RESUMEN
Sitosterolemia is a rare inherited disorder caused by mutations in the ABCG5/ABCG8 genes. These genes encode proteins involved in the transport of plant sterols. Mutations in these genes lead to decreased excretion of phytosterols, which can accumulate in the body and lead to a variety of health problems, including premature coronary artery disease. We conducted the first genome-wide association study (GWAS) in the Middle East/North Africa population to identify genetic determinants of plant sterol levels in Qatari people. GWAS was performed on serum levels of ß-sitosterol and campesterol using the Metabolon platform from Qatar Biobank (QBB) and genome sequence data provided by Qatar Genome Program. A trans-ancestry meta-analysis of data from our Qatari cohort with summary statistics from a previously published large cohort (9758 subjects) of European ancestry was conducted. Using conditional analysis, we identified two independent single nucleotide polymorphisms associated with ß-sitosterol (rs145164937 and rs4299376), and two others with campesterol (rs7598542 and rs75901165) in the Qatari population in addition to previously reported variants. All of them map to the ABCG5/8 locus except rs75901165 which is located within the Intraflagellar Transport 43 (IFT43) gene. The meta-analysis replicated most of the reported variants, and our study provided significant support for the association of variants in SCARB1 and ABO with sitosterolemia. Evaluation of a polygenic risk score devised from European GWAS data showed moderate performance when applied to QBB (adjusted-R2 = 0.082). These findings provide new insights into the genetic architecture of phytosterol metabolism while showing the importance including under-represented populations in future GWAS studies.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5 , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8 , Estudio de Asociación del Genoma Completo , Errores Innatos del Metabolismo Lipídico , Fitosteroles , Polimorfismo de Nucleótido Simple , Sitoesteroles , Humanos , Fitosteroles/sangre , Fitosteroles/genética , Fitosteroles/efectos adversos , Polimorfismo de Nucleótido Simple/genética , Sitoesteroles/sangre , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/sangre , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genética , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8/genética , Masculino , Femenino , Enfermedades Intestinales/genética , Enfermedades Intestinales/sangre , Adulto , Colesterol/sangre , Colesterol/análogos & derivados , Hipercolesterolemia/genética , Hipercolesterolemia/sangre , Persona de Mediana Edad , Lipoproteínas/sangre , Lipoproteínas/genética , Transportadoras de Casetes de Unión a ATP/genéticaRESUMEN
BACKGROUND: Sitosterolemia, an autosomal recessive condition, is characterized by impaired metabolism of plant sterols. Clinical symptoms include skin xanthoma, premature atherosclerotic disease, arthritis, and unexplained hematological abnormalities. However, there is a dearth of studies on sitosterolemia-related brain damage. METHODS: This study focused on the family of two sitosterolemia patients who presented with severe hypercholesterolemia and xanthoma. Radiological examinations, biopsies, whole-exome sequencing (WES), and plant sterol tests were conducted. RESULTS: The index patient, a 66-year-old female, initially exhibited weakness in both lower limbs and later developed urinary and fecal incontinence. Neuroimaging showed that the falx of the brain had irregular fusiform thickening. Significant tissue edema was observed around the lesions in the bilateral frontal-parietal lobes. Pathological analysis of the biopsied brain lesion revealed extensive cholesterol crystal deposition and lymphocyte infiltration in the matrix. The index patient who experienced cerebral impairment and her sister both carried two compound heterozygous variants in ATP binding cassette transporter G5 (ABCG5). These included the nonsense variants NM_022436: c.751 C > T (p.Q251X) in exon 6 and NM_022436: c.1336 C > T (p.R446X) in exon 10. A notable increase in plant sterol levels was observed in the younger sister of the index patient. CONCLUSION: This study highlights a previously unreported neurological aspect of sitosterolemia. Imaging and pathology findings suggest that cholesterol crystals may be deposited in connective tissues such as the cerebral falx and pia mater through blood circulation.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5 , Hipercolesterolemia , Enfermedades Intestinales , Errores Innatos del Metabolismo Lipídico , Fitosteroles , Humanos , Femenino , Fitosteroles/efectos adversos , Anciano , Hipercolesterolemia/genética , Hipercolesterolemia/patología , Hipercolesterolemia/complicaciones , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/patología , Errores Innatos del Metabolismo Lipídico/diagnóstico por imagen , Enfermedades Intestinales/genética , Enfermedades Intestinales/patología , Enfermedades Intestinales/diagnóstico por imagen , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genética , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Secuenciación del Exoma , Xantomatosis/patología , Xantomatosis/genética , Xantomatosis/diagnóstico por imagen , Linaje , Colesterol/sangre , Masculino , Sitoesteroles , LipoproteínasRESUMEN
Hypercholesterolemia is an independent risk factor for cardiovascular disease and lowering circulating levels of low-density lipoprotein cholesterol (LDL-C) can prevent and reduce cardiovascular events. MicroRNA-181d (miR-181d) can reduce the levels of triglycerides and cholesterol esters in cells. However, it is not known whether miR-181d-5p can lower levels of circulating LDL-C. Here, we generated two animal models of hypercholesterolemia to analyze the potential relationship between miR-181d-5p and LDL-C. In hypercholesterolemia model mice, adeno-associated virus (AAV)-mediated liver-directed overexpression of miR-181d-5p decreased the serum levels of cholesterol and LDL-C and the levels of cholesterol and triglyceride in the liver compared with control mice. Target Scan 8.0 indicated Proprotein convertase subtilisin/kexin type 9 (PCSK9) to be a possible target gene of miR-181d-5p, which was confirmed by in vitro experiments. miR-181d-5p could directly interact with both the PCSK9 3'-UTR and promoter to inhibit PCSK9 translation and transcription. Furthermore, Dil-LDL uptake assays in PCSK9 knockdown Huh7 cells demonstrated that miR-181d-5p promotion of LDL-C absorption was dependent on PCSK9. Collectively, our findings show that miR-181d-5p targets the PCSK9 3'-UTR to inhibit PCSK9 expression and to reduce serum LDL-C. miR-181d-5p is therefore a new therapeutic target for the development of anti-hypercholesterolemia drugs.
