Regulates Blood Cholesterol Research Articles

2′, 3′, 5′-tri-O-acetyl-N6-(3-hydroxyphenyl) adenosine alleviates diet-induced hyperlipidemia by modulating intestinal gene expression profiles and metabolic pathway

There is a growing body of evidence suggesting that the composition of intestinal flora plays a significant role in regulating lipid metabolism. 2′, 3′, 5′-tri-O-acetyl-N6-(3-hydroxyphenyl) adenosine (IMMH007) is a new candidate compound for regulating blood cholesterol and other lipids. In this study, we conducted metagenomic and metabolomic analyses on samples from high-fat diet-fed (HFD) hamsters treated with IMMH007. Our findings revealed that IMM-H007 reversed the imbalance of gut microbiota caused by a high-fat diet. Additionally, it activated adiponectin receptor and pantothenate and CoA biosynthesis pathway-related genes, which are known to regulate lipid and glucose metabolism. Furthermore, IMM-H007 promotes cholesterol metabolism by reducing the abundance of genes and species associated with 7α-dehydroxylation and bile salt hydrolase (BSH). Metabolomics and pharmacological studies have shown that IMM-H007 effectively improved glucose and lipid metabolism disorders caused by HFD, reduced the aggregation of secondary bile acids (SBAs), significantly increased the content of hyodeoxycholic acid (HDCA), and also activated the expression of VDR in the small intestine. As a result, there was a reduction in the leakage of diamine oxidase (DAO) into the bloodstream in hamsters, accompanied by an upregulation of ZO-1 expression in the small intestine. The results suggested that IMM-H007 regulated glucose and lipid metabolism, promoted cholesterol metabolism through activating the expression of VDR, inhibiting inflammatory and improving the permeability of the intestinal barrier. Thus, our study provides new understanding of how IMM-H007 interacts with intestinal function, microbiota, and relevant targets, shedding light on its mechanism of action.

Human Genetics and Dyslipidemia: From Non-synonymous Variants to Non-coding Variants

Dyslipidemia has strong heritability, with over 50% of dyslipidemia is caused by genetics in general population. Previously studies identify many non-synonymous variants in genes of LDLR, PCSK9, ANGPTL3, ABCG5/8, ARH et.al, which lay the fundation for durg development. However, these known non-synonymous variants can only explain about 10-20% of genetic risks. Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with dyslipidemia in large population. However, about 95% of these variants are located in genome noncoding regions and cluster in different loci. The disease-causing variant for each locus and underline mechanism remain largely unknown. We systematically analyzed these noncoding variants and found that rs1997243 is the disease-causing variant in locus 7p22, which is strongly associated with hypercholesterolemia. The rs1997243 risk allele is associated with increased expression of GPR146 in human and specifically up regulates GPR146 expression in cultured hepatocytes. GPR146 is an orphan G-protein coupled receptor that is located on plasma membrane and responses to stimulation of heat-inactivated serum. Disrupting gpr146 specifically in the liver decreases the blood cholesterol level and prevents high-fat or high-fat high-cholesterol diets induced hypercholesterolemia in mice. Mechanistic study suggests that GPR146 regulates blood cholesterol level mainly through regulating the catabolism of cholesterol rich lipoprotein particles. Thus we uncovered a novel G-protein coupled receptor that regulates blood cholesterol levels in both humans and mice. Our results also suggest that antagonizing GPR146 function will be an effective strategy to treat hypercholesterolemia. National Key Research and Development Program of China (2018YFA0800700), the National Natural Science Foundation of China (92057207, 91754101, 32021003, 31771304) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Reduction of Cardiovascular Risk Using Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors in Patients With Acute Coronary Syndrome: A Systematic Review.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a hepatic enzyme that regulates blood cholesterol levels by degrading low-density lipoprotein (LDL) receptors from the surface of hepatocytes. Studies have shown that inhibiting this molecule decreases the cardiovascularrisk in individuals with atherosclerotic cardiovascular disease (ASCVD)by lowering low-density lipoprotein cholesterol (LDL-C). Two major cardiovascular outcome trials showed that the use of the PCSK9 inhibitors (alirocumab and evolocumab) in patients with recent acute coronary syndrome (ACS) is associated with a lower risk of further cardiovascular (CV) events. Information regarding the use of these monoclonal antibodies for primary prevention has also been reported by these trials. The goal of this systematic review is to describe the mechanism of PCSK9 inhibitors and further discuss their ability to reduce CV risk in high-risk populations. The search strategy was used in a systematic way using PubMed Central, Google Scholar, and ScienceDirect. We included randomized control trials (RCTs), systematic reviews, and narrative reviews in English published in the last five years. Observational studies,case reports, and case studies were excluded. The quality of the studies was evaluated using the Cochrane Collaboration Risk of Bias Tool, Assessment of Multiple Systematic Reviews 2, and Scale for the Assessment of Narrative Review Articles. A total of 10 articles were included in this systematic review. These included an RCT, a systematic review, and eight narrative reviews. Our study suggested that adding PCSK9 inhibitors to background statin therapy for selected patients with high-risk factors demonstrated substantial benefits in reducing overall CV morbidity and mortality after ACS. Multiple studies have demonstrated the short-term safety of low LDL-C levels caused by these drugs. However, long-term safety must be assessed with further studies.

