Cholesterol Absorption Inhibitor Research Articles

Elucidating the binding mechanism of a cholesterol absorption inhibitor with a serum albumin: spectroscopic, zeta potential, voltammetric and computational studies

Elucidating the binding mechanism of a cholesterol absorption inhibitor with a serum albumin: spectroscopic, zeta potential, voltammetric and computational studies

Monosaccharide induced temporal delay in cholesterol self-aggregation

Self-assembly of cholesterol (CHL) is infamous for its diverse deleterious effects on human health. Clinical research over several decades indicates that a diet rich in CHL typically leads to arterial plaques, cataracts and gall stones among others. Carbohydrates like the β-glucans efficiently lower serum CHL, possibly by inhibiting CHL absorption in the digestive tract. Using molecular dynamics simulations, we explore how β-D-glucose (BGLC), the building block of β-glucans, interferes with CHL aggregation. BGLC slows down CHL diffusion and disrupts the formation of the robust hydrophobic CHL assembly. Estimation of the translational entropy of the CHL molecules shows the extent of retardation induced by BGLC. Coordination numbers obtained from the adjacency matrix and collective variable analysis of the packing of the CHL molecules in presence of BGLC show the time evolution of CHL aggregation. In presence of BGLC, small isolated CHL islands form, consolidate and disintegrate over time as compared to the blank CHL system. The predominance of smaller CHL clusters is an effect of the significant retardation of the translational motion of CHL molecules induced by BGLC. Communicated by Ramaswamy H. Sarma

Insulin Prevents Hypercholesterolemia by Suppressing 12α-Hydroxylated Bile Acids.

The risk of cardiovascular disease in type 1 diabetes remains extremely high, despite marked advances in blood glucose control and even the widespread use of cholesterol synthesis inhibitors. Thus, a deeper understanding of insulin regulation of cholesterol metabolism, and its disruption in type 1 diabetes, could reveal better treatment strategies. To define the mechanisms by which insulin controls plasma cholesterol levels, we knocked down the insulin receptor, FoxO1, and the key bile acid synthesis enzyme, CYP8B1. We measured bile acid composition, cholesterol absorption, and plasma cholesterol. In parallel, we measured markers of cholesterol absorption and synthesis in humans with type 1 diabetes treated with ezetimibe and simvastatin in a double-blind crossover study. Mice with hepatic deletion of the insulin receptor showed marked increases in 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol. This phenotype was entirely reversed by hepatic deletion of FoxO1. FoxO1 is inhibited by insulin and required for the production of 12α-hydroxylated bile acids, which promote intestinal cholesterol absorption and suppress hepatic cholesterol synthesis. Knockdown of Cyp8b1 normalized 12α-hydroxylated bile acid levels and completely prevented hypercholesterolemia in mice with hepatic deletion of the insulin receptor (n=5-30), as well as mouse models of type 1 diabetes (n=5-22). In parallel, the cholesterol absorption inhibitor, ezetimibe, normalized cholesterol absorption and low-density lipoprotein cholesterol in patients with type 1 diabetes as well as, or better than, the cholesterol synthesis inhibitor, simvastatin (n=20). Insulin, by inhibiting FoxO1 in the liver, reduces 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol levels. Thus, type 1 diabetes leads to a unique set of derangements in cholesterol metabolism, with increased absorption rather than synthesis. These derangements are reversed by ezetimibe, but not statins, which are currently the first line of lipid-lowering treatment in type 1 diabetes. Taken together, these data suggest that a personalized approach to lipid lowering in type 1 diabetes may be more effective and highlight the need for further studies specifically in this group of patients.

An integrated approach for very high cardiovascular risk patients. Intermediate results

