HMG-CoA Research Articles

The impact of SLCO1B1 single nucleotide polymorphism and non-genetic factors on statin-induced myopathy

Abstract Funding Acknowledgements None. Background Statins, also known as HMG CoA Reductase Inhibitors, are a class of drugs considered the drug of choice for treating hypercholesterolemia. Statins are well tolerated; however, they may cause severe myopathy in 20% to 30% of patients, due to the individual variation regarding its efficacy and related adverse effects. Of these, comes the Single Nucleotide Polymorphism (SNP) T521C of the SLCO1B1 gene that encodes the protein involved in the trafficking of statins from the blood to hepatocytes which is called Organic Anion Transport Protein 1B1 (OATP1B1). The T521C single nucleotide polymorphism (SNP) results in a substitute of valine with alanine resulting in a decreased or lack of functional protein. Purpose The aim is to determine the frequency of the high-risk C allele and to define its impact on statin-induced myopathy in Syrian patients on statins. In addition to the non-genetic factors that may affect the ability to develop statin-induced myopathy. Methods This was an observational case-control study that had ethical approval from Damascus University (No.433/ 2020). The case group included 44 patients on statins who experienced myopathy, 18 patients who had increased creatinine kinase levels (CK), and 26 patients with normal CK levels, while the control group encompassed 56 patients who were taking statins and had no muscular adverse events. The DNA was extracted from each sample and then genotyped using standard sequencing of specific PCR products using a specific pair of primers. Results The age of patients in the case arm ranged between 27 and 84 years with an average ± SD of (58.2 ± 12.7 years), 70% of them were males. In comparison with (53.34 ± 12.4 years) in the control arm, 66% of them were males without a statistically significant differences (p=0.672, 0.057) respectively. The statin type and dose have a statistically non-significant effect, the average statin dose in the case arm and the control arm was 26.02 mg and 31.27 mg respectively (p=0.072). While the statin type treatment varied as 59% used atorvastatin and 39% used rosuvastatin in the case group compared with 71% used atorvastatin and 27% used rosuvastatin in the control group, without a statistically significant difference (p=0.252). The frequency of the C allele reaches 19.3% and is distributed in three genotypes: wild-type TT (68%), heterozygote TC (25%), and homozygote CC (7%) in the case arm, while it does not exceed 8% in the control arm with the absence of the CC genotype. Only a statistically significant difference was found in the frequency of the CC genotype between these two groups (p=0.047). Conclusion Our study is the first to identify the frequency of the 521T>C SNP of the SLCO1B1 gene in Syrian patients taking statins. Our data reveals a high prevalence of risk allele C in the patients who suffer from statin-induced myopathy with a statically significant difference from the control arm (p=0.026).

Soy and Dragon Fruit Functional Drink : The Potential to Reduce Cholesterol Total Levels in Hypercholesterolemic Sprague Dawley Rats

Hypercholesterolemia is a lipid metabolism disorder characterized by increased blood cholesterol levels. The alternative functional drinks that can reduce cholesterol levels are beverage ingredients that contain flavonoids, such as red dragon fruit and soybeans. Flavonoids can inhibit cholesterol synthesis by inhibiting the HMG-CoA reductase enzyme. Soybeans are also have a hypocholesterolemic effect because they contain isoflavones. This study aimed to determined the potential of soybean and dragon fruit peel powder on the cholesterol levels of hypercholesterolemic Sprague Dawley rats. This study was a true-experimental design with a pretest - posttest with control group. The samples were 27 male Sprague Dawley rats, weighing 150-250 grams and aged 2 -3 months. The samples were divided into a control group and a treatment group that was given soybeans dragon fruit peel powder drink at a dose of 12.8 ml/kgBB/day for 14 days. Total cholesterol levels were measured using the CHOD–PAP method. Data were analyzed using the One Way Anova test, Post Hoc or Man Whitney test and Paired T-test. The results showed that there was a significant difference in total cholesterol levels in mice before and after the intervention (p= 0.003). Giving soybeans dragon fruit peels powder drink can significantly reduce total cholesterol levels in the treatment group (P) by 18.45% (p= 0.044).

