Elevated Low-density Lipoprotein Levels Research Articles

Levels of pretreatment blood lipids are prognostic factors in advanced NSCLC patients treated with anlotinib

BackgroundAnlotinib, a small molecule for multi-target tyrosine kinase inhibition, is the third or further line of defense for treatment of non-small cell lung cancer (NSCLC). Findings from an ALTER0303 phase III trial revealed that this drug confers significant survival benefits in patients. Although numerous inflammatory biomarkers have been shown to play vital roles in treatment, the clinical significance of blood lipid levels before treatment has not been evaluated. Here, this research aims to explore the relationship between blood lipids and efficacy of anlotinib, with a view of generating insights to guide future development of convenient and individualized treatment therapies.MethodsThis study analyzed basal blood lipids levels, including triglycerides (TG), total cholesterol (TC), low density lipoprotein (LDL), and high density lipoprotein (HDL), among other variables before treatment, in 137 patients with advanced NSCLC who received anlotinib as third or further-line treatment at the Ningbo Medical Center Lihuili Hospital, between July 2018 and December 2020. We determined the best cut off value for predicting treatment responses, generated survival curves using the Kaplan–Meier method, then applied univariate and multivariate Cox regression analyses to assess predictors of survival.ResultsThe entire study population recorded median progression-free survival (PFS) and overall survival (OS) of 4 (95% CI 3.142–4.858) and 8.3 (95% CI 6.843–9.757) months, respectively. Researchers observed statistically significant differences across subgroups, between blood lipid indexes with different efficacies, except in the HDL subgroup. The low disease control rate (DCR) was associated with significantly elevated TG, TC and LDL levels (P = 0.000). Multivariate analysis demonstrated that elevated TC and LDL levels were independently associated with poor PFS or OS (P ≤ 0.003). Then, we established a prediction model, and set high TC or high LDL as the risk factor, respectively. There were significant differences in PFS (p = 0.000) and OS (p = 0.012) between 0 and ≥ 1 scores.ConclusionsPrior to anlotinib therapy, TC and LDL levels, are independent prognostic indicators for patients with advanced NSCLC treated with this drug as a third or further-line treatment option. In addition, a risk score of 0 was attributed to a combination of low TC and low LDL, and these patients were exhibited excellent efficacies and survival rates.

Correlation of serum ferritin levels with neurological function-related indices and cognitive dysfunction in patients with cerebral hemorrhage

The purpose of this study was to explore the correlation of serum ferritin (FS) levels with neurological function-related indices, such as neuron-specific enolase (NSE) and S100β protein levels, and cognitive dysfunction in patients with cerebral hemorrhage. Patients with acute non-traumatic cerebral hemorrhage (cerebrovascular disease (VD), n = 128) and healthy controls (CON, n=128) were included. FS, NSE, and S100β levels were measured using ELISA. Cognitive functions were evaluated using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). The receiver operating characteristic (ROC) curve was used to assess the ability of SE, NSE, and serum S100β to predict the diagnosis of cognitive dysfunction in patients with cerebral hemorrhage. Multivariate logistic regression analysis was used to assess the risk factors of cognitive impairment in patients with cerebral hemorrhage. Cognitive impairment in patients with VD was closely related to the increased levels of SE, NSE, and S100β. There was a strong correlation between MoCA and MMSE scores and the levels of FS, NSE, and S100β. The independent risk factors leading to cognitive impairment in cerebral hemorrhage mainly include family history of cerebrovascular disease, body mass index, hypertension, smoking frequency, and elevated levels of low-density lipoproteins, NSE, FS, and S100β. NSE, FS, and S100β can be used as important markers for the diagnosis of cognitive impairment in patients with cerebral hemorrhage.

Cardiovascular risk factors and cervical carotid plaque features on CT angiography.

