of all the cholesterol fractions were related with the presence and severity of COVID-19, except for RLP-cholesterol levels and TG/HDL-cholesterol index. These alterations indicate a lipid metabolic disorder, characteristic of IR states in COVID-19 patients. RLP-cholesterol levels predicted severity and death in these patients.

Lipoproteins and cancer: The role of HDL-C, LDL-C, and cholesterol-lowering drugs.

Cholesterol is an amphipathic sterol molecule that is vital for maintaining normal physiological homeostasis. It is a relatively complicated molecule with 27 carbons whose synthesis starts with 2-carbon units. This in itself signifies the importance of this molecule. Cholesterol serves as a precursor for vitamin D, bile acids, and hormones, including estrogens, androgens, progestogens, and corticosteroids. Although essential, high cholesterol levels are associated with cardiovascular and kidney diseases and cancer initiation, progression, and metastasis. Although there are some contrary reports, current literature suggests a positive association between serum cholesterol levels and the risk and extent of cancer development. In this review, we first present a brief overview of cholesterol biosynthesis and its transport, then elucidate the role of cholesterol in the progression of some cancers. Suggested mechanisms for cholesterol-mediated cancer progression are plentiful and include the activation of oncogenic signaling pathways and the induction of oxidative stress, among others. The specific roles of the lipoprotein molecules, high-density lipoprotein (HDL) and low-density lipoprotein (LDL), in this pathogenesis, are also reviewed. Finally, we hone on the potential role of some cholesterol-lowering medications in cancer.

Relationship between Serum Angiopoietin-like Proteins 3 and 8 and Atherogenic Lipid Biomarkers in Non-Diabetic Adults Depends on Gender and Obesity.

Hypertriglyceridemia is an independent risk factor for coronary artery disease. Lipoprotein lipase (LPL) plays an essential role in the metabolism of triglyceride-rich lipoproteins (TRLs). Angiopoietin-like proteins ANGPTL3 and ANGPTL8 are shown to be important regulators of LPL activity. Increased concentrations of these proteins may reflect cardiovascular risk, and the treatment of patients with dyslipidemia with ANGPTLs inhibitors may decrease this risk. We assessed the gender-specific relationships of serum ANGPTL3 and ANGPTL8 with atherogenic lipid biomarkers and obesity in non-diabetic adults. The study comprised 238 participants aged 25-74 [122 with triglycerides (TG) <150 mg/dL (<1.7 mmol/L) and 116 with hypertriglyceridemia]. Total cholesterol, HDL-cholesterol, LDL-cholesterol, TG, C-reactive protein (CRP), glycated hemoglobin, apolipoprotein B, small dense LDL-C (sd-LDL-C), ANGPTL3, and ANGPTL8 were measured. Non-HDL-cholesterol, remnant cholesterol (remnant-C) concentrations, and body mass index (BMI) were calculated. Results: Women and men did not differ in terms of age, CRP levels, the percentage of obese subjects, and concentrations of atherogenic lipid biomarkers, except higher TG in males and higher ANGPTL3 concentrations in females. Positive correlations of both ANGPTLs with TG, remnant-C, and sdLDL-C levels were found in females. In males, only ANGPTL3 correlated positively with atherogenic biomarkers, but there were no correlations with ANGPTL8. Concentrations of ANGPTL3 were higher in obese men, whereas ANGPTL8 levels were higher in obese women. In women alone, ANGPTL8 showed very good discrimination power to identify subjects with hypertriglyceridemia (AUC = 0.83). Contrary to this, ANGPTL3 was a better discriminator of hypertriglyceridemia (AUC = 0.78) in male subjects. Regression models, adjusted for age, sex, and BMI showed a weak but significant effect of ANGPTL8 to increase the risk of hypertriglyceridemia. Conclusions: In females, ANGPTL8 is more strongly associated with TRLs metabolism, whereas in males, ANGPTL3 plays a more important role. We suggest sex differences be taken into consideration when applying new therapies with angiopoietin-like proteins inhibitors in the treatment of dyslipidemia.

Albino mice with the point mutation at the tyrosinase locus show high cholesterol diet-induced NASH susceptibility.