HMG-CoA reductase is a potential therapeutic target for migraine: a mendelian randomization study

Statins are thought to have positive effects on migraine but existing data are inconclusive. We aimed to evaluate the causal effect of such drugs on migraines using Mendelian randomization. We used four types of genetic instruments as proxies for HMG-CoA reductase inhibition. We included the expression quantitative trait loci of the HMG-CoA reductase gene and genetic variation within or near the HMG-CoA reductase gene region. Variants were associated with low-density lipoprotein cholesterol, apolipoprotein B, and total cholesterol. Genome-wide association study summary data for the three lipids were obtained from the UK Biobank. Comparable data for migraine were obtained from the International Headache Genetic Consortium and the FinnGen Consortium. Inverse variance weighting method was used for the primary analysis. Additional analyses included pleiotropic robust methods, colocalization, and meta-analysis. Genetically determined high expression of HMG-CoA reductase was associated with an increased risk of migraines (OR = 1.55, 95% CI 1.30–1.84, P = 6.87 × 10−7). Similarly, three genetically determined HMG-CoA reductase-mediated lipids were associated with an increased risk of migraine. These conclusions were consistent across meta-analyses. We found no evidence of bias caused by pleiotropy or genetic confounding factors. These findings support the hypothesis that statins can be used to treat migraine.

The Potential of Flavonoid Derivative Compounds as Inhibitors of the HMG-CoA Reductase Enzyme for Candidate of Hypercholesterolemia Drugs

Cardiovascular disease (CVD) is a disease that causes death in the world. Behavioral risk factors are crucial in dealing with CVD disease. High levels of cholesterol in the blood are associated with hypercholesterolemia. It can increase the risk of CVD disease. The HMG-CoA reductase enzyme is an enzyme that plays a role in cholesterol synthesis. It will convert the HMG-CoA compound into the mevalonate. Inhibition of this enzyme can reduce cholesterol synthesis because it inhibits the formation of mevalonate, which is the initial stage of cholesterol synthesis. Herbal compounds are compounds produced by plants. It has good benefits for the body. Flavonoid compounds can be beneficial for health. Molecular docking is a method used to determine the binding affinity and interaction values ​​of the enzyme protein interaction with the ligand to be bound. The results of Apigenin binding affinity values is -7.7 kcal/mol, Luteolin is -8 kcal/mol, Quercetin is -8.2 kcal/mol, Kaempferol is -7.4 kcal/mol, Phloretin is -6.8 kcal/mol, Chalconaringenin is -6.9 kcal/mol, Cyanidin is -7.9 kcal/mol, Delphinidin is -7.8 kcal/mol, Hesperetin is -7.7 kcal/mol, Narigenin is -7.8 kcal/mol, Daidzein is -6.8 kcal/mol, Genistein is -7 kcal/mol, Rutin is -9.2 kcal/mol, Taxifolin is -8 kcal /mol, Diosmetin is -7.6 kcal/mol, and its native ligand Rosuvastatin is -8.5 kcal/mol. Flavonoid derivative compounds can bind to the HMG-CoA reductase enzyme. They can be candidates for antihyperlipidemia drugs.

C.2 An in-depth analysis of pediatric inflammatory myopathies: findings from a comprehensive tertiary care hospital

Background: Pediatric inflammatory myopathies (PIM) are a rare, heterogenous group of disorders requiring prompt diagnosis and treatment to reduce complications and improve long-term outcome. This study reviews the clinical characteristics, management, and outcomes in PIM. Methods: A retrospective analysis of pediatric patients diagnosed with PIM at CHEO from January 2009 to December 2023 was performed. Patient data, including age at symptom onset, diagnostic testing performed, treatment, and follow-up durations, were evaluated. Results: A total of 25 patients with juvenile dermatomyositis (JDM), overlap syndromes, and necrotizing myopathy (HMG-CoA reductase and anti-SRP myositis) were identified. Symptoms began at an average age of 8.37 years (1.10-14.11), with formal diagnosis occurring at 8.57 years (2.02-16.11). Initial symptoms included skin changes, muscle weakness, joint pain, and fatigue. Diagnosis involved laboratory testing (CK, myositis antibodies), muscle MRI, electromyography, and/or muscle biopsy. Treatments included corticosteroids, IVIG, and steroid-sparing agents (methotrexate, mycophenolate mofetil, rituximab, hydroxychloroquine). Follow-up averaged 4.23 years (range: 0.5 to 13). Most patients displayed only mild residual symptoms with the exception of an anti-SRP myositis patient who became wheelchair-dependent, requiring ventilatory support. Conclusions: Inflammatory myopathies require prompt treatment to prevent complications. Most patients require multiple treatment modalities, however with early diagnosis and treatment the majority of patients’ symptoms resolve.

