Low Density Lipoprotein Receptor Gene Research Articles

Usefulness of Gemcabene in Homozygous Familial Hypercholesterolemia (from COBALT-1)

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated plasma low-density lipoprotein-cholesterol (LDL-C), and premature atherosclerotic cardiovascular disease. Depending on residual LDL receptor (LDLR) function, most HoFH patients respond modestly to statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. However, LDL-C typically remains markedly elevated necessitating additional therapies, including apheresis. Gemcabene is a novel lipid-lowering agent with a mechanism of action independent of the LDLR, which has previously demonstrated the ability to reduce levels of LDL-C on top of maximally tolerated statins. The present study (COBALT-1) assessed efficacy, tolerability, and safety of gemcabene as an adjunctive therapy to current lipid-lowering treatment for familial hypercholesterolemia patients. Eight patients with either a clinical or genetic diagnosis of HoFH on stable standard of care, including statins, ezetimibe, and PCSK9 inhibitors, were treated with gemcabene in an open-label study for 12 weeks. DNA analysis for mutations in the LDLR, apolipoprotein B, and PCSK9 genes was performed. Patients received 300 mg gemcabene for the first 4 weeks, 600 mg for the next 4 weeks, and 900 mg for the final 4 weeks. All patients completed the 12-week study. Mean change from baseline in LDL-C was -26% (p = 0.004) at Week 4 (300 mg), -30% (p = 0.001) at Week 8 (600 mg), and -29% (p = 0.001) at Week 12 (900 mg). In conclusion, the COBALT-1 study demonstrates gemcabene has potential to significantly reduce LDL-C levels when used as an adjunctive therapy to current lipid-lowering treatment for familial hypercholesterolemia patients.

Diabetes and family hypercholesterolemia in a child: is it real?

Diabetes mellitus type 1 is one of the most common chronic diseases among children. It is a pathology of carbohydrate, fat and protein metabolism caused by insulin deficiency in the target tissue. Changes in the lipid profile can be both secondary and primary. The article describes a clinical case of a combination of diabetes mellitus type 1 and family hypercholesterolemia in a child. It presents the clinical and laboratory results of the examination of the child and his parents. Familial hypercholesterolemia is confirmed by mutation of the low density lipoprotein receptor gene (LDLR) in the heterozygous state. In addition, the proband has a polymorphism of the SLCO1B1 gene, which should be considered when prescribing therapy. The demonstrated clinical case shows that familial hypercholesterolemia can be an independent disease, aggravating the course of diabetes mellitus and requiring correction of the therapy.

Impaired adult hippocampal neurogenesis in a mouse model of familial hypercholesterolemia: A role for the LDL receptor and cholesterol metabolism in adult neural precursor cells

ObjectiveIn familial hypercholesterolemia (FH), mutations in the low-density lipoprotein (LDL) receptor (LDLr) gene result in increased plasma LDL cholesterol. Clinical and preclinical studies have revealed an association between FH and hippocampus-related memory and mood impairment. We here asked whether hippocampal pathology in FH might be a consequence of compromised adult hippocampal neurogenesis. MethodsWe evaluated hippocampus-dependent behavior and neurogenesis in adult C57BL/6JRj and LDLr−/− mice. We investigated the effects of elevated cholesterol and the function of LDLr in neural precursor cells (NPC) isolated from adult C57BL/6JRj mice in vitro. ResultsBehavioral tests revealed that adult LDLr−/− mice showed reduced performance in a dentate gyrus (DG)-dependent metric change task. This phenotype was accompanied by a reduction in cell proliferation and adult neurogenesis in the DG of LDLr−/− mice, suggesting a potential direct impact of LDLr mutation on NPC. Exposure of NPC to LDL as well as LDLr gene knockdown reduced proliferation and disrupted transcriptional activity of genes involved in endogenous cholesterol synthesis and metabolism. The LDL treatment also induced an increase in intracellular lipid storage. Functional analysis of differentially expressed genes revealed parallel modulation of distinct regulatory networks upon LDL treatment and LDLr knockdown. ConclusionsTogether, these results suggest that high LDL levels and a loss of LDLr function, which are characteristic to individuals with FH, might contribute to a disease-related impairment in adult hippocampal neurogenesis and, consequently, cognitive functions.