Non-alcoholic fatty liver disease (NAFLD) constitutes a metabolic disorder with high worldwide prevalence and increasing incidence. The inflammatory progressive state, non-alcoholic steatohepatitis (NASH), leads to liver fibrosis and carcinogenesis. Here, we evaluated whether tyrosinase mutation underlies NASH pathophysiology. Tyrosinase point-mutated B6 (Cg)-Tyrc-2J/J mice (B6 albino) and C57BL/6J black mice (B6 black) were fed with high cholesterol diet (HCD) for 10 weeks. Normal diet-fed mice served as controls. HCD-fed B6 albino exhibited high NASH susceptibility compared to B6 black, a phenotype not previously reported. Liver injury occurred in approximately 50% of B6 albino from one post HCD feeding, with elevated serum alanine aminotransferase and aspartate aminotransferase levels. NASH was induced following 2 weeks in severe-phenotypic B6 albino (sB6), but B6 black exhibited no symptoms, even after 10 weeks. HCD-fed sB6 albino showed significantly higher mortality rate. Histological analysis of the liver revealed significant inflammatory cell and lipid infiltration and severe fibrosis. Serum lipoprotein analysis revealed significantly higher chylomicron and very low-density lipoprotein levels in sB6 albino. Moreover, significantly higher small intestinal lipid absorption and lower fecal lipid excretion occurred together with elevated intestinal NPC1L1 expression. As the tyrosinase point mutation represents the only genetic difference between B6 albino and B6 black, our work will facilitate the identification of susceptible genetic factors for NASH development and expand the understanding of NASH pathophysiology.

Spousal associations of serum metabolomic profiles by nuclear magnetic resonance spectroscopy.

Phenotype-based assortative mating is well established in humans, with the potential for further convergence through a shared environment. To assess the correlation within infertile couples of physical, social, and behavioural characteristics and 155 circulating metabolic measures. Cross sectional study at a tertiary medical center of 326 couples undertaking IVF. Serum lipids, lipoprotein subclasses, and low-molecular weight metabolites as quantified by NMR spectroscopy (155 metabolic measures). Multivariable and quantile regression correlations within couples of metabolite profiles. Couples exhibited statistical correlations of varying strength for most physical, social, and behavioural characteristics including age, height, alcohol consumption, education, smoking status, physical activity, family history and ethnicity, with correlation coefficients ranging from 0.22 to 0.73. There was no evidence of within couple associations for BMI and weight, where the correlation coefficients were - 0.03 (95% CI - 0.14, 0.08) and 0.01 (95% CI - 0.10, 0.12), respectively. Within spousal associations of the metabolite measurements were all positive but with weak to modest magnitudes, with the median correlation coefficient across all 155 measures being 0.12 (range 0.01-0.37 and interquartile range 0.10-0.18). With just four having associations stronger than 0.3: docosahexaenoic acid (0.37, 95% CI 0.22, 0.52), omega-3 fatty acids (0.32, 95% CI 0.20, 0.43) histidine (0.32, 95% CI 0.23, 0.41) and pyruvate (0.32, 95% CI 0.22, 0.43). Infertile couples exhibit spousal similarities for a range of demographic and serum metabolite measures, supporting initial assortative mating, with diet-derived metabolites suggesting possible subsequent convergence of their individual metabolic profile.

Lipid profiles of patients with manifest coronary versus peripheral atherosclerosis - Is there a difference?

AIM: Peripheral arterial disease (PAD) and coronary artery disease (CAD) are both caused by atherosclerosis. Serum lipids and lipoproteins are predictive of the development of atherosclerosis but it is not clear if they differ in the two manifestations, PAD and CAD. We tested whether a more detailed characterization of the lipid and lipoprotein patterns of PAD and CAD allows a clear differentiation between the two atherosclerotic phenotypes. METHODS: A cohort of 274 statin-naïve patients with either newly diagnosed imaging proven PAD (n = 89) or stable CAD (n = 185) was characterized using nuclear magnetic resonance- and liquid chromatography-tandem mass spectrometry-based advanced lipid and lipoprotein analysis. An independent cohort of 1239 patients with PAD and CAD was used for validation. RESULTS: We found a significant difference in markers of inflammation as well as ceramide and phosphatidylcholine levels between patients with PAD and CAD. In contrast, basic lipid markers including total cholesterol, LDL cholesterol, HDL cholesterol, lipoprotein(a) or detailed lipoprotein profiles did not differ significantly between patients with PAD and CAD. Applying ratios and scores derived from ceramides and phosphatidylcholines further improved the discrimination between PAD and CAD. These significant differences were independent of body composition, from the status of smoking or type 2 diabetes mellitus, and also from apolipoprotein C-III and other inflammatory parameters which were different between CAD and PAD. CONCLUSION: The present study clearly suggests that PAD and CAD differ in terms of their ceramide- and phosphatidylcholine-based lipid patterns but not in lipoprotein characteristics.