Little is known about the impact that cardiovascular (CV) risk factors have on the formation of various carotid atherosclerotic plaque features. This study set out to assess the association between CV risk factors and plaque characteristics on computed tomography (CT) angiography (CTA). A retrospective review was completed of consecutive patients that underwent a carotid endarterectomy and had CTA imaging of the head and neck vasculature. Atherosclerotic plaques of both carotid arteries were evaluated for calcification(s), low-density plaque (LDP) components, ulceration(s), and degree of stenosis. Various clinical CV risk factors were assessed using medical records. Last recorded laboratory levels were dichotomized into categories: total cholesterol <200 or ≥200 mg/dL, low-density lipoprotein (LDL) <130 or ≥130 mg/dL, high-density lipoprotein <35 or ≥35 mg/dL, and triglyceride <200 or ≥200 mg/dL. Of 97 included patients, 62 were male (63.9%); the average age was 72.7 (standard deviation = 9.5). Calcifications were in 95/97 (97.9%) of patients (one or both carotid plaques); LDP components were in 73/97 (75.3%), and ulcerations were in 21/97 (21.6%). Elevated total cholesterol and elevated LDL levels were both associated with a higher likelihood of LDP components (p = 0.004 and p = 0.02, respectively). There were no other statistically significant associations between individual plaque features or severity of arterial stenosis and CV risk factors. In carotid atherosclerotic plaques, LDP components are more frequently present in one or both carotid arteries in patients with elevated total cholesterol and/or LDL levels. Such findings raise the possibility that cholesterol levels may be directly related to the formation of specific high-risk plaque features.

Comparison of Lipid Profile in Patients With and Without Subclinical Hypothyroidism.

Introduction: Thyroid hormone affects lipid metabolism. Various studies have shown a contradictory relationship between lipid profile (LP) and subclinical hypothyroidism (SCH). Currently, there is a scarcity of regional data on the relationship between LP and SCH.Methods: This longitudinal study was conducted in the internal medicine and cardiology units of a tertiary care hospital in Pakistan from September 2019 to March 2021. A total of 900 participants, of either gender and between the ages of 40 to 70 years, were enrolled in the study. Blood samples were sent to the laboratory to determine lipid and thyroid parameters. Participants were divided into two groups based on the presence of SCH.Results: In our study, 179 (19.8%) participants had SCH. Total cholesterol (TC) and low-density lipoprotein (LDL) was significantly higher in participants with SCH compared to participants without SCH (228.41 ± 35.21 mg/dL vs. 171.21 ± 30.21 mg/dL; p-value: <0.00001) and (131.65 ± 28.22 mg/dL vs. 89.26 ± 18.52 mg/dL; p-value: <0.0001), respectively.Conclusion: In conclusion, this study found an increased incidence of dyslipidemias in patients with SCH. It is associated with elevated TC and LDL levels, which are risk factors for cardiovascular disease and mortality.

TRPM2, PDLIM5, BCL3, CD14, GBA Genes as Feasible Markers for Premature Coronary Heart Disease Risk.

Background: Beyond non-genetic risk factors, familial hypercholesterolemia (FH) plays a major role in the development of CHD. FH is a genetic disorder characterized by heritable and severely elevated levels of low-density lipoprotein (LDL) cholesterol, which can lead to premature cardiovascular disease, particularly familial coronary heart disease (FH-CHD).Method: To explore genes indicating a risk of familial (premature) coronary heart disease (FH-CHD) development in FH, 30 Thai male volunteers were enrolled: 7 healthy controls (N), 6 patients with hypercholesterolemia (H), 4 with FH, 10 with CHD, and 3 with FH-CHD. Transcriptome data were investigated using next-generation sequencing analysis in whole blood (n = 3). Genes that were significantly expressed in both FH and FH-CHD, but not in N, H, and CHD groups, were selected and functionally analyzed.Results: The findings revealed that 55 intersecting genes were differentially expressed between FH and FH-CHD groups. Ten of the 55 genes (MAPK14, TRPM2, STARD8, PDLIM5, BCL3, BLOC1S5, GBA, RBMS1, CD14, and CD36 were selected for validation. These 10 genes play potential roles in chronic inflammation and are involved in pathways related to pathogenesis of CHD. Using quantitative real-time PCR, we evaluated the mRNA expression of the selected genes in all 30 volunteers. TRPM2, PDLIM5, BCL3 were significantly upregulated and GBA was significantly downregulated in both FH and FH-CHD compared with the N, H, and CHD groups.Conclusion: our preliminary investigation reveals that the TRPM2, PDLIM5, BCL3, and GBA genes may have potential for further development as predictive markers for FH-CHD.