Diabetic Hemodialysis: Vitamin D Supplementation and its Related Signaling Pathways Involved in Insulin and Lipid Metabolism.

This study was conducted to determine the effects of vitamin D supplementation on some of the gene expressions related to insulin and lipid metabolism in diabetic hemodialysis (HD) patients. A double-blind, randomized, placebo-controlled clinical trial was carried out in 55 patients with diabetic HD. The current project used two groups in which each subject received vitamin D supplements (50,000 IU, n=28) or placebo (50,000 IU, n=27) every 2 weeks for 12 weeks. Gene expression analyses (RT-PCR) were included to obtain the rate of gene expression of the related insulin and lipid metabolism genes in peripheral blood mononuclear cells (PBMCs) of patients with diabetic HD. Our data revealed that consumption of vitamin D supplementation enables to overexpress the peroxisome proliferation-activated receptor gamma (PPAR-γ) (P=0.001), AKT (P=0.04), PI3K (P=0.02), insulin receptor substrate-1 (IRS1) (P0.008) and glucose transporter type 4 (GLUT-4) (P=0.01) and downregulate the expression of protein kinase C (PKC) (P=0.001) in patients with diabetic HD than control group following the 12-week intervention. In addition, vitamin D supplementation downregulated low-density lipoprotein receptor (LDLR) (P=0.03) expression in the subjects with diabetic HD than the control group. Vitamin D supplementation did not show any effects on the expression of pyruvate dehydrogenase kinase 1 (PDK1) (P=0.37), IRS2 (P=0.90) and lipoprotein (a) [Lp(a)] (P=0.05). Our findings confirmed that diabetic HD subjects who received the vitamin D supplementation (for 12 weeks), showed a significant overexpression in the PPAR-γ, AKT, PI3K, IRS1 and GLUT4 genes, and also showed a significant downregulation in the PKC and LDLR genes. Moreover, no effects on PDK1, IRS2 and Lp(a) expression were observed.

Cholesterol lowering attenuates pressure overload-induced heart failure in mice with mild hypercholesterolemia.

Epidemiological studies support a strong association between non-high-density lipoprotein cholesterol levels and heart failure incidence. The objective of the current study was to evaluate the effect of selective cholesterol lowering adeno-associated viral serotype 8 (AAV8)-mediated low-density lipoprotein receptor (LDLr) gene transfer on cardiac remodelling and myocardial oxidative stress following transverse aortic constriction (TAC) in female C57BL/6 LDLr-/- mice with mild hypercholesterolemia. Cholesterol lowering gene transfer resulted in a 65.9% (p<0.0001) reduction of plasma cholesterol levels (51.2 ± 2.2 mg/dl) compared to controls (150 ± 7 mg/dl). Left ventricular wall area was 11.2% (p<0.05) lower in AAV8-LDLr TAC mice than in control TAC mice. In agreement, pro-hypertrophic myocardial proteins were potently decreased in AAV8-LDLr TAC mice. The degree of interstitial fibrosis and perivascular fibrosis was 31.0% (p<0.001) and 29.8% (p<0.001) lower, respectively, in AAV8-LDLr TAC mice compared to control TAC mice. These structural differences were associated with improved systolic and diastolic function and decreased lung congestion in AAV8-LDLr TAC mice compared to control TAC mice. Cholesterol lowering gene therapy counteracted myocardial oxidative stress and preserved the potential for myocardial fatty acid oxidation in TAC mice. In conclusion, cholesterol lowering gene therapy attenuates pressure overload-induced heart failure in mice with mild hypercholesterolemia.