Evaluation of atherogenic lipoprotein-cholesterol to HDL cholesterol ratio as a prognostic test for ST-segment elevation myocardial infarction.

Background: The detectable component of triglyceride-rich lipoproteins (TGRLs), remnant lipoprotein cholesterol (RLP-c), has been proven being correlated with the progression of atherosclerosis and myocardial infarction. However, when taken as a risk predictor, the prognostic and diagnostic potential of RLP-c remains controversial in studies. In this study, we evaluated the hypothesis that atherogenic lipoprotein-cholesterol (AL-c), representing the sum of RLP-c and the sd-LDL-c, to the HDL-c ratio, could represent a better predictive indicator than RLP-c alone in ST-segment elevation myocardial infarction (STEMI). Methods: The 316 consecutive patients suffering from persistent chest discomfort admitted to the Shanghai General Hospital between January 2018 and June 2018 were enrolled. 149 STEMI patients (62% men, mean age 69.6 ± 13.3 years) were included as the study cohort. The AL-c/HDL-c ratio was calculated on admission in a cohort of electrocardiogram-confirmed STEMI patients and compared to other lipid profiles as a predictive indicator. Results: The AL-c/HDL-c ratio was significantly increased in STEMI patients compared with apparently healthy adults (0.93; IQR [0.71-1.18] vs 0.70; IQR [0.45-1.04]; p < 0.001). Gender dependency existed, and the male and female patients had median AL-c/HDL-c ratios of 1.01 and 0.79, respectively (p < 0.001). Compared to RLP-c, the AL-c/HDL-c ratio had a better prognostic value to predict STEMI risk in both sexes (AUC of 0.672 with a sensitivity of 0.794 in males and 0.613 with a sensitivity of 0.684 in females). Conclusions: The AL-c/HDL-c ratio could represent a convenient and sensitive biomarker for screening and predicting STEMI risk.

Dietary squalene modifies plasma lipoproteins and hepatic cholesterol metabolism in rabbits.

To evaluate the effects of squalene, the main unsaponifiable component of virgin olive oil, on lipid metabolism, two groups of male New Zealand rabbits were fed a 1% sunflower oil-enriched regular diet or the same diet containing 0.5% squalene for 4 weeks. Plasma triglycerides, total- and HDL-cholesterol and their lipoproteins were assayed. Analyses of hepatic lipid droplets, triglycerides, total- and non-esterified cholesterol, squalene, protein and gene expression, and cholesterol precursors were carried out. In the jejunum, the squalene content and mRNA and protein APOB expressions were measured. Finally, we studied the effect of cholesterol precursors in AML12 cells. Squalene administration significantly increased plasma total cholesterol, mainly carried as non-esterified cholesterol in IDL and large LDL, and corresponded to an increased number of APOB100-containing particles without accumulation of triglycerides and decreased reactive oxygen species. Despite no significant changes in the APOB content in the jejunum, the latter displayed increased APOB mRNA and squalene levels. Increases in the amounts of non-esterified cholesterol, squalene, lanosterol, dihydrolanosterol, lathosterol, cholestanol, zymostenol, desmosterol and caspase 1 were also observed in the liver. Incubation of AML12 cells in the presence of lanosterol increased caspase 1. In conclusion, squalene administration in rabbits increases the number of modified APOB-containing lipoproteins, and hepatic cholesterol biosynthesis is linked to caspase 1 probably through lanosterol.

The Relation Between Adult Weight Gain, Adipocyte Volume, and the Metabolic Profile at Middle Age.

CONTEXT: Weight gain during adulthood increases cardiometabolic disease risk, possibly through adipocyte hypertrophy. OBJECTIVE: We aimed to study the specific metabolomic profile of adult weight gain, and to examine its association with adipocyte volume. METHODS: Nuclear magnetic resonance-based metabolomics were measured in the Netherlands Epidemiology of Obesity (NEO) study (n = 6347, discovery) and Oxford Biobank (n = 6317, replication). Adult weight gain was calculated as the absolute difference between body mass index (BMI) at middle age and recalled BMI at age 20 years. We performed linear regression analyses with both exposures BMI at age 20 years and weight gain, and separately with BMI at middle age in relation to 149 serum metabolomic measures, adjusted for age, sex, and multiple testing. Additionally, subcutaneous abdominal adipocyte biopsies were collected in a subset of the Oxford Biobank (n = 114) to estimate adipocyte volume. RESULTS: Mean (SD) weight gain was 4.5 (3.7) kg/m2 in the NEO study and 3.6 (3.7) kg/m2 in the Oxford Biobank. Weight gain, and not BMI at age 20 nor middle age, was associated with concentrations of 7 metabolomic measures after successful replication, which included polyunsaturated fatty acids, small to medium low-density lipoproteins, and total intermediate-density lipoprotein. One SD weight gain was associated with 386 µm3 (95% CI, 143-629) higher median adipocyte volume. Adipocyte volume was associated with lipoprotein particles specific for adult weight gain. CONCLUSION: Adult weight gain is associated with specific metabolomic alterations of which the higher lipoprotein concentrations were likely contributed by larger adipocyte volumes, presumably linking weight gain to cardiometabolic disease.