Asunto(s)
Hipercolesterolemia , MicroARNs , Proproteína Convertasa 9 , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Animales , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Ratones , Humanos , LDL-Colesterol/sangre , LDL-Colesterol/metabolismo , Masculino , Hígado/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
Hypercholesterolemia is frequently intertwined with hepatosteatosis, hypertriglyceridemia, and hyperglycemia. This study is designed to assess the therapeutic efficacy of miR-206 in contrast to statins in the context of managing hypercholesterolemia in mice. We previously showed that miR-206 is a potent inhibitor of de novo lipogenesis (DNL), cholesterol synthesis, and gluconeogenesis in mice. Given that these processes occur within hepatocytes, we employed a mini-circle (MC) system to deliver miR-206 specifically to hepatocytes (designated as MC-miR-206). A single intravenous injection of MC-miR-206 maintained high levels of miR-206 in the liver for at least two weeks, thereby maintaining suppression of hepatic DNL, cholesterol synthesis, and gluconeogenesis. MC-miR-206 significantly reduced DNA damage, endoplasmic reticulum and oxidative stress, and hepatic toxicity. Therapeutically, both MC-miR-206 and statins significantly reduced total serum cholesterol and triglycerides as well as LDL cholesterol and VLDL cholesterol in mice maintained on the normal chow and high-fat high-cholesterol diet. MC-miR-206 reduced liver weight, hepatic triglycerides and cholesterol, and blood glucose, while statins slightly increased hepatic cholesterol and blood glucose and failed to affect levels of liver weight and hepatic triglycerides. Mechanistically, miR-206 alleviated hypercholesterolemia by inhibiting hepatic cholesterol synthesis, while statins increased HMGCR activity, hepatic cholesterol synthesis, and fecal-neutral steroid excretion. MiR-206 facilitates the regression of hypercholesterolemia, hypertriglyceridemia, hyperglycemia, and hepatosteatosis. MiR-206 outperforms statins by reducing hyperglycemia, hepatic cholesterol levels, and hepatic toxicity.
Asunto(s)
Colesterol , Inhibidores de Hidroximetilglutaril-CoA Reductasas , MicroARNs , Animales , MicroARNs/genética , MicroARNs/metabolismo , Ratones , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Colesterol/sangre , Colesterol/metabolismo , Masculino , Hígado/metabolismo , Hígado/efectos de los fármacos , Anticolesterolemiantes/farmacología , Anticolesterolemiantes/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Ratones Endogámicos C57BL , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Lipogénesis/efectos de los fármacos , Lipogénesis/genéticaRESUMEN
Hypercholesterolemia raises the risk for cardiovascular complications and overall health. Hypercholesterolemia is common, affecting 10% of the general population of the US, and heritable. Most individuals with hypercholesterolemia have a polygenic predisposition to the condition. Previously we identified a quantitative trait locus, Tachol1, linked to hypercholesterolemia on mouse chromosome 1 (Chr1) in a cross between C57BL/6J (B6) and TALLYHO/JngJ (TH) mice, a polygenic model for human obesity, type 2 diabetes and hyperlipidemia. Subsequently, using congenic mice that carry a TH-derived genomic segment of Chr1 on a B6 background, we demonstrated that the distal segment of Chr1, where Tachol1 maps, is necessary to cause hypercholesterolemia, as well as diet-induced obesity. In this study, we generated overlapping subcongenic lines to the distal segment of congenic region and characterized subcongenic mice carrying the smallest TH region of Tachol1, ~ 16.2 Mb in size (B6.TH-Chr1-16.2 Mb). Both male and female B6.TH-Chr1-16.2 Mb mice showed a significantly increased plasma total cholesterol levels compared to B6 on both chow and high fat (HF) diet. B6.TH-Chr1-16.2 Mb mice also had greater fat mass than B6 on HF diet, without increasing food intake. The gene and protein expression levels of absent in melanoma 2 (Aim2) gene were significantly upregulated in B6.TH-Chr1-16.2 Mb mice compared to B6. In summary, we confirmed the effect of Tachol1 on hypercholesterolemia and diet-induced obesity using subcongenic analysis.