Effects of cholesterol-lowering probiotics on intestinal barrier and gut microbiota in mice with non-alcoholic fatty liver disease and the possible mechanisms

Objective To investigate the effects of cholesterol-lowering probiotics, DM9054 combined with 86066, on the intestinal mucosal barrier and gut microbiota in mice with nonalcoholic fatty liver disease (NAFLD) induced by high-fat diet and the possible mechanisms. Methods Twenty-four male mice deficient in the low-density lipoprotein receptor gene (Ldlr- / - mice) were randomly divided into three groups including control, NAFLD model and probiotic intervention groups. Mice in the three groups were given normal chow diet+ normal saline, high-fat diet (HFD)+ normal saline, and HFD+ cholesterol-lowering probiotics, respectively. The mouse model of NAFLD was established by feeding mice with high-fat diet (45% of calories derived from fat diet) for 12 weeks. qPCR was performed to measure the expression of liver and intestinal inflammatory genes and liver cholesterol synthesis genes. Western blot assay was used to detect the expression of intestinal tight junction proteins and HMG-CoA reductase (HMGCR). Pathological changes in tissues were evaluated by HE staining. Features of gut microbiota were analyzed by 16S rRNA gene sequencing. Results Cholesterol-lowering probiotics intervention attenuated HFD-induced hepatic steatosis, inflammatory responses and obesity and decreased the synthesis of liver cholesterol (P<0.05). Moreover, inhibited gut inflammatory responses and improved intestinal barrier function were detected in the probiotic intervention group (P<0.05). The composition of gut microbiota in mice of the probiotic intervention group was different from that of the model group, but similar to that of the control group. Conclusions Cholesterol-lowering probiotics might attenuate NAFLD in mice through reducing liver cholesterol synthesis, alleviating liver and intestinal inflammation, improving intestinal mucosal barrier function and regulating intestinal microbiota. Key words: Nonalcoholic fatty liver disease (NAFLD); Probiotics; Intestinal barrier function; Intestinal microbiota

Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients

Background and aimsMore than 4970 variants in the low-density lipoprotein receptor (LDLR) gene and 350 variants in the proprotein convertase subtilisin/kexin 9 (PCSK9) gene have been reported in familial hypercholesterolemia (FH) patients. However, the effects of these variants on FH pathophysiology have not been fully clarified. We aimed to update the LDLR and PCSK9 variants in Japanese heterozygous FH (HeFH) patients and annotate their clinical significance for the genetic diagnosis of HeFH. MethodsA genetic analysis of the LDLR and PCSK9 genes was performed in 801 clinically diagnosed HeFH patients. The association of the pathogenic variants with the clinical FH phenotype was examined. ResultsPathogenic variants in the LDLR and PCSK9 genes were found in 46% (n = 296) and 7.8% (n = 51) of unrelated FH patients (n = 650), respectively. The prevalence of Achilles tendon thickness was low (44%) in patients harbouring PCSK9 pathogenic variants. Furthermore, 17% of unrelated FH patients harboured one of five frequent LDLR pathogenic variants: c.1845+2T > C, c.1012T > A: p.(Cys338Ser), c.1297G > C: p.(Asp433His), c.1702C > G: p.(Leu568Val), and c.2431A > T: p.(Lys811*). Patients harbouring the c.1845+2T > C and c.1702C > G: p.(Leu568Val) variants had significantly lower serum LDL-cholesterol levels and higher serum HDL-cholesterol levels, respectively, compared with those harbouring the other LDLR pathogenic variants. The proportion of LDLR pathogenic variants was higher in patients with a younger age of coronary artery disease (CAD) onset and significantly decreased as the age of CAD onset increased. ConclusionsThis study annotated the clinical significance and characteristics of LDLR and PCSK9 pathogenic variants in Japanese HeFH patients.

Dietary Cholesterol Is Highly Associated with Severity of Hyperlipidemia and Atherosclerotic Lesions in Heterozygous LDLR-Deficient Hamsters.