Concentrations of Phenolic Acids Are Differently Genetically Determined in Leaves, Flowers, and Grain of Common Buckwheat (Fagopyrum esculentum Moench).

Common buckwheat (Fagopyrum esculentum Moench) is a valuable source of proteins, B vitamins, manganese, tryptophan, phytochemicals with an antioxidant effect, and the natural flavonoid rutin. Due to its composition, buckwheat supports the human immune system, regulates blood cholesterol, and is suitable for patients with diabetes or celiac disease. The study aimed to compare the allocation of selected phenolic acids (neochlorogenic acid, chlorogenic acid, trans-caffeic acid, trans-p-coumaric acid, trans-sinapic acid, trans-ferulic acid) and flavonoids (rutin, vitexin, quercetin, kaempferol) in the leaves, flowers, and grain of buckwheat cultivars of different origin. The content of individual phenolics was determined by the HPLC-DAD method. The results confirmed the determining role of cultivar on the relative content of chlorogenic acid, trans-caffeic acid, trans-sinapic acid, vitexin, and kaempferol in buckwheat plants. A significantly negative correlation among concentrations of phenolic acids in different common buckwheat plant parts shows that there are different mechanisms of genetic influences on the concentration of phenolic substances in common buckwheat flowers, leaves, and grain. These differences should be taken into account when breeding buckwheat for a high concentration of selected phenolic substances.

PCSK9 and LRP5 in macrophage lipid internalization and inflammation

Atherosclerosis, the leading cause of cardiovascular diseases, is driven by high blood cholesterol levels and chronic inflammation. Low-density lipoprotein receptors (LDLR) play a critical role in regulating blood cholesterol levels by binding to and clearing LDLs from the circulation. The disruption of the interaction between proprotein convertase subtilisin/kexin 9 (PCSK9) and LDLR reduces blood cholesterol levels. It is not well known whether other members of the LDLR superfamily may be targets of PCSK9. The aim of this work was to determine if LDLR-related protein 5 (LRP5) is a PCSK9 target and to study the role of PCSK9 and LRP5 in foam cell formation and lipid accumulation. Primary cultures of human inflammatory cells (monocytes and macrophages) were silenced for LRP5 or PCSK9 and challenged with LDLs. We first show that LRP5 is needed for macrophage lipid uptake since LRP5-silenced macrophages show less intracellular CE accumulation. In macrophages, internalization of LRP5-bound LDL is already highly evident after 5 h of LDL incubation and lasts up to 24 h; however, in the absence of both LRP5 and PCSK9, there is a strong reduction of CE accumulation indicating a role for both proteins in lipid uptake. Immunoprecipitation experiments show that LRP5 forms a complex with PCSK9 in lipid-loaded macrophages. Finally, PCSK9 participates in TLR4/NFkB signalling; a decreased TLR4 protein expression levels and a decreased nuclear translocation of NFκB were detected in PCSK9 silenced cells after lipid loading, indicating a downregulation of the TLR4/NFκB pathway. Our results show that both LRP5 and PCSK9 participate in lipid uptake in macrophages. In the absence of LRP5, there is a reduced release of PCSK9 indicating that LRP5 also participates in the mechanism of release of soluble PCSK9. Furthermore, PCSK9 up-regulates TLR4/NFκB favouring inflammation.