A case of tamoxifen-induced hypertriglyceridemia monitoring the changes in lipoprotein fractions over time.

BACKGROUND: Tamoxifen, which is one of the selective estrogen receptor modulators (SERMs), can bring out life-threatening complication, e.g. hypertriglyceridemia-induced acute pancreatitis, although it is rare. We precisely report changes in lipoprotein metabolism before and after tamoxifen discontinuation because there have been few reports of it. CASE PRESENTATION: 47-year-old premenopausal woman with dyslipidemia, type 2 diabetes, nonalcoholic fatty liver disease and chronic kidney disease was prescribed tamoxifen as adjuvant therapy after operation of breast cancer. She experienced severe tamoxifen-induced hypertriglyceridemia several months after dosing tamoxifen. Before cessation of tamoxifen, lipoprotein fraction test revealed marked stagnation of VLDL and IDL metabolisms, resulting in severe hypertriglyceridemia (serum triglyceride level was 1881 mg/dL). Seven days after tamoxifen withdrawal, lipoprotein fraction test showed that the metabolisms of endogenous lipoproteins were changed drastically. CONCLUSIONS: From these results, we confirmed that tamoxifen certainly changes lipoprotein metabolism through suppression of post-heparin lipolytic activity. It is very important to evaluate the balance between benefit and risk before dosing tamoxifen and survey lipid profiles constantly during treatment to avoid life-threatening complication when prescription of tamoxifen is planned.

Prediagnostic circulating metabolites in female breast cancer cases with low and high mammographic breast density.

Mammographic breast density (MBD) is a strong independent risk factor for breast cancer (BC). We designed a matched case-case study in the EPIC Florence cohort, to evaluate possible associations between the pre-diagnostic metabolomic profile and the risk of BC in high- versus low-MBD women who developed BC during the follow-up. A case-case design with 100 low-MBD (MBD ≤ 25%) and 100 high-MDB BC cases (MBD > 50%) was performed. Matching variables included age, year and type of mammographic examination. 1H NMR metabolomic spectra were available for 87 complete case-case sets. The conditional logistic analyses showed an inverse association between serum levels of alanine, leucine, tyrosine, valine, lactic acid, pyruvic acid, triglycerides lipid main fraction and 11 VLDL lipid subfractions and high-MBD cases. Acetic acid was directly associated with high-MBD cases. In models adjusted for confounding variables, tyrosine remained inversely associated with high-MBD cases while 3 VLDL subfractions of free cholesterol emerged as directly associated with high-MBD cases. A pathway analysis showed that the "phenylalanine, tyrosine and tryptophan pathway" emerged and persisted after applying the FDR procedure. The supervised OPLS-DA analysis revealed a slight but significant separation between high- and low-MBD cases. This case-case study suggested a possible role for pre-diagnostic levels of tyrosine in modulating the risk of BC in high- versus low-MBD women. Moreover, some differences emerged in the pre-diagnostic concentration of other metabolites as well in the metabolomic fingerprints among the two groups of patients.

Effects of Resmetirom on Noninvasive Endpoints in a 36-Week Phase 2 Active Treatment Extension Study in Patients With NASH.