P.064 A case of late onset Pompe Disease presenting in 6th decade

Background: Late onset Pompe disease (LOPD), rare autosomal recessive lysosomal storage disease, resulting from mutation in alpha glucosidase enzyme (GAA) can present even in 6th decade of life. Slowly progressive, subtle, limb girdle pattern of weakness (LGPW), with auxiliary features such as ptosis, enlarged tongue, axial rigidity, facial diplegia, variable degree of respiratory weakness is not uncommon. Hypertrophic and electrical cardiac abnormalities are well described in LOPD. Methods: We present a case of 67-year-old male presenting with proximal weakness, subtle ptosis, bilateral quadriceps and shoulder girdle atrophy, and left toe numbness. PMHx: CABG, NSTEMI. Statin use. FMHx: noncontributory. Results: EMG: L5 radiculopathy, with unexpected myopathic units in hip/pelvic/ shoulder girdle muscles with active denervation and muscle irritability. CK, CRP, SPEP, ANA, LFTs, HMG-CoA reductase: normal. GAA enzymatic activity=0.96µmol/L/hr (low), genetics: pathogenic variants in GAA gene: c.-32-13T>G and c.1194+3G>C. ECHO: severe diastolic dysfunction, restrictive left ventricular filling. PFTs: normal. Diagnosed with LOPD, started on therapy. Conclusions: LOPD remains a differential for LGPW especially in older patient population with history of cardiopulmonary features. Age-appropriate conconminant pathologies may confound the diagnostic process.Symptoms may preceed diagnosis for years.GAA enzymatic activity followed by genetic testing remains readily available and can confirm diagnosis, preventing delay of approved therapy.

#843 Methylation of HMGCR gene promoter in patients on hemodialysis

Abstract Background and Aims Patients with chronic kidney disease (CKD) exhibit a pronounced risk for cardiovascular mortality; the most vulnerable group enrolls patients on hemodialysis. Unfortunately no meaningful decrease of cardiovascular risk after cholesterol lowering medication – inhibitors of HMGCR - was demonstrated in hemodialysed patients. The incidence of complications in CKD patients correlates with changed epigenetic mechanisms, the most studied epigenetic phenomenon is DNA methylation. The aim of this study was to elucidate the methylation status of HMGCR gene and evaluate its impact on cardiovascular morbidity and mortality in patients receiving hemodialysis. Method We analyzed DNA in plasma of 21 hemodialyzed patients before and after dialysis. Then bisulfite conversion was carried out to distinguish methylated and unmethylated form of DNA. The primers of HMGCR genes promoters were designed, after that methylation specific PCR and sequential analysis of PCR products were performed. Results Although the methylation rate of HMGCR gene dropped 9 patients during the hemodialysis session, no statistical significance of this demethylation was confirmed. No correlation of methylation status of HMGCR gene and cholesterol or phosphorus was confirmed. Hypomethylated promoter of HMGCR gene was found in 6 patients, who either underwent amputation of lower extremity due to arterial ischemia or has deceased due to cardiovascular event during next 6 month of follow-up period. Conclusion This study suggests that both DNA demethylation and consecutive increased expression of HMGCR gene could be predictors of high risk of cardiovascular morbidity and mortality in hemodialyzed diabetic patients.