The main objective of secondary prevention measures is to modify key risk factors such as hypertension (HTN) and dyslipidemia in patients with established cardiovascular diseases. Its proper implementation improves both short- and long-term outcomes. Telehealth technologies contributes to faster achievement of target levels and better control of key risk factors.Aim. To establish a comprehensive personalized follow-up framework for patients recovered from an acute coronary syndrome (ACS) that integrates telehealth software and to test its clinical and patient-centered efficacy.Material and methods. The three-month follow-up data of 50 patients (50% of planned enrollees; median age, 57 years [53; 61]; males, 84%) who suffered ACS with myocardial revascularization and low-density lipoprotein cholesterol (LDL-C) at least 2,5 mmol/L at admission. We introduced the simple and save telehealth software for home BP monitoring and lipid profiling. The basic demographic, clinical and laboratory characteristics of patients were described, as well as the changes lipid profile, office and home BP over this period was analyzed. The primary endpoint was a change in LDL-C after 3 months. In addition, we also focused on pharmacological therapy and its dynamics, as well as on remote counseling and patient’ experience with the mobile application.Results. Three months after inclusion, we have noted significant decrease of total cholesterol (-1,67 mmol/L, p<0,0001) and triglycerides (-0,48 mmol/L, p<0,0001). LDL-C changes were also significant (-1,49 mmol/L, adjusted for age, sex and lipid-lowering therapy; p<0,0001) and was associated only with the baseline LDL-C levels (R2=-0,521, p<0,0001). Thirty-nine (78%) patients achieved at least 1 mmol/L drop of LDL-C. Nine of them reached target LDL-C <1,4 mmol/L (and/or a decrease of 50% from baseline). Both high-density lipoprotein cholesterol (-0,48 mmol/l, p=0,348), office and home BP remained mostly unchanged. The proportion of patients with target office BP levels was almost the same (χ2=3,06, p=0,08). Patients who were recommended combined lipid-lowering therapy with cholesterol absorption inhibitor (ezetimibe) were more likely to achieve target LDL-C (χ2=10,95; p=0,003) than those with single agent (67% versus 17%, p=0,003). No differences were found in subgroups of patients in LDL-C reduction. In each patient an average of 15 remote consultations have been performed (from 1 to 54 per patient per 3 moths). Investigators have had to send reminders to 22 patients regarding the need for regular home BP monitoring. The majority of patients treated telehealth software as easy-to-use and user-friendly.Conclusion. According to the 3-month follow-up of patients after ACS who used the framework integrated with telemonitoring and remote counseling, a positive trend in reducing atherogenic lipid levels was demonstrated, but not in office BP. Only a fifth of patients reached the target LDL-C, but the vast majority had target BP. Despite the fact that the program is convenient to use, almost half of participants require additional reminders from physician on self-monitoring.

Ameliorative impact of ezetimibe on gentamicin-induced kidney damage; A histopathological perspective

Introduction: Gentamicin, despite its beneficial effects, has significant nephrotoxic effects that are observed in 20% of the patients. Ezetimibe is recognized as an inhibitor of cholesterol absorption. Objectives: The present study aimed to investigate the histopathological effects of ezetimibe on gentamicin-induced kidney damage. Material and Methods: Twenty male Wistar rats were randomly divided into five groups and treated as the following; group 1 (normal group), group 2 [gentamicin group, daily 80 mg/kg, intraperitoneal (i.p.) for seven days], group 3-5 (gentamicin 80 + ezetimibe at doses of 2.5, 12.5, and 37.5 mg/kg, respectively). Kidney sections were examined for histopathological parameters including vacuolization of the tubular renal cells, degeneration, necrosis, flattening of the tubular cells and debris in the tubular lumen. Results: Gentamicin injection significantly induced histopathological alterations (P< 0.05). Ezetimibe therapy significantly decreased the levels of vacuolization, degeneration, necrosis, flattening of the tubular cells and debris in the nephrotoxic rats (P< 0.05). Conclusion: The results illustrated that treatment with ezetimibe can improve kidney damage caused by gentamicin injection.

Effectiveness of a Novel ω-3 Krill Oil Agent in Patients With Severe Hypertriglyceridemia