Asunto(s)
Hipercolesterolemia , Ratones Endogámicos C57BL , Obesidad , Sitios de Carácter Cuantitativo , Animales , Obesidad/genética , Obesidad/metabolismo , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Ratones , Masculino , Femenino , Cromosomas de los Mamíferos/genética , Dieta Alta en Grasa/efectos adversos , Ratones Congénicos , Modelos Animales de Enfermedad , Predisposición Genética a la EnfermedadRESUMEN
The 9p21.3 genomic locus is a hot spot for disease-associated single-nucleotide polymorphisms (SNPs), and its strongest associations are with coronary artery disease (CAD). The disease-associated SNPs are located within the sequence of a long noncoding RNA ANRIL, which potentially contributes to atherogenesis by regulating vascular cell stress and proliferation, but also affects pancreatic ß-cell proliferation. Altered expression of a neighboring gene, CDKN2B, has been also recognized to correlate with obesity and hepatic steatosis in people carrying the risk SNPs. In the present study, we investigated the impact of 9p21.3 on obesity accompanied by hyperlipidemia in mice carrying a deletion of the murine ortholog for the 9p21.3 (Chr4Δ70/Δ70) risk locus in hyperlipidemic Ldlr-/-ApoB100/100 background. The Chr4Δ70/Δ70 mice showed decreased mRNA expression of insulin receptors in white adipose tissue already at a young age, which developed into insulin resistance and obesity by aging. In addition, the Sirt1-Ppargc1a-Ucp2 pathway was downregulated together with the expression of Cdkn2b, specifically in the white adipose tissue in Chr4Δ70/Δ70 mice. These results suggest that the 9p21.3 locus, ANRIL lncRNA, and their murine orthologues may regulate the key energy metabolism pathways in a white adipose tissue-specific manner in the presence of hypercholesterolemia, thus contributing to the pathogenesis of metabolic syndrome.
Asunto(s)
Hipercolesterolemia , Resistencia a la Insulina , Obesidad , Animales , Obesidad/genética , Obesidad/metabolismo , Resistencia a la Insulina/genética , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Hipercolesterolemia/complicaciones , Ratones , Humanos , Cromosomas Humanos Par 9/genética , Masculino , Eliminación de Gen , Sitios Genéticos , Ratones Endogámicos C57BL , Tejido Adiposo Blanco/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
The hepatic deletion of Rbpjκ (RbpjF/F::AlbCre) in the mouse leads to exhibition of the Alagille syndrome phenotype during early postnatal liver development with hyperlipidemia and cholestasis due to attenuated disruption of NOTCH signaling. Given the roles of NRF2 signaling in the regulation of lipid metabolism and bile ductal formation, it was anticipated that these symptoms could be alleviated by enhancing NRF2 signaling in the RbpjF/F::AlbCre mouse by hepatic deletion of Keap1 in compound Keap1F/F::RbpjF/F::AlbCre mice. Unexpectedly, these mice developed higher hepatic and plasma cholesterol levels with more severe cholestatic liver damage during the pre-weaning period than in the RbpjF/F::AlbCre mice. In addition, hypercholesterolemia and hepatic damage were sustained throughout the growth period unlike in the RbpjF/F::AlbCre mouse. These enhanced abnormalities in lipid metabolism appear to be due to NRF2-dependent changes in gene expression related to cholesterol synthetic and subsequent bile acid production pathways. Notably, the hepatic expression of Cyp1A7 and Abcb11 genes involved in bile acid homeostasis was significantly reduced in Keap1F/F::RbpjF/F::AlbCre compared to RbpjF/F::AlbCre mice. The accumulation of liver cholesterol and the weakened capacity for bile excretion during the 3 pre-weaning weeks in the Keap1F/F::RbpjF/F::AlbCre mice may aggravate hepatocellular damage level caused by both excessive cholesterol and residual bile acid toxicity in hepatocytes. These results indicate that a tuned balance of NOTCH and NRF2 signaling is of biological importance for early liver development after birth.