Objective: Familial hypercholesterolemia (FH) is a dominant inherited disease caused mainly by low-density lipoprotein receptor (LDLR) gene mutations. To different extents, both heterozygous and homozygous FH patients develop premature coronary heart disease (CHD). However, most of the experimental animal models with LDLR deficiency could not fully recapitulate FH because they develop hyperlipidemia and atherosclerosis only in homozygous, but not in heterozygous, form. In the current study, we investigated the responsiveness of the LDLR+/− hamster to dietary cholesterol and whether plasma cholesterol levels were positively associated with the severity of atherosclerosis. Approach and Methods: wild type WT and LDLR+/− hamsters were fed a high fat diet with different cholesterol contents (HCHF) for 12 or 16 weeks. Plasma lipids, (apo)lipoproteins, and atherosclerosis in both the aorta and coronary arteries were analyzed. After a HCHF diet challenge, the levels of total cholesterol (TC) in WT and LDLR+/− hamsters were significantly elevated, but the latter showed a more pronounced lipoprotein profile, with higher cholesterol levels that were positively correlated with dietary cholesterol contents. The LDLR+/− hamsters also showed accelerated atherosclerotic lesions in the aorta and coronary arteries, whereas only mild aortic lesions were observed in WT hamsters. Conclusions: Our findings demonstrate that, unlike other rodent animals, the levels of plasma cholesterol in hamsters can be significantly modulated by the intervention of dietary cholesterol, which were closely associated with severity of atherosclerosis in LDLR+/− hamsters, suggesting that the LDLR+/− hamster is an ideal animal model for FH and has great potential in the study of FH and atherosclerosis-related CHD.

LDLR Gene Polymorphisms (rs5925 and rs1529729) Are Associated with Susceptibility to Coronary Artery Disease in a South Indian Population.

Cardiovascular diseases (CVD) are a major cause of death in India and worldwide. Atherosclerosis is caused by the interaction of environmental and genetic factors. Hypercholesterolemia is an example of a classical risk factor for CVD. The low-density lipoprotein receptor (LDLR) is one of the regulating mechanisms the liver uses for cholesterol homeostasis. Gene variations in the LDLR have been reported to cause hypercholesterolemia and consequently CVD. We investigated the association of polymorphisms in the LDLR (rs5925 and rs1529729) with coronary artery disease (CAD) in 200 coronary artery disease patients and 200 matched healthy controls using allele-specific PCR (AS-PCR). The results indicated that the CT genotype of the rs1529729 polymorphism was associated a decreased susceptibility to CAD with an odds ratio (OR) = 0.42 (95% confidence interval (CI), 0.23–0.77), risk ratio (RR) = 0.59 (0.39–0.89), P = 0.0047. The TT genotype of the rs1529729 polymorphism was also associated with decreased susceptibility to CAD with an OR = 0.19 (95% CI, 0.076–0.47), RR = 0.57 (0.47–0.69), P = 0.0003. The GA genotype of the rs5925 polymorphism was associated with decreased susceptibility to CAD with an OR = 0.45 (95% CI, 0.27–0.75), RR = 0.65 (0.47–0.88), P = 0.002. We concluded that the CT and TT genotypes of the rs1529729 polymorphism and the GA genotype of the rs5925 polymorphism are probably associated with decreased susceptibility to CAD. The simplicity of AS-PCR makes it particularly suitable for the rapid, large-scale screening of gene variabilities in the LDLR. AS-PCR could provide significant benefits in clinical applications with its ability to amplify a lower quantity of samples in a cost-saving manner. Nevertheless, these findings need to be validated in well-designed studies with larger sample sizes and in different populations.

Identification of Key Biomarkers and Potential Molecular Mechanisms in Renal Cell Carcinoma by Bioinformatics Analysis.