Intense interest exists in novel ω-3 formulations with high bioavailability to reduce blood triglyceride (TG) levels. To determine the phase 3 efficacy and safety of a naturally derived krill oil with eicosapentaenoic acid and docosahexaenoic acid as both phospholipid esters (PLs) and free fatty acids (FFAs) (ω-3-PL/FFA [CaPre]), measured by fasting TG levels and other lipid parameters in severe hypertriglyceridemia. This study pooled the results of 2 identical randomized, double-blind, placebo-controlled trials. TRILOGY 1 (Study of CaPre in Lowering Very High Triglycerides) enrolled participants at 71 US centers from January 23, 2018, to November 20, 2019; TRILOGY 2 enrolled participants at 93 US, Canadian, and Mexican centers from April 6, 2018, to January 9, 2020. Patients with fasting TG levels from 500 to 1500 mg/dL, with or without stable treatment with statins, fibrates, or other agents to lower cholesterol levels, were eligible to participate. Randomization (2.5:1.0) to ω-3-PL/FFA, 4 g/d, vs placebo (cornstarch) for 26 weeks. The primary outcome was the mean percentage of change in TG levels at 12 weeks; persistence at 26 weeks was the key secondary outcome. Other prespecified secondary outcomes were effects on levels of non-high-density lipoprotein cholesterol (non-HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), HDL-C, and low-density lipoprotein cholesterol (LDL-C); safety and tolerability; and TG level changes in prespecified subgroups. A total of 520 patients were randomized, with a mean (SD) age of 54.9 (11.2) years (339 men [65.2%]), mean (SD) body mass index of 31.5 (5.1), and baseline mean (SD) TG level of 701 (222) mg/dL. Two hundred fifty-six patients (49.2%) were of Hispanic or Latino ethnicity; 275 (52.9%) had diabetes; and 248 (47.7%) were receiving statins. In the intention-to-treat analysis, TG levels were reduced by 26.0% (95% CI, 20.5%-31.5%) in the ω-3-PL/FFA group and 15.1% (95% CI, 6.6%-23.5%) in the placebo group at 12 weeks (mean treatment difference, -10.9% [95% CI, -20.4% to -1.5%]; P = .02), with reductions persisting at 26 weeks (mean treatment difference, -12.7% [95% CI, -23.1% to -2.4%]; P = .02). Compared with placebo, ω-3-PL/FFA had no significant effect at 12 weeks on mean treatment differences for non-HDL-C (-3.2% [95% CI, -8.0% to 1.6%]; P = .18), VLDL-C (-3.8% [95% CI, -12.2% to 4.7%]; P = .38), HDL-C (0.7% [95% CI, -3.7% to 5.1%]; P = .77), or LDL-C (4.5% [95% CI, -5.9% to 14.8%]; P = .40) levels; corresponding differences at 26 weeks were -5.8% (95% CI, -11.3% to -0.3%; P = .04) for non-HDL-C levels, -9.1% (95% CI, -21.5% to 3.2%; P = .15) for VLDL-C levels, 1.9% (95% CI, -4.8% to 8.6%; P = .57) for HDL-C levels, and 6.3% (95% CI, -12.4% to 25.0%; P = .51) for LDL-C levels. Effects on the primary end point did not vary significantly by age, sex, race and ethnicity, country, qualifying TG level, diabetes, or fibrate use but tended to be larger among patients taking statins or cholesterol absorption inhibitors at baseline (mean treatment difference, -19.5% [95% CI, -34.5% to -4.6%]; P = .08 for interaction) and with lower (less than median) baseline blood eicosapentaenoic acid plus docosahexaenoic acid levels (-19.5% [95% CI, -33.8% to -5.3%]; P = .08 for interaction). ω-3-PL/FFA was well tolerated, with a safety profile similar to that of placebo. This study found that ω-3 -PL/FFA, a novel krill oil-derived ω-3 formulation, reduced TG levels and was safe and well tolerated in patients with severe hypertriglyceridemia. ClinicalTrials.gov Identifiers: NCT03398005 and NCT03361501.

Therapeutic effectiveness of an intestinal cholesterol absorption inhibitor in ambulatory treatmentof patients with dislipidemy of middle and moderate cardiovascular risk

Therapeutic effectiveness of an intestinal cholesterol absorption inhibitor in ambulatory treatmentof patients with dislipidemy of middle and moderate cardiovascular risk

The physiological and pharmacological effects of Ziziphoratenuior L.: A review study.

Objective:Many reports have revealed preventive and therapeutic effects of Ziziphoratenuior; however, few systematic reviews have evaluated such effects. The present study reviews the physiological and pharmacological effects of Z. tenuior extract and its components.Materials and Methods:English articles were searched in international databases, such as Embase, Scopus, and PubMed; Persian studies were also searched in national databases such as SID and Magiran. Results:Pulegone is one of the most important effective compounds of Z. tenuior, which has analgesic, anti-inflammatory, and anti-stress properties as it affects serotonergic and opioidergic systems and decreases the gastric acid secretion. Moreover, this compound inhibits cholesterol absorption and synthesis, resulting in hyperlipidemic effects and weight loss. In addition to its antioxidant, antitumor, and antibacterial properties, this herb contains an antidiabetic effect mediated by increasing the number of pancreatic beta cells and insulin secretion, and inhibiting alpha-amylase. Although its effective dosage has no side effects, the overuse of its effective compounds, such as pulegone, may raise some liver and pulmonary disorders.Conclusion: Z. tenuior and its extract can have preventive and therapeutic effects on diabetes and hyperlipidemia-associated diseases. Since most studies on this herb were in vivo, it is necessary to design clinical trials to evaluate its effects.