Resmetirom (MGL-3196), a selective thyroid hormone receptor-ß agonist, was evaluated in a 36-week paired liver biopsy study (NCT02912260) in adults with biopsy-confirmed nonalcoholic steatohepatitis (NASH). The primary endpoint was relative liver fat reduction as assessed by MRI-proton density fat fraction (MRI-PDFF), and secondary endpoints included histopathology. Subsequently, a 36-week active treatment open-label extension (OLE) study was conducted in 31 consenting patients (including 14 former placebo patients) with persistently mild to markedly elevated liver enzymes at the end of the main study. In patients treated with resmetirom (80 or 100 mg orally per day), MRI-PDFF reduction at OLE week 36 was -11.1% (1.5%) mean reduction (standard error [SE]; P < 0.0001) and -52.3% (4.4%) mean relative reduction, P < 0.0001. Low-density lipoprotein (LDL) cholesterol (-26.1% [4.5%], P < 0.0001), apolipoprotein B (-23.8% [3.0%], P < 0.0001), and triglycerides (-19.6% [5.4%], P = 0.0012; -46.1 [14.5] mg/dL, P = 0.0031) were reduced from baseline. Markers of fibrosis were reduced, including liver stiffness assessed by transient elastography (-2.1 [0.8] mean kilopascals [SE], P = 0.015) and N-terminal type III collagen pro-peptide (PRO-C3) (-9.8 [2.3] ng/mL, P = 0.0004 (baseline ≥ 10 ng/mL). In the main and OLE studies, PRO-C3/C3M (matrix metalloproteinase-degraded C3), a marker of net fibrosis formation, was reduced in resmetirom-treated patients (-0.76 [-1.27, -0.24], P = 0.0044 and -0.68, P < 0.0001, respectively). Resmetirom was well tolerated, with few, nonserious adverse events. Conclusion: The results of this 36-week OLE study support the efficacy and safety of resmetirom at daily doses of 80 mg and 100 mg, used in the ongoing phase 3 NASH study, MAESTRO-NASH (NCT03900429). The OLE study demonstrates a potential for noninvasive assessments to monitor the response to resmetirom from an individual patient with NASH.

Tissue factor pathway inhibitor upregulates CXCR7 expression and enhances CXCL12-mediated migration in chronic lymphocytic leukemia.

The infiltration of chronic lymphocytic leukemia (CLL) cells into lymphoid organs correlates with disease severity. CXCL12 is a key chemotactic factor for the trafficking of CLL. Tissue factor pathway inhibitor (TFPI) is a serine protease inhibitor and plays a role in CXCL12-mediated hematopoietic stem cell homing. We aim to explore the role of TFPI in CXCL12-mediated migration of CLL cells. In this study, plasma TFPI concentrations were measured by ELISA. CLL cells were isolated from patients and used for trans-endothelial migration (TEM) assays. Quantitative RT-PCR and Western blotting were used to detect the expression of CXCR7, CXCR4 and ß-catenin. Immunofluorescence and co-immunoprecipitation was used to detect the binding of TFPI and glypican-3 (GPC3). We found that plasma TFPI levels in CLL patients were higher than in healthy controls, particularly in the patients with advanced disease. TFPI enhanced CXCL12-mediated TEM of CLL cells by increasing the expression of the CXCL12 receptor CXCR7, but not of the CXCL12 receptor CXCR4. The effect of TFPI on TEM was abolished by the CXCR7 inhibitor, CCX771, while the CXCR4 inhibitor AMD3100 strongly increased TEM. TFPI co-localized with GPC3 on the cell surface. An antibody to GPC3, HS20, decreased CXCR7 expression and abolished the effect of TFPI on TEM. TFPI activated ß-catenin and the Wnt/ß-catenin inhibitor IWP4 repressed the effect of TFPI on CXCR7 expression and TEM. We conclude that TFPI may contribute to organ infiltration in CLL patients.

Palmitic acid-rich oils with and without interesterification lower postprandial lipemia and increase atherogenic lipoproteins compared with a MUFA-rich oil: A randomized controlled trial.

BACKGROUND: Interesterified (IE) fats are widely used in place of trans fats; however, little is known about their metabolism. OBJECTIVES: To test the impact of a commonly consumed IE compared with a non-IE equivalent fat on in vivo postprandial and in vitro lipid metabolism, compared with a reference oil [rapeseed oil (RO)]. METHODS: A double-blinded, 3-phase crossover, randomized controlled trial was performed in healthy adults (n = 20) aged 45-75 y. Postprandial plasma triacylglycerol and lipoprotein responses (including stable isotope tracing) to a test meal (50 g fat) were evaluated over 8 h. The test fats were IE 80:20 palm stearin/palm kernel fat, an identical non-IE fat, and RO (control). In vitro, mechanisms of digestion were explored using a dynamic gastric model (DGM). RESULTS: Plasma triacylglycerol 8-h incremental area under the curves were lower following non-IE compared with RO [-1.7 mmol/L⋅h (95% CI: -3.3, -0.0)], but there were no differences between IE and RO or IE and non-IE. LDL particles were smaller following IE and non-IE compared with RO (P = 0.005). Extra extra large, extra large, and large VLDL particle concentrations were higher following IE and non-IE compared with RO at 6-8 h (P < 0.05). No differences in the appearance of [13C]palmitic acid in plasma triacylglycerol were observed between IE and non-IE fats. DGM revealed differences in phase separation of the IE and non-IE meals and delayed release of SFAs compared with RO. CONCLUSIONS: Interesterification did not modify fat digestion, postprandial lipemia, or lipid metabolism measured by stable isotope and DGM analysis. Despite the lower lipemia following the SFA-rich fats, increased proatherogenic large triacylglycerol-rich lipoprotein remnant and small LDL particles following the SFA-rich fats relative to RO adds a new postprandial dimension to the mechanistic evidence linking SFAs to cardiovascular disease risk.