STUDYING THE HYPOLYPIDEMIC ACTIVITY OF FLAVONOIDS AND ISOFLAVONOIDS OF THE ONONIS ARVENSIS L. METHODS BY IN SILICO

Introduction. Today, one of the reliably known causes of mortality in the Russian Federation is diseases of the cardiovascular system, a significant part of which is associated with atherosclerotic disease. Combination therapy for diseases of the cardiovascular system includes, among other things, the use of modern lipid-lowering drugs, the use of which is often limited due to their pronounced side effects. In this regard, it seemed appropriate to search for new compounds of natural origin that potentially have lipid-lowering activity with minimal side effects. According to the scientific literature, natural phenolic compounds, namely substances from the group of flavonoids and isoflavonoids, have a set of such characteristics. In this regard, steelgrass (Ononis arvensis L.), the chemical composition of which is extremely rich and diverse in terms of flavonoids and isoflavonoids, can be a ra-ther promising source for searching and screening compounds with a given activity. The aim of the study. The purpose of the work was to study and predict the hypolipidemic activity of flavonoids and isoflavonoids of Ononis arvensis L. using in silico methods. Material and methods. The objects of the study were the structural formulas of flavonoids and isoflavonoids of field steelhead. Calculation of mo-lecular properties was carried out using the Molinspiration chemoinformatic software. Computer prediction of lipid-lowering activity was carried out us-ing the PASS-online service. Molecular docking was performed using the CB-Dock2 services for blind docking and Webina 1.0.5 for active site docking. Hepatotoxicity, mutagenicity and cytotoxicity of the analyzed biologically active substances were studied using the ProTox-II resource. Results. As a result of in silico studies, it was found that most of the studied flavonoids and isoflavonoids correspond to the Lipinski rule and the drug-likeness concept. In addition, for all studied biologically active substances, activities associated with a decrease in lipid fractions in the body were predicted. The results of molecular docking indicate that all analyzed compounds are capable of potentially inhibiting the enzyme HMG-CoA reductase, which makes it possible to predict the required lipid-lowering effect. Studying the toxicity of the research objects, most of them in silico demonstrated a high level of safety. Conclusions. The prospects for further research on the development of targeted technology for obtaining herbal preparations from steelhead, enriched with flavonoids and isoflavonoids, as well as subsequent tests to confirm hypolipidemic activity in in vitro and in vivo experiments are shown.

Potential Benefits of Statin Therapy in Reducing Osteoarthritis Risk: A Mendelian Randomization Study.

The purpose of this study was to determine the causal effect of statins on osteoarthritis (OA) risk using Mendelian randomization (MR). Single nucleotide polymorphism-based genome-wide association analyses of statins were collected from the UK Biobank and FinnGen dataset, and OA data were collected from the UK Biobank and Arthritis Research UK Osteoarthritis Genetics (arcOGEN) study. Two-sample MR analyses were performed using the inverse-variance weighted (IVW) technique. MR-Egger, weighted median, and weighted mode served as supplementary analyses. MR-Egger regression, Cochran's Q test, and Mendelian Randomization Pleiotropy Residual Sum and Outlier analysis were performed as sensitivity analyses. Hydroxymethylglutaryl-coenzyme A reductase (HMGCR) expression and OA risk were evaluated using summary data-based MR (SMR). MR analyses consistently supported a causal connection between statin use and OA risk. A causal effect was observed for atorvastatin (IVW: β = -2.989, P = 0.003) and rosuvastatin (IVW: β = -14.141, P = 0.006) treatment on hip OA. Meta-analysis showed the association between atorvastatin and knee OA was statistically significant (odds ratio 0.15; P = 0.004). Simvastatin use exhibited a protective effect against knee (IVW: β = -1.056, P = 0.004) and hip OA (IVW: β = -1.405, P = 0.001). Statin medication showed a protective effect on hip OA (IVW: β = -0.054, P = 0.013). HMGCR correlated significantly with a reduced risk of knee OA (β = -0.193, PSMR = 0.017), rather than hip OA (β = 0.067, PSMR = 0.502), which suggested that statins' protective effect on OA may not be related to its lipid-lowering effect. This MR study provides compelling evidence that statin treatment may be a protective factor for OA. Further research is required to clarify its underlying mechanism.

Understanding the (epi)genetic dysregulation in Parkinson's disease through an integrative brain competitive endogenous RNA network