Cholesterol absorption blocker ezetimibe prevents muscle wasting in severe dysferlin-deficient and mdx mice.

BackgroundMuscular dystrophy (MD) causes muscle wasting and is often lethal in patients due to a lack of proven therapies. In contrast, mouse models of MD are notoriously mild. We have previously shown severe human‐like muscle pathology in mdx [Duchenne MD (DMD)] and dysferlin‐deficient limb‐girdle MD type 2B (LGMD2B) mice by inactivating the gene encoding for apolipoprotein E (ApoE), a lipid transporter synthesized by the liver, brain and adipocytes to regulate lipid and fat metabolism. Having recently established that human DMD is a novel type of primary genetic dyslipidaemia with elevated cholesterol, we sought to determine whether cholesterol could exacerbate the muscle wasting process observed in severe rodent MD.MethodsSevere mdx and dysferlin knock‐out mice lacking ApoE were treated with ezetimibe (15 mg/kg/day), a clinically approved drug exhibiting few pleiotropic effects. In separate studies, dietary cholesterol was raised (from 0.2% to 2% cholesterol) in combination with experimental micro‐injury and direct cholesterol injection assays. Muscles were assessed histologically for changes in collagen and adipocyte infiltration and both transcriptomic and cellular changes by RNA‐seq and fluorescence‐activated cell sorting analysis.ResultsTreatment of severe DMD and LGMD2B mice with ezetimibe completely prevented clinical signs of ambulatory dysfunction (0% incidence vs. 33% for vehicle treatment; P < 0.05). Histological analyses revealed that ezetimibe‐reduced fibro‐fatty infiltration up to 84% and 63% in severely affected triceps (P ≤ 0.0001) and gastrocnemius (P ≤ 0.003) muscles, resulting in a respective 1.9‐fold and 2.2‐fold retention of healthy myofibre area (P ≤ 0.0001). Additionally, raising dietary cholesterol and thus concentrations of plasma low‐density lipoprotein‐associated cholesterol (by 250%; P < 0.0001) reduced overall survivability (by 100%; P < 0.001) and worsened muscle damage in the LGMD2B triceps by 767% (P < 0.03). Micro‐pin‐induced mechanical injury in LGMD2B mice fed a high cholesterol diet exacerbated muscle damage by 425% (P < 0.03) and increased macrophage recruitment (by 98%; P = 0.03) compared with those injured on a chow diet. Parallel RNA‐seq analyses revealed that injury in cholesterol‐fed mice also modulated the expression of 3671 transcripts (1953 up‐regulated), with fibrogenic, inflammatory and programmed cell death‐associated pathways among the most enriched. Mice lacking dysferlin also displayed heightened muscle necrosis (by 123%; P < 0.0001) following a direct intramuscular injection of cholesterol compared with control mice.ConclusionsCholesterol exacerbates rodent MD. Specific inhibition of cholesterol absorption with ezetimibe may safely attenuate human MD severity and delay death.

Flaxseed-derived peptide, IPPF, inhibits intestinal cholesterol absorption in Caco-2 cells and hepatic cholesterol synthesis in HepG2 cells.

Flaxseed peptides reduced serum cholesterol levels in Sprague-Dawley rats fed with a high-cholesterol diet. However, the mechanism of this action remains unclear. Flaxseed-hydrolyzed proteins were separated through ultrafiltration. The fifth fraction (FP5 , ≤ 1kDa) had the highest cholesterol micelle solubility inhibition rate (CMSR) of 72.39% among the other fractions. Eleven peptides were identified from FP5 . Ile-Pro-Pro-Phe (IPPF), which had the highest CMSR of 93.47%, was selected for further analyses. IPPF substantially reduced the cholesterol transported content in Caco-2 cells and the total cholesterol content in HepG2 cells. Moreover, IPPF modulated the protein levels of NCP1L1 and ABCG5/8 (cholesterol transporters) in Caco-2 cells and reduced the mRNA levels of Srebp-2 and Hmgcr (cholesterol synthesis enzymes) in HepG2 cells. IPPF inhibits cholesterol intestinal absorption by modulating the cholesterol transporters expression and reduces hepatic cholesterol synthesis by inhibiting the SREBP2-regulated mevalonate pathway. IPPF is a new food-derived cholesterol-lowering nutritional supplement. PRACTICAL APPLICATIONS: We isolated active peptides with cholesterol-lowering properties from flaxseed protein, a by-product of industrial oil production, which greatly improved the economic and medicinal value of flaxseed protein. According to our research, IPPF can be used as a new food-derived type of cholesterol intestinal absorption inhibitor to reduce dietary cholesterol absorption and cholesterol synthesis inhibitor (same pharmacological mechanism as statins). IPPF provide a nutritional therapy component for hypercholesterolemia and prevent atherosclerosis. Our research provides theoretical basis for development and utilization of new nutritional supplements and plant proteins.