Asunto(s)
Hepatomegalia , Hipercolesterolemia , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas , Proteína 1 Asociada A ECH Tipo Kelch , Hígado , Animales , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Ratones , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patología , Hígado/metabolismo , Hígado/patología , Hepatomegalia/genética , Hepatomegalia/metabolismo , Hepatomegalia/patología , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/genética , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Metabolismo de los Lípidos/genética , Eliminación de Gen , Transducción de Señal , Colesterol/metabolismo , Ratones Noqueados , Masculino , Ácidos y Sales Biliares/metabolismoRESUMEN
Although observational studies have found both a positive and negative association between depression and hypercholesterolemia, the findings are mixed and contradictory. To our knowledge, this is the first study that employs the bidirectional Mendelian randomization (MR) and multivariable MR analysis with extensive genome-wide association studies (GWAS) data to examine the causal effect between depression and hypercholesterolemia. Using summary statistics obtained from GWAS of individuals with European ancestry, we utilize a bidirectional 2-sample MR approach to explore the potential causal association between hypercholesterolemia and depressive symptoms. Multivariable Mendelian randomization analysis was used to examine whether the direct causal effect of depression on the risk of hypercholesterolemia can be affected by traits associated with the increased risk of hypercholesterolemia. This MR analysis utilized inverse variance weighted (IVW), MR-Egger regression, weighted mode, and weighted median methods. Data on the summary level of depression were acquired from a GWAS that involved 500,199 participants. We used summary GWAS datasets for hypercholesterolemia including 206,067 participants. We also used another GWAS databases of hypercholesterolemiat (nâ =â 463,010) to validate our results. By utilizing IVW, it was discovered that there is a possibility of a 31% rise in the risk of hypercholesterolemia due to depression (ORâ =â 1.31, 95% CIâ =â 1.10-1.57, Pâ =â .002). We found a consistent causal effect of depression on hypercholesterolemia from the IVW analyses using different hypercholesterolemia datasets. After adjustment of smoking, physical activity, and obesity, there remains significant causal relationship between depression and hypercholesterolemia (ORâ =â 1.25, 95% CIâ =â 1.01-1.54, Pâ =â .040). However, we did not find any evidence indicating that hypercholesterolemia leads to depression in the opposite direction. Directional pleiotropy was not observed in the MR-Egger regression analysis. Additionally, the MR-PRESSO analysis validated these discoveries. Neither the leave-one-out sensitivity test nor the funnel plots revealed any outliers. In both the unadjusted and adjusted estimates, depression has a consistent direct causal effect on hypercholesterolemia. Our study has led to an improved comprehension of the causal connections between hypercholesterolemia and depression, which could aid in the prevention and treatment of hypercholesterolemia.
Asunto(s)
Depresión , Estudio de Asociación del Genoma Completo , Hipercolesterolemia , Análisis de la Aleatorización Mendeliana , Humanos , Hipercolesterolemia/genética , Hipercolesterolemia/epidemiología , Depresión/genética , Depresión/epidemiología , Causalidad , Factores de RiesgoRESUMEN
Low-density lipoprotein cholesterol (LDL-c) is both a therapeutic target and a risk factor for cardiovascular disease (CVD). MicroRNA (miRNA) has been shown to regulate cholesterol homeostasis, and miRNA in blood circulation has been linked to hypercholesterolemia. However, few studies to date have associated miRNA with phenotypes like LDL-c in a healthy population. To this end, we analyzed circulating miRNA in relation to LDL-c in a healthy cohort of 353 participants using two separate bioinformatic approaches. The first approach found that miR-15b-5p and miR-16-5p were upregulated in individuals with at-risk levels of LDL-c. The second approach identified two miRNA clusters, one that positively and a second that negatively correlated with LDL-c. Included in the cluster that positively correlated with LDL-c were miR-15b-5p and miR-16-5p, as well as other miRNA from the miR-15/107, miR-30, and let-7 families. Cross-species analyses suggested that several miRNAs that associated with LDL-c are conserved between mice and humans. Finally, we examined the influence of diet on circulating miRNA. Our results robustly linked circulating miRNA with LDL-c, suggesting that miRNA could be used as biomarkers for hypercholesterolemia or targets for developing cholesterol-lowering drugs.NEW & NOTEWORTHY This study explored the association between circulating microRNA (miRNA) and low-density lipoprotein cholesterol (LDL-c) in a healthy population of 353 participants. Two miRNAs, miR-15b-5p and miR-16-5p, were upregulated in individuals with at-risk LDL-c levels. Several miRNA clusters were positively and negatively correlated with LDL-c and are known to target mRNA involved in lipid metabolism. The study also investigated the influence of diet on circulating miRNA, suggesting potential biomarkers for hypercholesterolemia.