The Relationship of Modifiable Risk Factors with Indicators of Arterial Stiffness and Vascular Age in Patients with Arterial Hypertension

Aim. To study the relationship of modifiable risk factors (RF) with indicators of arterial stiffness and vascular age based on the contour analysis of the pulse wave velocity in hypertensive patients.Material and methods. The material of the study was the data from a survey of patients undergoing clinical observation at the polyclinic of MMC SOGAZ. A total of 107 patients were examined, in which 70 were men and 37 were women. The average age was 52.3±18.29. Photoplethysmography was used as a special research method, performed using the AngioScan-01 diagnostic complex. The main indicators used to evaluate the stiffness of large vessels were: stiffness index (SI), reflection index (RI), augmentation index (Alp75), age index (AGI), pulse wave types (PV) and vascular age (VA).Results. The mean values of arterial stiffness indices in patients with essential arterial hypertension (AH) and healthy individuals (control) had significant differences. The mean SI, Alp75, and VA values in the group of patients with AH were 7.8±1.03, 7.0±14.44 and 50.8±15.93 versus 7.2±1.73, 0.5±18.02 and 43.8±16.94, respectively (p&lt; 0.05). In both groups, a strong inverse correlation of passport age with C-type PV was revealed (r=0.74, p&lt; 0.01), which reflected the dynamics of a gradual age-dependent decrease in vascular compliance. The average VA value in the control group was 63.1±16.99 years with an average passport age of 59.5±8.79 years, which significantly differed from VA in hypertensive patients (p&lt; 0,05). Overweight, hypercholesterolemia, elevated low-density lipoprotein levels, lack of adequate antihypertensive control, and left ventricular diastolic dysfunction were significantly associated with early vascular (arterial) aging.Conclusion. Patients with hypertension, in addition to high blood pressure, significantly differ from normotensive control in terms of arterial stiffness. The lack of control over modifiable RF of patients with hypertension is associated with early vascular aging.

Evinacumab for Homozygous Familial Hypercholesterolemia

BackgroundHomozygous familial hypercholesterolemia is characterized by premature cardiovascular disease caused by markedly elevated levels of low-density lipoprotein (LDL) cholesterol. This disorder is associated with genetic variants that result in virtually absent (null–null) or impaired (non-null) LDL-receptor activity. Loss-of-function variants in the gene encoding angiopoietin-like 3 (ANGPTL3) are associated with hypolipidemia and protection against atherosclerotic cardiovascular disease. Evinacumab, a monoclonal antibody against ANGPTL3, has shown potential benefit in patients with homozygous familial hypercholesterolemia.MethodsIn this double-blind, placebo-controlled, phase 3 trial, we randomly assigned in a 2:1 ratio 65 patients with homozygous familial hypercholesterolemia who were receiving stable lipid-lowering therapy to receive an intravenous infusion of evinacumab (at a dose of 15 mg per kilogram of body weight) every 4 weeks or placebo. The primary outcome was the percent change from baseline in the LDL cholesterol level at week 24.ResultsThe mean baseline LDL cholesterol level in the two groups was 255.1 mg per deciliter, despite the receipt of maximum doses of background lipid-lowering therapy. At week 24, patients in the evinacumab group had a relative reduction from baseline in the LDL cholesterol level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of –49.0 percentage points (95% confidence interval [CI], –65.0 to –33.1; P<0.001); the between-group least-squares mean absolute difference in the LDL cholesterol level was –132.1 mg per deciliter (95% CI, –175.3 to –88.9; P<0.001). The LDL cholesterol level was lower in the evinacumab group than in the placebo group in patients with null–null variants (–43.4% vs. +16.2%) and in those with non-null variants (–49.1% vs. –3.8%). Adverse events were similar in the two groups.ConclusionsIn patients with homozygous familial hypercholesterolemia receiving maximum doses of lipid-lowering therapy, the reduction from baseline in the LDL cholesterol level in the evinacumab group, as compared with the small increase in the placebo group, resulted in a between-group difference of 49.0 percentage points at 24 weeks. (Funded by Regeneron Pharmaceuticals; ELIPSE HoFH ClinicalTrials.gov number, NCT03399786.)