NPC1L1 Deficiency Suppresses Ileal Fibroblast Growth Factor 15 Expression and Increases Bile Acid Pool Size in High-Fat-Diet-Fed Mice.

Niemann–Pick C1-like 1 (NPC1L1) mediates intestinal uptake of dietary and biliary cholesterol and is the target of ezetimibe, a cholesterol absorption inhibitor used to treat hypercholesterolemia. Genetic deletion of NPC1L1 or ezetimibe treatment protects mice from high-fat diet (HFD)-induced obesity; however, the molecular mechanisms responsible for this therapeutic benefit remain unknown. A major metabolic fate of cholesterol is its conversion to bile acids. We found that NPC1L1 knockout (L1-KO) mice fed an HFD had increased energy expenditure, bile acid pool size, and fecal bile acid excretion rates. The elevated bile acid pool in the HFD-fed L1-KO mice was enriched with tauro-β-muricholic acid. These changes in the L1-KO mice were associated with reduced ileal mRNA expression of fibroblast growth factor 15 (FGF15) and increased hepatic mRNA expression of cholesterol 7α-hydroxylase (Cyp7A1) and mitochondrial sterol 27-hydroxylase (Cyp27A1). In addition, mRNA expression of the membrane bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and type 2 iodothyronine deiodinase (Dio2) were elevated in brown adipose tissue of L1-KO mice, which is known to promote energy expenditure. Thus, altered bile acid homeostasis and signaling may play a role in protecting L1-KO mice against HFD-induced obesity.

Sexual dimorphism in intestinal absorption and lymphatic transport of dietary lipids.

Although the basic process of intestinal lipid absorption and transport is understood, many critical aspects remain unclear. One question in particular is whether intestinal lipid absorption and transport differ between the sexes. Using a well-established lymph fistula model, we found that intact female mice exhibited lower lymphatic output of triacylglycerol (TAG) than male mice. Further analysis revealed that the female mice segregated into two groups: the high group having similar lymphatic TAG transport to the males, and the low group having significantly less lymphatic output, implying the impact of cyclical variation of ovarian hormonal levels. These led us to examine whether oestradiol (E2) and progesterone (P) affect intestinal absorption and lymphatic transport of dietary lipids. In ovariectomized (OVX) rats, E2 treatment significantly reduced [3 H]-TAG lymphatic output through reducing TAG transport; and P treatment decreased [14 C]cholesterol (Chol) lymphatic output by inhibiting Chol absorption, compared to vehicle treatment. Gene expression data suggested that E2 enhances vascular endothelial growth factor-A (VEGF-A) signalling to reduce the permeability of lacteals, leading to reduced CM transport through the lymphatic system. Interestingly, E2 treatment also increased lymphatic output of apolipoprotein A-I (apoA-I), but not apoB-48 and apoA-IV, in the OVX rats. Collectively, these data suggested that ovarian hormone-induced reductions of intestinal lipid absorption and lymphatic transport, as well as increased lymphatic output of apoA-I, may contribute to a beneficial protection from atherosclerosis in females. KEY POINTS: Significant differences in intestinal lipid absorption and lymphatic transport were found between female and male animals. Oestrogen treatment significantly reduced [3 H]triacylglycerol (TAG) lymphatic output through suppressing TAG transport in ovariectomized (OVX) rats, and this effect is associated with enhanced vegfa gene expression in the intestine. Progesterone treatment significantly decreased the output of [14 C]cholesterol in lymph by inhibiting cholesterol absorption in the OVX rats. Oestrogen treatment also increased lymphatic output of apolipoprotein A-I (apoA-I) in the OVX rats, which may contribute to the reduced risk of atherosclerosis in females.

Lipid lowering in patients 75 years and older.