Asunto(s)
LDL-Colesterol , MicroARN Circulante , MicroARNs , Humanos , Masculino , Femenino , LDL-Colesterol/sangre , Persona de Mediana Edad , Estudios de Cohortes , Adulto , MicroARN Circulante/sangre , MicroARN Circulante/genética , MicroARNs/sangre , MicroARNs/genética , Animales , Ratones , Biomarcadores/sangre , Estados Unidos , Lípidos/sangre , Hipercolesterolemia/genética , Hipercolesterolemia/sangre , AncianoRESUMEN
PURPOSE OF REVIEW: Here, we summarize the key findings from preclinical studies that tested the concept that editing of hepatic genes can lower plasma low-density lipoprotein (LDL)-cholesterol levels to subsequently reduce atherosclerotic cardiovascular disease risk. RECENT FINDINGS: Selective delivery of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated gene editing tools targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) to hepatocytes, i.e., through encapsulation into N-acetylgalactosamine-coupled lipid nanoparticles, is able to induce a stable ~ 90% decrease in plasma PCSK9 levels and a concomitant 60% reduction in LDL-cholesterol levels in mice and non-humane primates. Studies in mice have shown that this state-of-the-art technology can be extended to include additional targets related to dyslipidemia such as angiopoietin-like 3 and several apolipoproteins. The use of gene editors holds great promise to lower plasma LDL-cholesterol levels also in the human setting. However, gene editing safety has to be guaranteed before this approach can become a clinical success.
Asunto(s)
Edición Génica , Terapia Genética , Hipercolesterolemia , Proproteína Convertasa 9 , Edición Génica/métodos , Humanos , Animales , Hipercolesterolemia/terapia , Hipercolesterolemia/genética , Terapia Genética/métodos , Proproteína Convertasa 9/genética , LDL-Colesterol/sangre , Sistemas CRISPR-CasRESUMEN
Sitosterolemia is an autosomal recessive and very rare disease. Its main characteristic is that there is a greater absorption and a decrease in the excretion of sterols, which leads to them being deposited in tissues. It is given by mutations in the ABCG5 or ABCG8 genes found on chromosome 2p21. In this clinical note, we describe the first two patients with familial sitosterolemia described in Colombia, brothers, one of them with xanthomas in extremities as the only symptom, and the other, completely asymptomatic. Genetic studies were performed as a diagnostic test in both patients, where a pathogenic homozygous variant could be identified in the ABCG8 gene in the first case (symptomatic), and a heterozygous variant in the ABCG8 gene in the second case (asymptomatic); the first patient has responded to treatment with ezetimibe. In conclusion, xanthomas should be studied in depth in pediatric age as they may be the only visible sign of such complex and hereditary diseases as familial sitosterolemia, which can be controlled and prevent cardiovascular complications of the disease.
Asunto(s)
Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8 , Ezetimiba , Hipercolesterolemia , Enfermedades Intestinales , Errores Innatos del Metabolismo Lipídico , Fitosteroles , Humanos , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/diagnóstico , Masculino , Colombia , Fitosteroles/efectos adversos , Fitosteroles/genética , Enfermedades Intestinales/genética , Enfermedades Intestinales/diagnóstico , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8/genética , Hipercolesterolemia/genética , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/diagnóstico , Ezetimiba/uso terapéutico , Xantomatosis/genética , Xantomatosis/patología , Xantomatosis/diagnóstico , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/administración & dosificación , Mutación , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genética , Homocigoto , Niño , Heterocigoto , Lipoproteínas/genéticaRESUMEN
ABSTRACT: Sitosterolemia is a rare autosomal recessive genetic disorder in which patients develop hypercholesterolemia and may exhibit abnormal hematologic and/or liver test results. In this disease, dysfunction of either ABCG5 or ABCG8 results in the intestinal hyperabsorption of all sterols, including cholesterol and, more specifically, plant sterols or xenosterols, as well as in the impaired ability to excrete xenosterols into the bile. It remains unknown how and why some patients develop hematologic abnormalities. Only a few unrelated patients with hematologic abnormalities at the time of diagnosis have been reported. Here, we report on 2 unrelated pedigrees who were believed to have chronic immune thrombocytopenia as their most prominent feature. Both consanguineous families showed recessive gene variants in ABCG5, which were associated with the disease by in silico protein structure analysis and clinical segregation. Hepatosplenomegaly was absent. Thrombopoietin levels and megakaryocyte numbers in the bone marrow were normal. Metabolic analysis confirmed the presence of strongly elevated plasma levels of xenosterols. Potential platelet proteomic aberrations were longitudinally assessed following dietary restrictions combined with administration of the sterol absorption inhibitor ezetimibe. No significant effects on platelet protein content before and after the onset of treatment were demonstrated. Although we cannot exclude that lipotoxicity has a direct and platelet-specific impact in patients with sitosterolemia, our data suggest that thrombocytopenia is neither caused by a lack of megakaryocytes nor driven by proteomic aberrations in the platelets themselves.