Assessing the Prevalence of Dyslipidemia in Apparently Healthy Urban Obese Adults Residing in South Delhi, India

The present research study was conducted to assess the prevalence and pattern of dyslipidemia in apparently healthy urban obese adults residing in South Delhi. Dyslipidemia and obesity are two prominent contributing risk factors for cardiovascular disease. This cross-sectional study was conducted among 150 apparently healthy obese adults with a body mass index of ≥25 kg/m2. Data regarding the socio-demographic characteristics as well as anthropometric parameters were collected. To evaluate serum lipid levels fasting blood samples were collected by trained technicians and analysis was carried out in a certified laboratory. Dyslipidemia was defined as the presence of hypercholesterolemia, high levels of low-density lipoprotein (LDL) cholesterol, and /or lower concentration of high-density lipoprotein (HDL), present alone or in combination. The overall prevalence of dyslipidemia was noted to be 78%. The prevalence was observed to be much higher in the obese female subjects (81.43%) than the obese males (75%). Mean triglycerides levels were significantly higher in the obese men than females while, HDL–C levels were higher in the female subjects (p<0.05). Further, it was seen that low concentration of HDL was the most prevailing deranged lipid parameter (52.67%) followed by elevated triglycerides levels (49.33%) and elevated LDL levels (39.33%) in these obese adults. The study thus highlights the importance of regular and timely screening for apparently healthy populations. Advocating suitable and timely medical and dietary interventions can help in both monitoring and avoiding further health-related complications.

Dyslipidemia is the hallmark of the metabolic syndrome in postmenopausal women

The incidence of cardiovascular diseases (CVD) increases after menopause and may be due to changes in the plasma lipid-lipoprotein levels that occur following menopausal transition. Physiological estrogen withdrawal during menopause plays a major role in abnormal lipid metabolism such as elevated low-density lipoprotein concentration. The aim of this study was to determine the relationship between dyslipidemia and the causative factors of metabolic syndrome in postmenopausal women. In this cross-sectional study, 290 postmenopausal Sudanese women were included. Lipid profiles were measured by spectrophotometer, estrogen hormone determined by ELISA, insulin resistance determined by HOMA-2 calculator and lipid accumulation product was calculated by the following equation (waist circumference in cm X triglyceride concentration in mM). The results revealed that total cholesterol, triglycerides, low-density lipoprotein levels and very low-density lipoprotein levels were significantly higher in the postmenopausal women with metabolic syndrome (MS) in comparison to those without the MS. Elevated total cholesterol levels were seen in 51.7 %, elevated triglycerides were seen in 49.7% and elevated low-density lipoprotein levels were seen in 29.3% whereas reduced high density lipoprotein levels were seen in 16.89% of the postmenopausal women. Total cholesterol, triglycerides and very low-density lipoprotein values showed a significant positive correlation with insulin resistance and lipid accumulation and a significant negative correlation with the estrogen hormone level. In addition, high density lipoproteins showed a significant negative correlation with lipid accumulation levels.

Plasma cholesterol in Alzheimer's disease and frontotemporal dementia.

BackgroundThe relationship between the apolipoprotein E (APOE)-ε4 allele, triglyceride (TG) level, and cholesterol level and an increased risk of developing Alzheimer’s disease (AD) has been well established, but their relationship with behavioral-variant frontotemporal dementia (bvFTD) is not well-known.MethodologyThe levels of TGs, total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein were measured in bvFTD and AD patients and in normal controls (NCs). DNA was extracted, and APOE was genotyped.ResultsThe APOE-ε4 allele frequency was higher in the AD group than in the NC group, but no difference was found between the AD and the bvFTD groups. The bvFTD group had higher LDL than the AD group, and significant differences were also found for the cholesterol level in the dementia groups compared with the NC group. Elevated LDL level was positively correlated with appetite and eating score in the bvFTD group. Compared with the AD patients and NCs without the APOE-ε4 allele, those with the APOE-ε4 allele had higher TC, but its correlation with the bvFTD group was absent.ConclusionsThe bvFTD and the AD groups had higher cholesterol levels. The APOE-ε4 allele and eating behavior might modify lipid metabolism in dementia. TG and cholesterol analyses may offer a new opportunity for targeted treatments.

Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage.

Observational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH. We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses. We identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10-100 ). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85-0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81-0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65-0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42-0.82; p = 0.002), respectively. Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56-66.

Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia

BackgroundFamilial hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. Monoclonal antibodies directed against proprotein convertase subtilisin–kexin type 9 (PCSK9) have been shown to reduce LDL cholesterol levels by more than 50% but require administration every 2 to 4 weeks. In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia.MethodsIn this phase 3, double-blind trial, we randomly assigned, in a 1:1 ratio, 482 adults who had heterozygous familial hypercholesterolemia to receive subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The two primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540.ResultsThe median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% confidence interval [CI], −43.7 to −35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of −47.9 percentage points (95% CI, −53.5 to −42.3; P<0.001). The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% (95% CI, −41.1 to −35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of −44.3 percentage points (95% CI, −48.5 to −40.1; P<0.001). There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia. Adverse events and serious adverse events were similar in the two groups.ConclusionsAmong adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile. (Funded by the Medicines Company; ORION-9 ClinicalTrials.gov number, NCT03397121.)

Predictive value of plasma lipid levels for coronary artery disease (CAD)

Coronary artery disease (CAD) is a major cause of mortality and morbidity all over the world including Pakistan. CAD events are caused by the interplay of genetic and environmental factors, the effects of which are mainly mediated through cardiovascular risk factors. The major risk factors for CAD include hypertension, dyslipidemia, family history of premature atheroscleclerotic disease, obesity and sedentary lifestyle. However, it is clear from the existing literature that dyslipidemia plays a central role. This study was designed to examine the plasma lipid profile in coronary artery disease patients of both sexes receiving clinical care at various government hospitals in Lahore. Blood samples were collected from a total of 500 CAD patients and 250 healthy (control) subjects and subsequently analyzed for total cholesterol (TC), triglyceride (TG) and very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein cholesterol (HDL) levels. These measurements showed that TC, LDL, TG and VLDL levels were significantly elevated, whereas HDL levels were significantly reduced in CAD patients as compared to ethnically matched controls (p < 0.0001). However, lipid levels did not differ significantly between the male and female patients. Furthermore, the lipid profile parameters were strongly associated with CAD status and association of LDL/HDL remained significant even after making an adjustment for confounders. In addition, patients with comorbidities exhibited severe lipid abnormalities. In conclusion, this study revealed elevated plasma TG, TC, VLDL and LDL levels and attenuated plasma HDL levels in the Pakistani patients with coronary artery disease. Also, plasma lipid levels have the potential to serve as biomarkers for CAD in Pakistani population.

LDL induces cholesterol loading and inhibits endothelial proliferation and angiogenesis in Matrigels: correlation with impaired angiogenesis during wound healing.

Hypercholesterolemia is a major risk factor for adverse cardiovascular outcomes, but its effect on angiogenesis and wound healing is not well understood. In this study, using a combination of mass spectrometry and laurdan two-photon imaging, we show that elevated levels of low-density lipoprotein (LDL), like those seen in hypercholesterolemic patients, lead to an increase in both free cholesterol and cholesterol esters, as well as increase in lipid order of endothelial cell membranes. Notably, these effects are distinct and opposite to the lack of cholesterol loading and the disruption of lipid order observed in our earlier studies in response to oxidized LDL (oxLDL). The same pathological level of LDL leads to a significant inhibition of endothelial proliferation and cell cycle arrest in G2/M phase, whereas oxLDL enhances endothelial proliferation in S phase of the cycle. LDL but not oxLDL suppresses the expression of vascular endothelial growth factor receptor-2 while enhancing the expression of vascular endothelial growth factor (VEGF). Furthermore, we show that aged (8-10 mo) hypercholesterolemic apolipoprotein E-deficient (ApoE-/-) mice display delayed wound closure compared with age-matched C57/BL6 wild-type controls following a skin punch biopsy. The delay in wound healing is associated with a decreased expression of cluster of differentiation 31 platelet endothelial cell adhesion molecule endothelial marker and decreased angiogenesis within the wound bed. Furthermore, decreased endothelial responsiveness to the growth factors VEGF and basic fibroblast growth factor is observed in ApoE-/- mice in Matrigel plugs and in Matrigels with high levels of LDL in wild-type mice. We propose that plasma hypercholesterolemia is antiangiogenic due to elevated levels of LDL.

Protective Role of Loranthus regularis against Liver Dysfunction, Inflammation, and Oxidative Stress in Streptozotocin Diabetic Rat Model.