More than twenty years ago, knowledge about the importance of cholesterol absorption and the potential therapeutic effect of its inhibition led to the discovery and clinical application of the first and only cholesterol absorption inhibitor to date – ezetimibe. Since then, ezetimibe has become a well-recognized player in lipid-lowering therapy. Recent findings of IMPROVE-IT and EWTOPIA 75 imply that elderly patients over the age of 75 years in particular benefit from ezetimibe. This review summarizes the evidence, discusses the possible underlying pathophysiological mechanisms and calls for a change in future dyslipidemia guidelines.

Lactobacillus mediates the expression of NPC1L1, CYP7A1, and ABCG5 genes to regulate cholesterol.

Hypercholesterolemia is the main cause of cardiovascular disease worldwide, and the regulation of cholesterol homeostasis is essential for human health. Lactobacillus is present in large quantities in the human intestine. As the normal flora in the gut, lactobacillus plays an important role in regulating metabolism in the human body. Lactobacillus can regulate the cholesterol content by regulating the expression of genes involved in cholesterol synthesis, metabolism, and absorption. This article reviews the biological effects and mechanisms of lactobacillus that mediate the expression of NPC1L1, CYP7A1, ABCG5, ABCG8, and other genes to inhibit cholesterol absorption, and discusses the mechanism of reducing cholesterol by lactobacillus in cells in vitro, to provide a theoretical basis for the development and utilization of lactobacillus resources.

Oxidized Low-Density Lipoprotein Links Hypercholesterolemia and Bladder Cancer Aggressiveness by Promoting Cancer Stemness.

Hypercholesterolemia is a prevalent metabolic disorder that has been implicated in the development of steroid-targeted cancers. However, the link between hypercholesterolemia and urinary bladder cancer (UBC), a non-steroid-targeted cancer, remains unresolved. Here we show that diet-induced and Ldlr deficiency-induced hypercholesterolemia enhances both UBC stemness and progression. Inhibition of intestinal cholesterol absorption by ezetimibe reversed diet-induced hypercholesterolemia and cancer stemness. As a key component in hypercholesterolemic sera, oxidized low-density lipoprotein (ox-LDL), but not native low-density lipoprotein-cholesterol or metabolite 27-hydroxycholesterol, increased cancer stemness through its receptor CD36. Depletion of CD36, ectopic expression of an ox-LDL binding-disabled mutant form of CD36(K164A), and the neutralization of ox-LDL and CD36 via neutralizing antibodies all reversed ox-LDL-induced cancer stemness. Mechanistically, ox-LDL enhanced the interaction of CD36 and JAK2, inducing phosphorylation of JAK2 and subsequently activating STAT3 signaling, which was not mediated by JAK1 or Src in UBC cells. Finally, ox-LDL levels in serum predicted poor prognosis, and the ox-LDLhigh signature predicted worse survival in patients with UBC. These findings indicate that ox-LDL links hypercholesterolemia with UBC progression by enhancing cancer stemness. Lowering serum ox-LDL or targeting the CD36/JAK2/STAT3 axis might serve as a potential therapeutic strategy for UBCs with hypercholesterolemia. Moreover, elevated ox-LDL may serve as a biomarker for UBC. SIGNIFICANCE: This study demonstrates how hypercholesterolemia-induced oxidized LDL promotes urinary bladder cancer stemness via a CD36/STAT3 signaling axis, highlighting these factors as biomarkers and potential therapeutic targets of aggressive disease.

Lipids-lowering effects of equol on low density lipoprotein receptor knockout hamsters

Used low density lipoprotein receptor knockout(LDLR KO) hamster as the model similar to human dyslipidemia to observe the lipid-lowering effect of equol on heterozygotes. With soy-free high cholesterol high fat diet, 12-week-old LDLR KO female heterozygous hamsters were randomly divided into negative control group(no addition), positive control group(add 0.004% ezetimibe), genistein group(add 0.1%), and low, medium and high-dose groups of equol(add 0.025%, 0.05%, 0.1% respectively). Body weight, food consumption and blood lipid were continuously monitored for 12 weeks after feeding each group. Finally, liver morphology and lipid metabolism related genes expressions were checked. There was no significant difference in body weight and average weekly food intake among the groups. The blood lipids in negative control group increased over time, and the cholesterol and triglyceride levels of LDLR KO heterozygous hamsters were significantly reduced by ezetimibe in the second week, while the high-density lipoprotein cholesterol was also significantly decreased. The lipid-lowering effects of genistein and equol were weaker than ezetimibe, and there was significant difference between the two groups after 12 weeks, but the decrease of HDL-c was not as significant as ezetimibe. Compared with genistein, the effect of medium and high dose equol was stronger. At 12 weeks, the liver weight ratio also decreased significantly, and the liver lipid accumulation was inhibited, especially in the high dose of equol. The expression of ApoAI, SREBP-2 and HMGCR were significantly up-regulated by equol and genistein. Equol could reduce female LDLR KO hamster blood lipid. It may play a role in lipid lowering by inhibiting cholesterol absorption besides estrogen receptor pathway, but it is weaker than NPC1 L1 inhibitor. At the same time, up-regulation of ApoAI inhibits the decrease of high-density lipoprotein and reduces lipid accumulation in liver.