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5 , Plaquetas , Hipercolesterolemia , Enfermedades Intestinales , Errores Innatos del Metabolismo Lipídico , Fitosteroles , Proteómica , Trombocitopenia , Humanos , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genética , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8/genética , Plaquetas/metabolismo , Plaquetas/patología , Hipercolesterolemia/sangre , Hipercolesterolemia/genética , Hipercolesterolemia/complicaciones , Enfermedades Intestinales/sangre , Enfermedades Intestinales/diagnóstico , Enfermedades Intestinales/genética , Enfermedades Intestinales/etiología , Enfermedades Intestinales/metabolismo , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/sangre , Errores Innatos del Metabolismo Lipídico/complicaciones , Lipoproteínas , Linaje , Fitosteroles/efectos adversos , Fitosteroles/sangre , Proteoma , Proteómica/métodos , Trombocitopenia/diagnóstico , Trombocitopenia/sangre , Trombocitopenia/etiología , Trombocitopenia/metabolismoRESUMEN
Familial hypercholesterolemia (FH) is one of the most prevalent monogenetic disorders leading to cardiovascular disease (CVD) worldwide. Mutations in Ldlr, encoding a membrane-spanning protein, account for the majority of FH cases. No effective and safe clinical treatments are available for FH. Adenine base editor (ABE)-mediated molecular therapy is a promising therapeutic strategy to treat genetic diseases caused by point mutations, with evidence of successful treatment in mouse disease models. However, due to the differences in the genomes between mice and humans, ABE with specific sgRNA, a key gene correction component, cannot be directly used to treat FH patients. Thus, we generated a knock-in mouse model harboring the partial patient-specific fragment and including the Ldlr W490X mutation. LdlrW490X/W490X mice recapitulated cholesterol metabolic disorder and clinical manifestations of atherosclerosis associated with FH patients, including high plasma low-density lipoprotein cholesterol levels and lipid deposition in aortic vessels. Additionally, we showed that the mutant Ldlr gene could be repaired using ABE with the cellular model. Taken together, these results pave the way for ABE-mediated molecular therapy for FH.
Asunto(s)
Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Humanos , Ratones , Animales , ARN Guía de Sistemas CRISPR-Cas , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/terapia , Mutación , Hipercolesterolemia/genética , Colesterol , Receptores de LDL/genética , Receptores de LDL/metabolismoRESUMEN
This article focuses on a case study of sitosterolemia in a child who initially presented with hemolytic anemia and thrombocytopenia. Sitosterolemia is a rare autosomal recessive lipid metabolism disorder, difficult to diagnose due to its non-typical clinical manifestations. The 8-year-old patient was initially misdiagnosed with pyruvate kinase deficiency. Comprehensive biochemical and molecular biology analyses, including gene sequencing, eventually led to the correct diagnosis of sitosterolemia. This case highlights the complexity and diagnostic challenges of sitosterolemia, emphasizing the need for increased awareness and accurate diagnosis in patients presenting with similar symptoms.
Asunto(s)
Anemia Hemolítica , Hipercolesterolemia , Enfermedades Intestinales , Errores Innatos del Metabolismo Lipídico , Fitosteroles , Fitosteroles/efectos adversos , Trombocitopenia , Niño , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/genética , Fitosteroles/genética , Anemia Hemolítica/diagnóstico , Enfermedades Intestinales/diagnóstico , Enfermedades Intestinales/genética , Trombocitopenia/diagnósticoRESUMEN
Proprotein convertase subtilisin/kexin 9 (PCSK9) is a protein that plays a key role in the metabolism of low-density lipoprotein (LDL) cholesterol. The gain-of-function mutations of the PCSK9 gene lead to a reduced number of surface LDL receptors by binding to them, eventually leading to endosomal degradation. This, in turn, is the culprit of hypercholesterolemia, resulting in accelerated atherogenesis. The modern treatment for hypercholesterolemia encompasses the use of biological drugs against PCSK9, like monoclonal antibodies and gene expression modulators such as inclisiran-a short, interfering RNA (siRNA). Peptide nucleic acid (PNA) is a synthetic analog of nucleic acid that possesses a synthetic peptide skeleton instead of a phosphate-sugar one. This different structure determines the unique properties of PNA (e.g., neutral charge, enzymatic resistance, and an enormously high affinity with complementary DNA and RNA). Therefore, it might be possible to use PNA against PCSK9 in the treatment of hypercholesterolemia. We sought to explore the impact of three selected PNA oligomers on PCSK9 gene expression. Using a cell-free transcription/translation system, we showed that one of the tested PNA strands was able to reduce the PCSK9 gene expression down to 74%, 64%, and 68%, as measured by RT-real-time PCR, Western blot, and HPLC, respectively. This preliminary study shows the high applicability of a cell-free enzymatic environment as an efficient tool in the initial evaluation of biologically active PNA molecules in the field of hypercholesterolemia research. This cell-free approach allows for the omission of the hurdles associated with transmembrane PNA transportation at the early stage of PNA selection.