Renal cell carcinoma (RCC) is the most common form of kidney cancer, caused by renal epithelial cells. RCC remains to be a challenging public health problem worldwide. Metastases that are resistant to radiotherapy and chemotherapy are the major cause of death from cancer. However, the underlying molecular mechanism regulating the metastasis of RCC is poorly known. Publicly available databases of RCC were obtained from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified using GEO2R analysis, whereas the Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed by Gene Set Enrichment Analysis (GSEA) and Metascape. Protein-protein interaction (PPI) network of DEGs was analyzed by STRING online database, and Cytoscape software was used for visualizing PPI network. Survival analysis of hub genes was conducted using GEPIA online database. The expression levels of hub genes were investigated from The Human Protein Atlas online database and GEPIA online database. Finally, the comparative toxicogenomics database (CTD; http://ctdbase.org) was used to identify hub genes associated with tumor or metastasis. We identified 229 DEGs comprising 135 downregulated genes and 94 upregulated genes. Functional analysis revealed that these DEGs were associates with cell recognition, regulation of immune, negative regulation of adaptive immune response, and other functions. And these DEGs mainly related to P53 signaling pathway, cytokine-cytokine receptor interaction, Natural killer cell mediated cytotoxicity, and other pathways are involved. Ten genes were identified as hub genes through module analyses in the PPI network. Finally, survival analysis of 10 hub genes was conducted, which showed that the MMP2 (matrix metallo peptidase 2), DCN, COL4A1, CASR (calcium sensing receptor), GPR4 (G protein-coupled receptor 4), UTS2 (urotensin 2), and LDLR (low density lipoprotein receptor) genes were significant for survival. In this study, the DEGs between RCC and metastatic RCC were analyzed, which assist us in systematically understanding the pathogeny underlying metastasis of RCC. The MMP2, DCN, COL4A1, CASR, GPR4, UTS2, and LDLR genes might be used as potential targets to improve diagnosis and immunotherapy biomarkers for RCC.

Inhibitors of AKT kinase increase LDL receptor mRNA expression by two different mechanisms.

Protein kinase B (AKT) is a serine/threonine kinase that functions as an important downstream effector of phosphoinositide 3-kinase. We have recently shown that MK-2206 and triciribine, two highly selective AKT inhibitors increase the level of low density lipoprotein receptor (LDLR) mRNA which leads to increased amount of cell-surface LDLRs. However, whereas MK-2206 induces transcription of the LDLR gene, triciribine stabilizes LDLR mRNA, raising the possibility that the two inhibitors may actually affect other kinases than AKT. In this study, we aimed to ascertain the role of AKT in regulation of LDLR mRNA expression by examining the effect of five additional AKT inhibitors on LDLR mRNA levels. Here we show that in cultured HepG2 cells, AKT inhibitors ARQ-092, AKT inhibitor VIII, perifosine, AT7867 and CCT128930 increase LDLR mRNA levels by inducing the activity of LDLR promoter. CCT128930 also increased the stability of LDLR mRNA. To study the role of AKT isoforms on LDLR mRNA levels, we examined the effect of siRNA-mediated knockdown of AKT1 or AKT2 on LDLR promoter activity and LDLR mRNA stability. Whereas knockdown of either AKT1 or AKT2 led to upregulation of LDLR promoter activity, only knockdown of AKT2 had a stabilizing effect on LDLR mRNA. Taken together, these results provide strong evidence for involvement of AKT in regulation of LDLR mRNA expression, and point towards the AKT isoform specificity for upregulation of LDLR mRNA expression.

Significant association between RETN genetic polymorphisms and alcohol-induced osteonecrosis of femoral head.

BackgroundAlcohol‐induced osteonecrosis of femoral head (ONFH) is a complex disease and genetic factors are one of the causes. The purpose of this study is to investigate the effects of RETN (resistin; OMIM: 605565) and LDLR (low density lipoprotein receptor; OMIM: 606945) polymorphisms on the risk of alcohol‐induced ONFH in Chinese Han population.MethodsA case–control study including 201 patients and 201 controls was designed. Seven single nucleotide polymorphisms (SNPs) in RETN gene and four SNPs in LDLR gene were genotyped using Agena MassARRAY platform. In allele model and genetic model, chi‐square test and logistic regression were used to study the associations between these SNPs and ONFH susceptibility. In addition, the relationships between these SNPs, clinical phenotypes, and blood lipid level with one‐way analysis of variance were analyzed.ResultsIn the allele model, rs7408174 and rs3745369 in RETN were associated with increased risk of alcohol‐induced ONFH, whereas rs34861192 and rs3219175 in RETN showed reduced risk of alcohol‐induced ONFH. In the genetic model, rs7408174 was associated with increased risk of alcohol‐induced ONFH in dominant model and log‐additive model. Rs3745369 showed an increased risk in codominant model, recessive model, and log‐additive model. Rs34861192 showed a decreased risk in codominant model, dominant model, and log‐additive model, and rs3219175 showed a decreased risk in dominant model and log‐additive model. The rs3745368 in RETN was associated with the clinical stage of the disease.ConclusionThese results suggest that RETN genetic polymorphisms are associated with the susceptibility of alcohol‐induced ONFH in Chinese Han population.