Parkinson’s disease (PD) is a rapidly growing neurodegenerative disorder characterized by dopaminergic neuron loss in the substantia nigra pars compacta (SN) and aggregation of α-synuclein. Its aetiology involves a multifaceted interplay among genetic, environmental, and epigenetic factors. We integrated brain gene expression data from PD patients to construct a comprehensive regulatory network encompassing messenger RNAs (mRNAs), microRNAs (miRNAs), circular RNAs (circRNAs) and, for the first time, RNA binding proteins (RBPs). Expression data from the SN of PD patients and controls were systematically selected from public databases to identify combined differentially expressed genes (DEGs). Brain co-expression analysis revealed modules comprising significant DEGs that function cooperatively. The relationships among co-expressed DEGs, miRNAs, circRNAs, and RBPs revealed an intricate competitive endogenous RNA (ceRNA) network responsible for post-transcriptional dysregulation in PD. Many genes in the ceRNA network, including the TOMM20 and HMGCR genes, overlap with the most relevant genes in our previous Alzheimer’s disease-associated ceRNA network, suggesting common underlying mechanisms between both conditions. Moreover, in the ceRNA subnetwork, the RBP Aly/REF export factor (ALYREF), which acts as an RNA 5-methylcytosine(m5C)-binding protein, stood out. Our data sheds new light on the potential role of brain ceRNA networks in PD pathogenesis.

Bioactive peptides derived from the enzymatic hydrolysis of cowhide collagen for the potential treatment of atherosclerosis: A computational approach

Cowhide collagen hydrolysates (CCHs) are peptides and amino acids obtained from the partial hydrolysis of collagen. These have numerous potential applications in the food, biomedical, and pharmaceutical industries. The study analyzed the physicochemical, antioxidant, and anti-atherosclerosis properties of collagen hydrolysates (CCHs) from cowhide using in silico methods. Proteins were identified in silico based on their molecular weights and origin from the protein database (UniProtKB). Using bioinformatics tools, numerous physicochemical properties (toxicity and amino acid composition) were determined. The identified proteins were subsequently subjected to an in silico enzymatic hydrolysis using pepsin, thermolysin, and proteinase K. The peptides obtained were characterized. Molecular docking was conducted between the peptides generated in silico and the three target enzymes (3-Hydroxy-3-Methylglutaryl-CoA (HMG-CoA) reductase, cyclooxygenase-2, and Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase). Two cowhide collagens were identified, F1MJQ6 and G3MZI7, with molecular weights of 172,076 and 184,867 ​Da, respectively. A compositional analysis of F1MJQ6 and G3MZI7 revealed the significant presence of glycine residues at 25% and 23%, and proline residues at 16% and 18%, respectively. The G3MZI7 and F1MJQ6 proteins exhibited a high concentration of both essential and semi-essential amino acids. The molecular docking results indicate that the antioxidant peptides ADF, PHF, and LW (novel potential anti-atherosclerosis peptides released by enzymatic hydrolysis with pepsin, thermolysin, and proteinase K) are the most promising candidates for further development as inhibitors of HMG-CoA reductase, cyclo-oxygenase-2, and NADPH oxidase. In silico analysis revealed that cowhide collagen hydrolysates exhibited particularly significant antioxidant and anti-atherosclerosis properties.

Examining the Causal Connection between Lipid-lowering Medications and Malignant Meningiomas through Drug-target Mendelian Randomization Analysis

Objectives: This study aims to investigate the causal link between the use of statins, a type of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, and the risk of developing malignant meningiomas, which are aggressive and recurrent tumors of the central nervous system with limited treatment options. Methods: Using Mendelian Randomization (MR) analysis, the study explored the relationship between genetic variants related to the expression of lipid-lowering drug targets (HMGCR, PCSK9, NPC1L1, and APOB) and malignant meningiomas. The analysis utilized data from Genome-Wide Association Studies (GWAS) and expression quantitative trait loci (eQTL) databases, with a focus on the genetic homogeneity of the Finnish population. Instrumental variables for the MR analysis were derived from significant eQTLs for the mentioned drug targets. Results: The MR analysis found a significant association between genetic variants linked to HMGCR inhibitor (statin) exposure and a reduced risk of malignant meningiomas. Specifically, an increased expression of the HMGCR gene in the blood was associated with lower susceptibility to malignant meningiomas (Odds Ratio [OR] = 2.57, 95% Confidence Interval [CI] = 1.05 - 6.31; p = 0.039). No significant associations were observed for other lipid-lowering drug targets. Conclusion: Preliminary evidence suggests that statin use may lower the risk of developing malignant meningiomas, indicating a potential therapeutic benefit for managing this type of cancer. However, further research, including clinical trials, is necessary to confirm these findings and understand the mechanisms behind the protective effect of statins against malignant meningiomas.