Momordica charantia: A natural medicinal plant

Natural products play an important role in the treatment of several diseases inflicted on mankind and in drug discovery procedures. Drugs synthesized from naturally available products are usually safe, cheap in cost, easily available and more effective than pure synthetic drugs in the treatment of several diseases. Bitter melon containing numerous bioactive compounds like saponins, alkaloids, polypeptides, minerals, vitamins, with the ability to fight against several disorders, i.e. diabetes mellitus, abdominal pain, tumor proliferation, cancer, kidney (stone), scabies and fever. The key constituent of BM called charantin, which is steroidal saponins, act like peptides and certain alkaloids that control sugar levels in blood. The medicinal properties of M.charantia are beneficial in regulating blood cholesterol to minimise cardiovascular disorders like atherosclerosis. There are several classes of secondary metabolites, such as tannins, flavonoids, and alkaloids in the fresh and dried leaves extracts of Bitter melon with antimicrobial activity. This phytochemical composition of both the leaves reported antimicrobial activity against different bacteria, like Salmonella, E. coli, Pseudomonas aeruginosa, Bacillus and Streptococcus.

Identification and characterization of prescription drugs that change levels of 7-dehydrocholesterol and desmosterol

Regulating blood cholesterol (Chol) levels by pharmacotherapy has successfully improved cardiovascular health. There is growing interest in the role of Chol precursors in the treatment of diseases. One sterol precursor, desmosterol (Des), is a potential pharmacological target for inflammatory and neurodegenerative disorders. However, elevating levels of the precursor 7-dehydrocholesterol (7-DHC) by inhibiting the enzyme 7-dehydrocholesterol reductase is linked to teratogenic outcomes. Thus, altering the sterol profile may either increase risk toward an adverse outcome or confer therapeutic benefit depending on the metabolite affected by the pharmacophore. In order to characterize any unknown activity of drugs on Chol biosynthesis, a chemical library of Food and Drug Administration-approved drugs was screened for the potential to modulate 7-DHC or Des levels in a neural cell line. Over 20% of the collection was shown to impact Chol biosynthesis, including 75 compounds that alter 7-DHC levels and 49 that modulate Des levels. Evidence is provided that three tyrosine kinase inhibitors, imatinib, ponatinib, and masitinib, elevate Des levels as well as other substrates of 24-dehydrocholesterol reductase, the enzyme responsible for converting Des to Chol. Additionally, the mechanism of action for ponatinib and masitinib was explored, demonstrating that protein levels are decreased as a result of treatment with these drugs.

Regulatory effects of glycyrrhizae radix extract on DSS-induced ulcerative colitis.

BackgroundGlycyrrhizae Radix (GR) is a Korean traditional herb medicine that is widely-used in clinical health care. The clinical functions of GR include relief of toxicity, anti-cancer, regulating blood cholesterol and anti-inflammation. This study investigated the role of GR on ulcerative colitis in a dextran sulfate sodium (DSS)-induced mouse model of colitis.MethodWestern blot analysis and enzyme-linked immunosorbent assay (ELISA) analyses were done on male BALB/c mice administered 5 % DSS during the experimental period. Ethanol extracts of GR were orally administered at same time daily to control mice. The severity of colitis was measured by body weight change and colon length.ResultDSS-treated mice displayed weight loss and shortened colon length compared with control mice. Mice were administered GR showed less weight loss and longer colon length than the DSS-treated group. Inflammatory cytokines were decreased by GR treatment. Treatment also reduced DSS-induced microscopic damage to colon tissue. GR regulated the phosphorylation of transcription factors such as NF-κB p65 and IκB α.ConclusionsGR has beneficial effects in a colitis model. GR might be a useful herb medicine in the treatment of ulcerative colitis.

Oral administration of a Ketone Ester regulates blood cholesterol in rats and humans

Control of cholesterol in Type 2 Diabetics and Pre‐diabetics has been problematic as statins increase blood glucose. We propose that a unique β‐hydroxybutyrate (βHB) Ester can provide non‐lipogenic calories and decrease cholesterol synthesis without increasing glucose. The ketone bodies, βHB and Acetoacetate, can be metabolized by most tissues, but not liver, limiting cholesterol precursors. In humans, a single meal containing this ketone ester (KE) dose dependently decreased plasma mevalonate, a marker for cholesterol synthesis, without directly inhibiting HMG‐CoA Reductase. After two days of KE, rats had 31% lower plasma cholesterol and 26% lower mevalonate than controls. In a 30 day study, KE fed rats had lower plasma total cholesterol (‐40%) and mevalonate (‐27%) than controls. Levels of mevalonate precursors, Acetoacetyl‐CoA and HMG‐CoA were lower by 33% and 54% respectively, but Acetyl‐CoA was unaffected. Low liver cholesterol increases absorption of cholesterol through the Low Density Lipoprotein receptor (LDL‐R), KE feeding increased LDL‐R levels in whole cell (+24%) and membrane preparations (+67%). KE fed animals had increased protein levels of SREBP‐2, a key transcriptional activator of LDL‐R, both full length and transcriptionally active forms increased, by 91% and 140%. A 5 day study of KE effect on cholesterol in human Type 2 Diabetics showed not only lower total cholesterol (‐10%) but also lower fasting glucose (‐17%) and Triglycerides (‐18%). We report preliminary findings that KE decreases cholesterol and its synthetic precursors while decreasing fasting blood glucose and triglycerides.