Low density lipoprotein receptor (LDLR) gene and ocular manifestation in Malay patients with familial hypercholesterolaemia

Introduction: Corneal arcus and eyelid xanthelasma are the common ocular findings but not exclusively found in familial hypercholesterolaemia (FH) patients. Low density lipoprotein receptor (LDLR) gene is the one of the most common genes investigated in FH. There is no study predicting ocular manifestations with genetic variations of the LDLR gene.Purpose: To associate common ocular manifestations of FH and LDLR gene in Malays.Material and methods: A cross-sectional study involving 50 unrelated Malay patients with FH were recruited. FH was diagnosed based on Dutch Lipid Clinic Network diagnostic criteria. The right eye was examined for eyelid xanthelasma and corneal arcus, while mean retinal nerve fibre layer thickness (RNFL) was assessed using Heidelberg retinal tomography II. Venepuncture was performed and genomic deoxyribonucleotide acid (DNA) was extracted. LDLR gene variations were screened using denaturing high-performance liquid chromatography and confirmed through DNA sequencing.Results: Corneal arcus was detected in 86.0% of patients, while eyelid xanthelasma was detected in 2.0% of patients. Mean RNFL thickness was 254.16 μm (SD: 60.67 μm). LDLR gene variations were identified in 32 patients (64.0%), including 5 mutations and 9 single nucleotide polymorphisms (SNPs). Two novel mutations were detected: c.1705+117T&gt;G and p.Asp139His. There was significant association between genotype frequency of LDLR variations c.940+36G&gt;A, p.Glu201Lys and p.Asp304Asn with FH, p.Glu201Lys with corneal arcus, and p.Cys255Ser and c.1705+117T&gt;G with mean RNFL thickness.Conclusion: LDLR gene variations were not uncommon in Malay patients with FH. Two novel variations, c.1705+117T&gt;G and p.Asp139His, were identified. LDLR gene is a potential predictor genetic marker for corneal arcus in Malay patients with FH. c.1705+117T&gt;G is associated with thinner mean RNFL thickness.

Lipid-lowering effect of Phyllanthus embilica and Alpinia galanga extracts on HepG2 cell line

Dyslipidemia is a key risk factor for cardiovascular diseases. Although statins are powerful therapeutic option for achieving target low- and high-density lipoprotein levels, it is of interest to seek for alternative treatments for dyslipidemia. Phyllanthus emblica and Alpinia galanga were found to have hypolipidemic effects. However, the mechanisms underlying their bioactivity have not yet been elucidated. Lipid-lowering effects of the hydroethanolic extracts from a Phyllanthus emblica (PE), Alpinia galangal (AG) and a combination between P. emblica and A. galangal (PEAG; ratio 7:3 w/w) on expression of low-density lipoprotein receptor (LDLR), 3-hydroxyl-3-methylglutaryl-CoA reductase (HMGCR), apolipoprotein A1 (ApoA1) and scavenger receptor class B1 (SR-BI) genes were assessed in HepG2 cell line using quantitative RT-PCR (qRT-PCR). It was demonstrated from the MTT cytotoxic assay that PE and PEAG were not cytotoxic to HepG2 cell line. AG, gallic acid and simvastatin were more cytotoxic to HepG2 cell line. PEAG was found to be the most promising therapeutic agent for clearance of circulating LDL-C due to its enhancing expression of the LDLR gene. It could contribute towards enhancement of the HDL-C levels due to its upregulation expression of the APOA1 and SR-B1 mRNA transcripts in HepG2 cells.