Verification and comparison of three prediction models of ischemic stroke in young adults based on the back propagation neural networks.

ABSTRACT: This work aims to explore risk factors for ischemic stroke in young adults and analyze the Traditional Vascular Risk Factors Model based on age, hypertension, diabetes, smoking history, and drinking history. Further, the Lipid Metabolism Model was analyzed based on lipoprotein a [LP (a)], high-density lipoprotein (HDL), low-density lipoprotein (LDL), apolipoprotein AI (apo AI), apolipoprotein B (apo B), and the Early Renal Injury Model based on urinary microalbuminuria/creatinine ratio (UACR). Besides, we estimated glomerular filtration rate (eGFR), cystatin C (Cys-C), homocysteine (Hcy), ß2 microglobulin (ß2m), and validated their predictive efficacy and clinical value for the development of ischemic stroke in young adults.We selected and retrospectively analyzed the clinical data of 565 young inpatients admitted to Zhejiang Provincial Hospital of Chinese Medicine between 2010 and 2020, 187 of whom were young stroke patients. A single-factor analysis was used to analyze the risk factors for stroke in young people and developed a traditional vascular risk factors model, a lipid metabolism model, and an early kidney injury model based on backpropagation (BP) neural networks technology to predict early stroke occurrence. Moreover, the prediction performance by the area under the receiver operating characteristics (ROC) curve (AUC) was assessed to further understand the risk factors for stroke in young people and apply their predictive role in the clinical setting.Single-factor analysis showed that ischemic stroke in young adults was associated with hypertension, diabetes, smoking history, drinking history, LP(a), HDL, LDL, apo AI, apo B, eGFR, Cys-C, and ß2m (P < .05). The BP neural networks technique was used to plot the ROC curves for the Traditional Vascular Risk Factors Model, the Lipid Metabolism Model, and the Early Kidney Injury Model in enrolled patients, and calculated AUC values of 0.7915, 0.8387, and 0.9803, respectively.The early kidney injury model precisely predicted the risk of ischemic stroke in young adults and exhibited a certain clinical value as a reference for morbidity assessment. Whereas the prediction performance of the Traditional Vascular Risk Factors Model and the Lipid Metabolism Model were inferior to that of the early kidney injury model.

Laparoscopic sleeve gastrectomy alters 1H-NMR-measured lipoprotein and glycoprotein profile in patients with severe obesity and nonalcoholic fatty liver disease.

Patients with morbid obesity frequently present non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) associated with pro-atherogenic alterations. Laparoscopic sleeve gastrectomy (LSG) is an effective treatment for weight reduction, and for the remission of hepatic alterations. Using 1H-nuclear magnetic resonance (1H-NMR), we investigated the effects of LSG on lipoprotein and glycoprotein profile in patients with morbid obesity and liver disease. We included 154 patients with morbid obesity (49 non-NASH, 54 uncertain NASH, 51 definite NASH). A blood sample was obtained before surgery and, in patients with definite NASH, one year after surgery. Patients with NASH had increased concentrations of medium and small VLDL particles, VLDL and IDL cholesterol concentrations, IDL, LDL, and HDL triglyceride concentrations, and elevated glycoprotein levels. These changes were more marked in patients with type 2 diabetes mellitus. LSG produced significant decreases in the concentration of VLDL particles, VLDL cholesterol and triglycerides, an increase in the concentration LDL particles and LDL cholesterol concentrations, and a decrease in protein glycation. We conclude that patients with obesity and NASH had significant alterations in circulating levels of lipoproteins and glycoproteins that were associated with the severity of the disease. Most of these changes were reversed post-LSG.