Liver X receptor activation in chronic myelogenous leukemia cells yields distinct mass fingerprints by whole cell MALDI-TOF MS, which correspond to changes in cell viability, gene expression, and differentiation markers

Liver X receptor (LXR) agonists, including synthetic ligands or naturally-occurring oxysterols, exert promising lipid-modulating, anti-inflammatory, and anti-tumor effects. Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) whole cell mass spectrometry (MS) shows promise in chronic disease and food science research, clinical diagnostics of cancer cells and bacterial pathogens, and drug/nutraceutical discovery due to its relatively low-cost, rapid, reliable, and high-throughput ability to identify unique cell phenotypes and differentiation states of immune cells that play essential roles in chronic metabolic and inflammatory disease pathophysiology. However, optimization of whole cell MALDI-TOF MS-based methods to assess cellular changes in response to pharmaceutical and/or nutraceutical treatment warrants further study. Thus, we investigated whether whole cell MALDI-TOF MS could detect cellular phenotype changes of human stem-like erythroleukemia K562 cells – a model for chronic myelogenous leukemia (CML) – induced by the LXR agonist TO-901317, a synthetic ligand that mimics effects of naturally-occurring oxysterols, which are oxidized cholesterol derivatives formed under conditions of high cellular cholesterol concentrations and in food products. TO-901317 dose- and time-dependently altered mRNA expression of cholesterol flux genes, including ATP-binding cassette transporter A1 (ABCA1), LDL-receptor (LDLR), HMG-CoA reductase (HMGCR), and reduced cellular cholesterol content by 22.9% at 24 h. TO-901317 additionally dose- and time-dependently impacted K562 cell viability, number, size, and reduced mRNA expression of the anti-apoptotic gene BCL2L1 by 43.3%. These effects corresponded to induced gene expression of erythroid markers and hemoglobin content, suggesting that LXR activation may promote erythroid lineage differentiation. Whole cell MALDI-TOF MS mass fingerprinting revealed distinct proteomic phenotypes between TO-901317 vs. untreated cells, and identified histone 2 A and histone H4 as uniquely expressed proteins. These findings not only elucidate a novel role for LXR agonists in a model of CML, but demonstrate that mass fingerprints obtained by whole cell MALDI-TOF mass spectrometry effectively distinguish between treatment-induced cell phenotypes.

Doenjang Ameliorates Diet-Induced Hyperlipidemia and Hepatic Oxidative Damage by Improving Lipid Metabolism, Oxidative Stress, and Inflammation in ICR Mice.

Hyperlipidemia, characterized by elevated cholesterol, lipids, and triglycerides in the bloodstream, is linked to hepatic oxidative damage. Doenjang, a traditional Korean condiment made from fermented soybeans, is known for its health benefits, yet its anti-hyperlipidemic effects remain understudied. Our study aimed to assess the hypolipidemic and hepatic protective effects of Doenjang on male ICR mice fed a high-fat cholesterol diet for 8 weeks. Mice were divided into three groups: the normal diet (ND), the high-fat cholesterol diet (HD), and the Doenjang-supplemented HD diet (DS) group. Doenjang supplementation significantly regulated total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol levels compared to the HD group. It also downregulated lipogenic genes, including PPARγ, FAS, and ACC, and positively influenced the cholesterol metabolism-related genes HMGCR and LXR. Moreover, Doenjang intake increased serum glutathione levels, activated oxidative stress defense genes (NRF2, SOD, GPx1, and CAT), positively modulated inflammation genes (NF-kB and IL6) in hepatic tissue, and reduced malondialdehyde levels. Our findings highlight the effectiveness of traditional Doenjang in preventing diet-induced hyperlipidemia and protecting against hepatic oxidative damage.

Combined hypolipidemic therapy with rosuvastatin and ezetimibe is the key to success in the treatment and prevention of cardiovascular diseases

Combined hypolipidemic therapy with rosuvastatin and ezetimibe is the key to success in the treatment and prevention of cardiovascular diseases

Effects of HMGCR deficiency on skeletal muscle development.