At what time is the heart failure?

Autosomal dominant hypercholesterolemia, being referred to as familial hypercholesterolemia (FH), is mainly due to defective LDL receptor (LDLR) function, but is also associated with variants in genes encoding APOB (LDLR ligand) and PCSK9, the catabolic regulator of LDLR. The signal-transducing adaptor family member 1 (STAP1) gene has been recently linked to FH. We describe the case of a 56-year-old male patient found to have hypercholesterolemia at age 34, but who did not continue follow-up nor received treatment with lipid-lowering drugs. At age 55 he suffered a myocardial infarction. A systematic NGS analysis did not show point mutations in the LDLR, APOB, LDLRAP1, or PCSK9 genes, nor large rearrangements of the LDLR gene, but revealed the heterozygous missense variant rs199787258 of STAP1 (c.526C > T; p.Pro176Ser). This variant was also found in heterozygosis in the two siblings of the index case, who also had hypercholesterolemia, but did not cosegregate in his progeny. A bioinformatics analysis and available structural information predicts p.Pro176Ser as the most damaging of all STAP1 missense variants associated with familial hypercholesterolemia. Our findings confirm and extend the linkage between STAP1 variants and FH, and point to an important role of this adaptor protein within a signaling pathway that affects cholesterol homeostasis.

A rare low-density lipoprotein receptor (LDLR) gene mutation associated with heterozygous familial hypercholesterolemia

A rare low-density lipoprotein receptor (LDLR) gene mutation associated with heterozygous familial hypercholesterolemia

A Structured Pine Nut Oil Has Hypocholesterolemic Activity by Increasing LDLR Gene Expression in the Livers of Obese Mice

A structured pine nut oil (SPNO) is previously developed with pinolenic acid (PLA) evenly distributed at all sn positions on the glycerol backbone, whereas natural pine nut oil (NPNO) has PLA positioned mostly at the sn‐3 position. This SPNO exhibited greater lymphatic PLA absorption than NPNO, although SPNO and NPNO contained equal amounts (≈13 wt%) of PLA. In this study, SPNO containing ≈13 wt% PLA (SPNO13) and ≈44 wt% PLA (SPNO44) is produced via Novozym 435‐catalyzed esterification of glycerol with the free fatty acids containing ≈13 wt% and ≈44 wt% PLA from NPNO (from Pinus koraiensis Siebold &amp; Zucc.). Five‐week‐old C57/BL6J mice are fed either a low‐ or high‐fat diet (HFD) containing NPNO, SPNO13, or SPNO44 for 15 weeks. Supplementation with SPNO44, but not NPNO or SPNO13, significantly attenuates HFD‐induced increases in final body weight, weight gain, and retroperitoneal and liver masses in diet‐induced obese mice, without affecting food intake. SPNO44 also significantly reduces serum total and LDL cholesterol levels, as well as serum triacylglycerol levels and hepatic lipid accumulation. The hypocholesterolemic activity of SPNO44 is attributed to the greater hepatic accumulation of PLA from it causing increased SREBP2 levels and upregulation of LDL receptor gene expression in the livers of obese mice.Practical Applications: PLA has received much attention due to its anti‐obesity and anti‐dyslipidemia effects. NPNO is the sole source of PLA, but it can be converted into SPNO. The authors hypothesized that SPNO should improve PLA's health benefits due to the enhanced lymphatic absorption of PLA from SPNO. When compared to NPNO, SPNO44 may provide several advantages, such as enhanced anti‐obesity and anti‐dyslipidemia effects for food and nutraceutical applications. In future studies, the lymphatic absorption of SPNO44 and NPNO or SPNO13 should be compared.SPNO44, a structured pine nut oil containing ≈44 wt% pinolenic acid (PLA) and an even distribution of PLA on the glycerol backbone, has hypocholesterolemic activity by increasing sterol regulatory element‐binding protein 2 (SREBP2) levels and upregulating LDLR gene expression in the livers of obese mice.