Asunto(s)
Hipercolesterolemia , Inhibidores de PCSK9 , Ácidos Nucleicos de Péptidos , Humanos , Expresión Génica , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/genética , Ácidos Nucleicos de Péptidos/farmacología , Proproteína Convertasa 9/efectos de los fármacos , Proproteína Convertasa 9/genética , Proproteína Convertasas/genética , Receptores de LDL/genética , Receptores de LDL/metabolismo , Subtilisina/genética , Inhibidores de PCSK9/farmacologíaRESUMEN
This clinical study examined the influence of SLCO1B1 c.521T>C (rs4149056) on plasma atorvastatin concentrations in pediatric hypercholesterolemia. The participants (8-21 years), including heterozygous (c.521T/C, n = 13), homozygous (c.521C/C, n = 2) and controls (c.521T/T, n = 13), completed a single-oral-dose pharmacokinetic study. Similar to in adults, the atorvastatin (AVA) area-under-concentration-time curve from 0 to 24 h (AUC0-24) was 1.7-fold and 2.8-fold higher in participants with c.521T/C and c.521C/C compared to the c.521T/T participants, respectively. The inter-individual variability in AVA exposure within these genotype groups ranged from 2.3 to 4.8-fold, indicating that additional factors contribute to the inter-individual variability in the AVA dose-exposure relationship. A multivariate model reinforced the SLCO1B1 c.521T>C variant as the central factor contributing to AVA systemic exposure in this pediatric cohort, accounting for ~65% of the variability in AVA AUC0-24. Furthermore, lower AVA lactone concentrations in participants with increased body mass index contributed to higher exposure within the c.521T/T and c.521T/C genotype groups. Collectively, these factors contributing to higher systemic exposure could increase the risk of toxicity and should be accounted for when individualizing the dosing of atorvastatin in eligible pediatric patients.
Asunto(s)
Hipercolesterolemia , Adulto , Humanos , Niño , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/genética , Atorvastatina/uso terapéutico , Genotipo , Heterocigoto , Variación Genética , Transportador 1 de Anión Orgánico Específico del Hígado/genéticaRESUMEN
BACKGROUND: Current antiplatelet agents exhibit reduced antithrombotic efficacy in high-risk populations such as populations with hypercholesterolemia. The class II PI3-kinase, PI3KC2α, is a recently discovered target for novel antiplatelet therapy. PI3KC2α inhibition is antithrombotic in healthy mouse models, but whether this is preserved in hypercholesterolemia remains unknown. OBJECTIVES: This study aimed to examine whether genetic deficiency or pharmacologic inhibition of PI3KC2α provides antithrombotic effects in blood from hypercholesterolemic mice. METHODS: Hypercholesterolemic PI3KC2α-deficient mice were generated by breeding into an ApoE-/- background. Thrombosis was examined using an ex vivo whole blood thrombosis assay. The effect of pharmacologic inhibition of PI3KC2α was examined in whole blood from ApoE-/- mice treated with the PI3KC2α inhibitor MIPS-21335. RESULTS: ApoE-/- mice exhibited the anticipated prothrombotic effect of hypercholesterolemia, with a 1.5-fold increase in thrombus volume in blood from ApoE-/- vs wild-type mice. This prothrombotic phenotype in blood from hypercholesterolemic mice was significantly reduced with PI3KC2α deficiency. Acute pharmacologic inhibition of PI3KC2α with MIPS-21335 similarly reduced thrombosis in blood from ApoE-/- mice. CONCLUSION: These findings demonstrate that targeting PI3KC2α results in a potent antithrombotic effect in hypercholesterolemic mice and suggest that PI3KC2α is a promising target for antithrombotic therapy in patients with hypercholesterolemia at a high risk of thrombotic events.
Asunto(s)
Hipercolesterolemia , Trombosis , Animales , Ratones , Apolipoproteínas E/farmacología , Apolipoproteínas E/uso terapéutico , Plaquetas , Fibrinolíticos/farmacología , Fibrinolíticos/uso terapéutico , Hipercolesterolemia/complicaciones , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/genética , Trombosis/tratamiento farmacológico , Trombosis/prevención & controlRESUMEN
Familial hypercholesterolemia (FH) is a metabolic condition caused mainly by a mutation in the low-density lipoprotein (LDL) receptor gene (LDLR), which is highly prevalent in the population. Besides being an important causative factor of cardiovascular diseases, FH has been considered an early risk factor for Alzheimer's disease. Cognitive and emotional behavioral impairments in LDL receptor knockout (LDLr-/-) mice are associated with neuroinflammation, blood-brain barrier dysfunction, impaired neurogenesis, brain oxidative stress, and mitochondrial dysfunction. Notably, today, LDLr-/- mice, a widely used animal model for studying cardiovascular diseases and atherosclerosis, are also considered an interesting tool for studying dementia. Here, we reviewed the main findings in LDLr-/- mice regarding the relationship between FH and brain dysfunctions and dementia development.