Digestion and Absorption of Milk Phospholipids in Newborns and Adults.

Milk polar lipids provide choline, ethanolamine, and polyunsaturated fatty acids, which are needed for the growth and plasticity of the tissues in a suckling child. They may also inhibit cholesterol absorption by interacting with cholesterol during micelle formation. They may also have beneficial luminal, mucosal, and metabolic effects in both the neonate and the adult. The milk fat globule membrane contains large proportions of sphingomyelin (SM), phosphatidylcholine (PC), and phosphatidylethanolamine (PE), and some phosphatidylserine (PS), phosphatidylinositol (PI), and glycosphingolipids. Large-scale technical procedures are available for the enrichment of milk fat globule membrane (MFGM) in milk replacement formulations and food additives. Pancreatic phospholipase A2 (PLA2) and mucosal phospholipase B digest glycero-phospholipids in the adult. In the neonate, where these enzymes may be poorly expressed, pancreatic lipase-related protein 2 probably has a more important role. Mucosal alkaline SM-ase and ceramidase catalyze the digestion of SM in both the neonate and the adult. In the mucosa, the sphingosine is converted into sphingosine-1-phosphate, which is both an intermediate in the conversion to palmitic acid and a signaling molecule. This reaction sequence also generates ethanolamine. Here, we summarize the pathways by which digestion and absorption may be linked to the biological effects of milk polar lipids. In addition to the inhibition of cholesterol absorption and the generation of lipid signals in the gut, the utilization of absorbed choline and ethanolamine for mucosal and hepatic phospholipid synthesis and the acylation of absorbed lyso-PC with polyunsaturated fatty acids to chylomicron and mucosal phospholipids are important.

Hyperlipidemia Condition and Novel-Drug Therapies: A Overall Study

Hyperlipidaemia is an condition that increases the chance of coronary heart disease (CHD) and atherosclerotic disease (ASHD) in blood vessels. Hyperlipidaemia occurs in response to smoking, obesity, sedentary lifestyle, and other risk factors to extend CHD. Cardiovascular disease (CVD) is the reason for death.&#x0D; Hyperlipidaemia is divided into two broad classifications: Primary (familial) and Secondary (acquired).&#x0D; Primary hyperlipidemia has been generated by hereditary defects and climatic factors or by undisclosed mechanisms. Secondary hyperlipidemia concern to the metabolic disorders linked with the diabetes mellitus, liver complication, thyroid, and kidney complications. Hyperlipidemia also refers to as elevated levels of lipids within the blood. Circulating lipid are carried in lipoproteins that transport the lipids to varied tissues for energy use, lipid deposition, hormone production, and steroid formation. The lipoprotein consists of esterified and unesterified cholesterol, triglycerides, phospholipids, and protein. The general public who have hyperlipidemia experience no symptoms. Hyperlipidemia is most oftenly correlated with high-fat diets, a stationary lifestyle, obesity and diabetes mellitus. Four different classes of cholesterol-lowering drugs namely, statins, niacin, resins, and fibrates are available to treat hyperlipidemia; however, statins are now considered to be the first line therapy. The preventable causes of hyperlipidemia can include: Smoking, Being overweight, Physical inactivity, Steroid use, Alcohol consumption &amp; Diet high in saturated fat, &amp; cholesterol such as cheese, meat, fried &amp; processed foods and egg yolk. The treatment of hyperlipidemia includes statins, bile acid sequestrants, fibric acids, niacin, and cholesterol absorption inhibitors.&#x0D; There are some of the novel drugs which are selected for the treatment of hyperlipidemia which includes: Evolocumab, Alirocumab, Bempedoic acid, Lomitapide, Evinacumab, and Sebelipase alfa.