Cholesterol-Lowering Gene Therapy Prevents Heart Failure with Preserved Ejection Fraction in Obese Type 2 Diabetic Mice.

Hypercholesterolemia may be causally related to heart failure with preserved ejection fraction (HFpEF). We aimed to establish a HFpEF model associated with hypercholesterolemia and type 2 diabetes mellitus by feeding a high-sucrose/high-fat (HSHF) diet to C57BL/6J low-density lipoprotein receptor (LDLr)−/− mice. Secondly, we evaluated whether cholesterol-lowering adeno-associated viral serotype 8 (AAV8)-mediated LDLr gene transfer prevents HFpEF. AAV8-LDLr gene transfer strongly (p < 0.001) decreased plasma cholesterol in standard chow (SC) mice (66.8 ± 2.5 mg/dl versus 213 ± 12 mg/dl) and in HSHF mice (84.6 ± 4.4 mg/dl versus 464 ± 25 mg/dl). The HSHF diet induced cardiac hypertrophy and pathological remodeling, which were potently counteracted by AAV8-LDLr gene transfer. Wet lung weight was 19.0% (p < 0.001) higher in AAV8-null HSHF mice than in AAV8-null SC mice, whereas lung weight was normal in AAV8-LDLr HSHF mice. Pressure–volume loop analysis was consistent with HFpEF in AAV8-null HSHF mice and showed a completely normal cardiac function in AAV8-LDLr HSHF mice. Treadmill exercise testing demonstrated reduced exercise capacity in AAV8-null HSHF mice but a normal capacity in AAV8-LDLr HSHF mice. Reduced oxidative stress and decreased levels of tumor necrosis factor-α may mediate the beneficial effects of cholesterol lowering. In conclusion, AAV8-LDLr gene therapy prevents HFpEF.

Current status of familial hypercholesterolemia in Chinese populations.

Heterozygous familial hypercholesterolemia often went unrecognized in China when population cholesterol levels were low, but rapid economic development has changed the situation. This review will discuss the current position of awareness, diagnosis, and management of familial hypercholesterolemia in Chinese populations. The phenotype of familial hypercholesterolemia in China and other Chinese populations has become similar to that in Western countries, although it may still be somewhat less severe. The prevalence in Chinese populations is also similar to that in other countries and it has been found in up to 7% of Chinese patients with premature coronary heart disease. Most of the mutations are in the low-density lipoprotein receptor gene but the pattern of mutations differs from that in Whites. Chinese patients may be more responsive to statins than Whites but patients with familial hypercholesterolemia are often undertreated. Increasing population cholesterol levels have changed the phenotype of familial hypercholesterolemia in China and Chinese patients now resemble those in Western countries. International initiatives are facilitating increased awareness and identification of cases and more effective management of the condition.

Analisis Polimorfisme Nukleotida Tunggal (SNP) Daerah 3’UTR Gen LDLR Penduduk Papua

Single nucleotide polymorphism (SNP) is a single nucleotide difference in the arrangement of DNA base strands that can show genetic variation. The LDLR gene is a low density lipoprotein (LDL-R) receptor gene that functions to regulate cholesterol levels in the blood. The LDLR gene is composed of 18 exons and contains a 3’untranslated region (3’UTR) which plays an important role in regulating gene expression. This study aims to analyze the SNP in an area of 3'UTR LDLR genes from 6 University of Papua students from Papua. The research was carried out by polymerase chain reaction method to multiply the number of target DNA, then sequenced to find out the sequence of nucleotide bases. The results of this study were from 6 individuals, found 2 SNPs at position *52 and *504 with nucleotide diversity (π) of 0.00149. These polymorphisms forms 3 types of haplotypes, namely GG, GA and AA with a haplotype diversity of 0.600 ± 0.215.