Asunto(s)
Enfermedad de Alzheimer , Enfermedades Cardiovasculares , Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Humanos , Animales , Ratones , Hipercolesterolemia/epidemiología , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Enfermedades Cardiovasculares/genética , Factores de Riesgo , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo II/genética , Encéfalo/metabolismo , Cognición , Factores de Riesgo de Enfermedad CardiacaRESUMEN
BACKGROUND AND AIMS: Dendritic cells (DCs), professional antigen-presenting cells, play an important role in pathologies by controlling adaptive immune responses. However, their adaptation to and functionality in hypercholesterolemia, a driving factor in disease onset and progression of atherosclerosis remains to be established. METHODS: In this study, we addressed the immediate impact of high fat diet-induced hypercholesterolemia in low-density lipoprotein receptor deficient (Ldlr-/-) mice on separate DC subsets, their compartmentalization and functionality. RESULTS: While hypercholesterolemia induced a significant rise in bone marrow myeloid and dendritic cell progenitor (MDP) frequency and proliferation rate after high fat diet feeding, it did not affect DC subset numbers in lymphoid tissue. Hypercholesterolemia led to almost immediate and persistent augmentation in granularity of conventional DCs (cDCs), in particular cDC2, reflecting progressive lipid accumulation by these subsets. Plasmacytoid DCs were only marginally and transiently affected. Lipid loading increased co-stimulatory molecule expression and ROS accumulation by cDC2. Despite this hyperactivation, lipid-laden cDC2 displayed a profoundly reduced capacity to stimulate naïve CD4+ T cells. CONCLUSION: Our data provide evidence that in hypercholesterolemic conditions, peripheral cDC2 subsets engulf lipids in situ, leading to a more activated status characterized by cellular ROS accumulation while, paradoxically, compromising their T cell priming ability. These findings will have repercussions not only for lipid driven cardiometabolic disorders like atherosclerosis, but also for adaptive immune responses to pathogens and/or endogenous (neo) antigens under conditions of hyperlipidemia.
Asunto(s)
Aterosclerosis , Hipercolesterolemia , Ratones , Animales , Linfocitos T , Especies Reactivas de Oxígeno/metabolismo , Hipercolesterolemia/genética , Células Dendríticas , Aterosclerosis/metabolismo , LípidosRESUMEN
BACKGROUND: Observational studies have shown a causal association between dyslipidemia and osteoporosis, but the genetic causation and complete mechanism of which are uncertain. The disadvantage of previous observational studies is that they are susceptible to confounding factors and bias, that makes it difficult to infer a causal link between those two diseases. Abnormal epigenetic modifications, represented by DNA methylation, are important causes of many diseases. However, there are no studies showing a bridging role for methylation modifications in blood lipid metabolism and osteoporosis. METHODS: SNPs for lipid profile (Blood VLDL cholesterol (VLDL-C), blood LDL cholesterol (LDL-C), blood HDL cholesterol (HDL-C), blood triglycerides (TG), diagnosed pure hypercholesterolaemia, blood apolipoprotein B (Apo B), blood apolipoprotein A1(Apo A1)), and bone mineral density (BMD) in different body parts (Heel BMD, lumbar BMD, whole-body BMD, femoral neck BMD) were obtained from large meta-analyses of genome-wide association studies as instrumental variables for two-sample Mendelian randomization. Assessment of the genetic effects of lipid profile-associated methylation sites and bone mineral density was carried out using the summary-data-based Mendelian randomization (SMR) method. RESULTS: Two-sample Mendelian randomization showed that there was a negative causal association between hypercholesterolaemia and heel BMD (p = 0.0103, OR = 0.4590), and total body BMD (p = 0.0002, OR = 0.2826). LDL-C had a negative causal association with heel BMD (p = 8.68E-05, OR = 0.9586). VLDL-C had a negative causal association with heel BMD (p = 0.035, OR = 0.9484), lumbar BMD (p = 0.0316, OR = 0.9356), and total body BMD (p = 0.0035, OR = 0.9484). HDL-C had a negative causal association with heel BMD (p = 1.25E-05, OR = 0.9548), lumbar BMD (p = 0.0129, OR = 0.9358), and total body BMD (p = 0.0399, OR = 0.9644). Apo B had a negative causal association with heel BMD (p = 0.0001, OR = 0.9647). Apo A1 had a negative causal association with heel BMD (p = 0.0132, OR = 0.9746) and lumbar BMD (p = 0.0058, OR = 0.9261). The p-values of all positive results corrected by the FDR method remained significant and sensitivity analysis showed that there was no horizontal pleiotropy in the results despite the heterogeneity in some results. SMR identified 3 methylation sites associated with lipid profiles in the presence of genetic effects on BMD: cg15707428(GREB1), cg16000331(SREBF2), cg14364472(NOTCH1). CONCLUSION: Our study provides insights into the potential causal links and co-pathogenesis between dyslipidemia and osteoporosis. The genetic effects of dyslipidaemia on osteoporosis may be related to certain aberrant methylation genetic modifications.