Activation of CXCR7 Limits Atherosclerosis and Improves Hyperlipidemia by Increasing Cholesterol Uptake in Adipose Tissue

The aim of this study was to determine the role of the chemokine receptor CXCR7 in atherosclerosis and vascular remodeling. CXCR7 is the alternative receptor of CXCL12, which regulates stem cell-mediated vascular repair and limits atherosclerosis via its receptor, CXCR4. Wire-induced injury of the carotid artery was performed in mice with a ubiquitous, conditional deletion of CXCR7 and in mice treated with the synthetic CXCR7 ligand CCX771. The effect of CCX771 treatment on atherosclerosis was studied in apolipoprotein E-deficient (Apoe(-/-)) mice fed a high-fat diet for 12 weeks. Lipoprotein fractions were quantified in the plasma of Apoe(-/-) mice by fast protein liquid chromatography. Uptake of DiI-labeled very low-density lipoprotein to adipose tissue was determined by 2-photon microscopy. We show that genetic deficiency of Cxcr7 increased neointima formation and lesional macrophage accumulation in hyperlipidemic mice after vascular injury. This was related to increased serum cholesterol levels and subsequent hyperlipidemia-induced monocytosis. Conversely, administration of the CXCR7 ligand CCX771 to Apoe(-/-) mice inhibited lesion formation and ameliorated hyperlipidemia after vascular injury and during atherosclerosis. Treatment with CCX771 reduced circulating very low-density lipoprotein levels but not low-density lipoprotein or high-density lipoprotein levels and increased uptake of very low-density lipoprotein into Cxcr7-expressing white adipose tissue. This effect of CCX771 was associated with an enhanced lipase activity and reduced expression of Angptl4 in adipose tissue. CXCR7 regulates blood cholesterol by promoting its uptake in adipose tissue. This unexpected cholesterol-lowering effect of CXCR7 is beneficial for atherosclerotic vascular diseases, presumably via amelioration of hyperlipidemia-induced monocytosis, and can be augmented with a synthetic CXCR7 ligand.

Arabinoxylans and Arabinogalactans: A Comprehensive Treatise

The functional and nutraceutical importance of various foods is often attributed to the bioactive molecules present in them. A number of components have been studied but dietary fiber and its different constituents are of prime consideration. Among these, arabinoxylan (AX) and arabinogalactan (AG) are of significant importance in that they hold potential in improving the quality of the baked products along with providing health benefits against various ailments. However, the improvements are dependent on their molecular weights, cross linkages, and solubility. Water-Extractable Arabinoxylan (WEAX) is more effective as compared to Water-Unextractable Arabinoxylan (WUEAX). In this review article, efforts were directed to describe the structural and molecular conformations of these functional ingredients. The discussion has been made regarding the functional properties of AX and AG, for example, improvements in water absorption capacities, dough stability time, and viscosity. They also improve the baking absorption of flour that is positively correlated with bread volume, the most important criterion for stakeholders. The arguments are also provided on the detrimental effects on gluten quality with some possible solutions. Their role in improving the quality and extending the shelf life of bread by reducing the process of staling and retrogradation is the main idea presented in the article. The nutraceutical perspectives were also highlighted as they are helpful in regulating blood cholesterol which thereby protect the body from cardiovascular disorders like atherosclerosis. Additionally, they act as prebiotics for microorganisms residing in the gastrointestinal tract.

AN OVERVIEW OF THE CARDIOVASCULAR DISEASE RISK FACTORS OF DIETARY ORIGIN

Many of the risk factors for cardiovascular disease can be lowered. Several can be lowered by dietary change. Achieving and maintaining desirable weight levels is important for control of abnormal glucose intolerance, high blood pressure and elevated blood cholesterol levels. Controlling the type of fat we consume is important for regulating blood cholesterol levels. Restricting sodium intake is important to many with high blood pressure. We do not have all the answers about the influence of food on cardiovascular health, but we know enough to take action. Today in the United States one person dies every minute of a heart attack. That makes this problem yours and mine.