Earlier studies revealed the potential therapeutic values of Loranthus regularis (L. regularis). This study evaluated Loranthus regularis (L. regularis) extract systemic antidiabetic effects and benefits against diabetic hepatocellular injuries through antioxidant and anti-inflammatory pathways using the streptozotocin (STZ) model in Wistar albino rats. After diabetes induction, animals were orally treated with L. regularis extract for 4 weeks. Serum levels of glucose, insulin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), total triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were estimated. Furthermore, tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), caspase-3, nitric oxide (NO), and prostaglandin E-2 (PGE-2) were estimated in serum. In liver, thiobarbituric acid reactive substances (TBARSs) and reduced glutathione (GSH) as well as the proinflammatory cytokines and enzymatic activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reeducates (GR), and glutathione-S-transferase (GST) were assayed. Finally, the degree of hepatic tissue damage was evaluated histologically. Treatment of the diabetic rats with L. regularis extract markedly reduced the elevated serum levels of glucose, ALT, AST, TC, TG, LDL, TNF-α, IL-1β, IL-6, caspase-3, NO, and PGE-2. L. regularis extract also improved serum levels of insulin and HDL. The elevated TBARS, TNF-α, IL-1β, and IL-6 levels in hepatic tissue of diabetic animals were reduced by L. regularis. Moreover, L. regularis extract significantly restored the diminished hepatic GSH level and enzymatic activities of SOD, CAT, GPx, GR, and GST in diabetic animals. The biochemical protective effects of L. regularis were associated with improved histological hepatocellular integrity and architecture. Taken together, L. regularis has therapeutic effects against diabetic-induced hepatic complications. The restored liver functions and cellular damage might be mediated through free radicals scavenging and proinflammatory cytokine inhibition.

Proteolysis of the low density lipoprotein receptor by bone morphogenetic protein-1 regulates cellular cholesterol uptake

The development of cardiovascular disease is intimately linked to elevated levels of low-density lipoprotein (LDL) cholesterol in the blood. Hepatic LDL receptor (LDLR) levels regulate the amount of plasma LDL. We identified the secreted zinc metalloproteinase, bone morphogenetic protein 1 (BMP1), as responsible for the cleavage of human LDLR within its extracellular ligand-binding repeats at Gly171↓Asp172. The resulting 120 kDa membrane-bound C-terminal fragment (CTF) of LDLR had reduced capacity to bind LDL and when expressed in LDLR null cells had compromised LDL uptake as compared to the full length receptor. Pharmacological inhibition of BMP1 or siRNA-mediated knockdown prevented the generation of the 120 kDa CTF and resulted in an increase in LDL uptake into cells. The 120 kDa CTF was detected in the livers from humans and mice expressing human LDLR. Collectively, these results identify that BMP1 regulates cellular LDL uptake and may provide a target to modulate plasma LDL cholesterol.

Genetic Testing and Risk Scores: Impact on Familial Hypercholesterolemia.

Familial Hypercholesterolemia (FH) is an inherited lipid disorder affecting 1 in 220 individuals resulting in highly elevated low-density lipoprotein levels and risk of premature coronary disease. Pathogenic variants causing FH typically involve the LDL receptor (LDLR), apolipoprotein B-100 (APOB), and proprotein convertase subtulisin/kexin type 9 genes (PCSK9) and if identified convey a risk of early onset coronary artery disease (ASCVD) of 3- to 10-fold vs. the general population depending on the severity of the mutation. Identification of monogenic FH within a family has implications for family-based testing (cascade screening), risk stratification, and potentially management, and it has now been recommended that such testing be offered to all potential FH patients. Recently, robust genome wide association studies (GWAS) have led to the recognition that the accumulation of common, small effect alleles affecting many LDL-c raising genes can result in a clinical phenotype largely indistinguishable from monogenic FH (i.e., a risk of early onset ASCVD of ~3-fold) in those at the extreme tail of the distribution for these alleles (i.e., the top 8% of the population for a polygenic risk score). The incorporation of these genetic risk scores into clinical practice for non-FH patients may improve risk stratification but is not yet widely performed due to a less robust evidence base for utility. Here, we review the current status of FH genetic testing, potential future applications as well as challenges and pitfalls.