Efficacy evaluation of PCSK9 monoclonal antibody (Evolocumab) in combination with Rosuvastatin and Ezetimibe on cholesterol levels in patients with coronary heart disease (CHD): A retrospective analysis from a single center in China

Background and purposeProprotein convertase subtilisin-kexin type 9(PCSK9) monoclonal antibody (Mab; Evolocumab) has been reported to inhibit low-density lipoprotein cholesterol (LDL-C) and Lipoprotein(a) [LP(a)] in coronary heart diseases (CHD) patients in America, Europe and Japan. However, little is known about the effect of Evolocumab in Chinese population. This retrospective study in Chinese CHD patients compared the efficacy without or with Evolocumab therapy added to the conventional treatment with a statin (Rosuvastatin) and a gut cholesterol absorption inhibitor (Ezetimibe). MethodsCHD patients from our hospital were divided into three therapeutic groups, A) the statin monotherapy group (10 mg Rosuvastatin every night); B) the statin/cholesterol absorption inhibitor group (10 mg Rosuvastatin and 10 mg Ezetimibe daily); and C) the triple therapy with PCSK9 Mab group (10 mg Rosuvastatin daily, 10 mg Ezetimibe daily, and 140 mg Evolocumab once 2 weeks). The plasma lipid data were collected at 0, 4, 12, and 24 Week(s). The Graphpad Prism 7 program was used to perform all the statistical analysis. ResultsOut of 103 patients 91 were eligible for further evaluation with 31 in group A, 31 in group B, and 29 in group C. The plasma LDL-C levels were reduced only by 33.82% in the Rosuvastatin monotherapy group, 52.13% in the Rosuvastatin/Ezetimibe group, and 73.59% in the Evolocumab/Rosuvastatin/Ezetimibe group (P < 0.0001) at 24 weeks compared to the prior therapy levels. Neither the statin therapy alone (5.95%; P = 0.6), nor the double therapy (5.27%; P = 0.7) affected LP(a) levels. In contrast, addition of Evolocumab to the double therapy significantly decreased LP(a) level by 37.2% (P < 0.0001). ConclusionAddition of Evolocumab to the standard double therapy in Chinese CHD patients improved the efficacy in LDL-C reduction when compared to Rosuvastatin alone or in Rosuvastatin/Ezetimibe double therapy. Furthermore, the addition of Evolocumab lowered LP(a) level in Chinese CHD patients.

Dietary intake of plant sterols in cardiovascular diseases: a population-based study of Polish adults

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute of Cardiology, Warsaw, Poland Introduction. Cardiovascular diseases (CVD) are a major cause of premature mortality and disability in developed countries. Among various risk factors, disorders of lipid metabolism are prevalent. Scientific evidence shows that plant sterols have a positive effect on dyslipidemia. The primary mechanism of hypolipemic effect of plant sterols is inhibition of cholesterol absorption in the small intestine, and this effect depends on the dose. Purpose. The aim of the study was to determine the intake of plant sterols, which was never studied in the Polish population. Methods. In total, 5690 participants of the population-based cross-sectional Polish National Multicenter Health Examination Survey WOBASZ II (2013-2014), aged 20+, were evaluated in the study (1). Nutritional data were collected using a single 24-hour dietary recall method. A dietary plant sterol database was compiled from available experimental data including total and individual plant sterols such as β-sitosterol, campesterol and stigmasterol. Plant sterol intakes were calculated taking into account plant sterol contents in individual food products and the volume of food consumption. Statistical calculations were performed using Statistical Analysis System (SAS), version 9.4 (SAS Institute Inc., Cary, NC, USA). Results. The dietary plant sterol intake (DPSI) for the general population, 283 mg/day, was dependent on the age and gender. The intake of sterols among people over 65 years of age (264 mg/day in men and 208 mg/day in women) was lower than in younger age groups (20-44 years) of participants (343 mg/day in men and 259 mg/day in women). The main dietary plant sterol for both genders was β-sitosterol (∼62% of intake), followed by campesterol (∼21%) and stigmasterol (∼9%). Overall, men and women with cardiovascular disease had significantly lower DPSI (p &amp;gt; 0.002) than men and women without cardiovascular disease, 298.6 and 237.8 vs. 326.1 and 255.9 mg/d, respectively, and men but not women with diabetes had significantly (p &amp;gt; 0.04) lower DPSI than men without diabetes, 301.7 vs. 323.3, respectively. Conclusions. In the view of current recommendations to lower cholesterol, this research confirms findings for other populations, that the dietary intake of plant sterols in the Polish population is insufficient to beneficially modulate lipid metabolism, especially in CVD and diabetic patients.