Mipomersen and its use in familial hypercholesterolemia

ABSTRACTIntroduction: Familial Hypercholesterolemia (FH) is an inherited disorder characterized by a defect in the binding and internalization of low-density lipoprotein (LDL) particles, resulting in markedly elevated LDL levels and premature atherosclerosis. It is one of the most common inherited disorders of lipid metabolism. Many FH patients, especially those with homozygous FH do not reach LDL goals with traditional LDL therapies and may require additional, less often used, therapies.Areas covered: Mipomersen is an anti-sense oligonucleotide that prevents production of apolipoprotein B leading to decreased levels of very low-density lipoprotein (VLDL) and LDL. In this review the authors discuss the pharmacokinetics of the drug, the clinical trials evaluating its efficacy and safety, and risks and challenges associated with its clinical implementation. Its use as therapy for the treatment of FH is also discussed.Expert opinion: Mipomersen is approved for use only in homozygous FH. It has frequent adverse effects, such as injection site reactions, flu-like symptoms, and hepatoxicity. It is useful only in patients who have failed other therapies, and it faces competition from other medications that have more tolerable side effect profiles.

Genomic and Transcriptomic Analysis of Hypercholesterolemic Rabbits: Progress and Perspectives.

Rabbits (Oryctolagus cuniculus) are one of the most widely used animal models for the study of human lipid metabolism and atherosclerosis because they are more sensitive to a cholesterol diet than other experimental animals such as rodents. Currently, two hypercholesterolemic rabbit models are frequently used for atherosclerosis studies. One is a cholesterol-fed wild-type rabbit and the other is the Watanabe heritable hyperlipidemic (WHHL) rabbit, which is genetically deficient in low density lipoprotein (LDL) receptor function. Wild-type rabbits can be easily induced to develop severe hypercholesterolemia with a cholesterol-rich diet due to the marked increase in hepatically and intestinally derived remnant lipoproteins, called β-very low density lipoproteins (VLDL), which are rich in cholesteryl esters. WHHL rabbits are characterized by elevated plasma LDL levels on a standard chow diet, which resembles human familial hypercholesterolemia. Therefore, both rabbit models develop aortic and coronary atherosclerosis, but the elevated plasma cholesterol levels are caused by completely different mechanisms. In addition, cholesterol-fed rabbits but not WHHL rabbits exhibit different degrees of hepatosteatosis. Recently, we along with others have shown that there are many differentially expressed genes in the atherosclerotic lesions and livers of cholesterol-fed rabbits that are either significantly up- or down-regulated, compared with those in normal rabbits, including genes involved in the regulation of inflammation and lipid metabolism. Therefore, dietary cholesterol plays an important role not only in hypercholesterolemia and atherosclerosis but also in hepatosteatosis. In this review, we make an overview of the recent progress in genomic and transcriptomic analyses of hypercholesterolemic rabbits. These transcriptomic profiling data should provide novel insight into the relationship between hypercholesterolemia and atherosclerosis or hepatic dysfunction caused by dietary cholesterol.

Antidiabetic and antihyperlipidemic potential of ethanol extract of Salacia lehmbachii stem bark in alloxan-induced diabetic rats.

Background Salacial lehmbachii stem bark is used traditionally for the treatment of diabetes mellitus and its associated complications. Treatment of diabetes is necessary to reduce these complications. Methods In this study, the antidiabetic and antihyperlipidemic potential of S. lehmbachii ethanol stem bark extract was evaluated in alloxan-induced diabetic rats at a dose of 100 mg/kg, 200 mg/kg, and 400 mg/kg p.o. daily for 21 days. Blood glucose levels, serum total cholesterol (TC), triglycerides (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), and very low density lipoprotein (VLDL) were assessed in the animals. Results Treatment of alloxan-induced diabetic rats with S. lehmbachii stem bark extract showed significant (p<0.01) reduction in blood glucose levels when compared with diabetic control. The elevated levels of serum cholesterol, triglycerides, LDL, and VLDL were significantly (p<0.01) reduced by S. lehmbachii stem bark extract, while the level of HDL significantly (p<0.01) increased. Conclusions The results obtained suggest that S. lehmbachii stem bark extract has the potential to treat diabetes condition and hyperlipidemic disorders.