Pathogenic variants in HMGCR were recently linked to a limb-girdle muscular dystrophy (LGMD) phenotype. The protein product HMG CoA reductase (HMGCR) catalyzes a key component of the cholesterol synthesis pathway. The two other muscle diseases associated with HMGCR, statin-associated myopathy (SAM) and autoimmune anti-HMGCR myopathy, are not inherited in a Mendelian pattern. The mechanism linking pathogenic variants in HMGCR with skeletal muscle dysfunction is unclear. We knocked down Hmgcr in mouse skeletal myoblasts, knocked down hmgcr in Drosophila, and expressed three pathogenic HMGCR variants (c.1327C>T, p.Arg443Trp; c.1522_1524delTCT, p.Ser508del; and c.1621G>A, p.Ala541Thr) in Hmgcr knockdown mouse myoblasts. Hmgcr deficiency was associated with decreased proliferation, increased apoptosis, and impaired myotube fusion. Transcriptome sequencing of Hmgcr knockdown versus control myoblasts revealed differential expression involving mitochondrial function, with corresponding differences in cellular oxygen consumption rates. Both ubiquitous and muscle-specific knockdown of hmgcr in Drosophila led to lethality. Overexpression of reference HMGCR cDNA rescued myotube fusion in knockdown cells, whereas overexpression of the pathogenic variants of HMGCR cDNA did not. These results suggest that the three HMGCR-related muscle diseases share disease mechanisms related to skeletal muscle development.

Simvastatin attenuates silica-induced pulmonary inflammation and fibrosis in rats via the AMPK-NOX pathway

BackgroundSimvastatin (Sim), a hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been widely used in prevention and treatment of cardiovascular diseases. Studies have suggested that Sim exerts anti-fibrotic effects by interfering fibroblast proliferation and collagen synthesis. This study was to determine whether Sim could alleviate silica-induced pulmonary fibrosis and explore the underlying mechanisms.MethodsThe rat model of silicosis was established by the tracheal perfusion method and treated with Sim (5 or 10 mg/kg), AICAR (an AMPK agonist), and apocynin (a NOX inhibitor) for 28 days. Lung tissues were collected for further analyses including pathological histology, inflammatory response, oxidative stress, epithelial mesenchymal transformation (EMT), and the AMPK-NOX pathway.ResultsSim significantly reduced silica-induced pulmonary inflammation and fibrosis at 28 days after administration. Sim could reduce the levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α and transforming growth factor-β1 in lung tissues. The expressions of hydroxyproline, α-SMA and vimentin were down-regulated, while E-cad was increased in Sim-treated rats. In addition, NOX4, p22pox, p40phox, p-p47phox/p47phox expressions and ROS levels were all increased, whereas p-AMPK/AMPK was decreased in silica-induced rats. Sim or AICAR treatment could notably reverse the decrease of AMPK activity and increase of NOX activity induced by silica. Apocynin treatment exhibited similar protective effects to Sim, including down-regulating of oxidative stress and inhibition of the EMT process and inflammatory reactions.ConclusionsSim attenuates silica-induced pulmonary inflammation and fibrosis by downregulating EMT and oxidative stress through the AMPK-NOX pathway.

Effect of finger millet (Eleusine coracana) flour and malt on sirtuin1 protein in hypercholesterolemic rats

Finger millets are consumed as flour and malt with both forms promoting good health. Sirtuin1 protein impact metabolic pathways and improves health. Hypercholesterolemia is leading cause of several degenerative disorders. Since effect of flour and malt on sirtuin1 protein remains elusive so present study was designed to explore potential of finger millet flour and malt in hypercholesterolemic rats. The results showed that high-cholesterol (H) fed animals lowered sirtuin1 protein by 19.4%, 23.8%, 11.8% in liver, heart and kidneys respectively. Sirtuin1 protein was enhanced by flour (16.6%, 13.7% in liver and heart respectively); malt (14.8% and 13.4% in liver and heart respectively). H-fed rats showed reduction in cholesterol (21.8%, 59%, 25.1% by flour; 28.2%, 35.7%, 20.2% by malt in liver, heart and kidneys respectively), triglycerides (11.5%, 34%, 16.7% by flour in liver heart, adipose respectively; 29.1% and 15.5% by malt in heart and adipose respectively). Elevation in lipid peroxidation due H was reduced (35.8%, 28.6%, 15.8% by flour and 16%, 22%, and 19.5% by malt in liver, heart and kidneys respectively) along with increase in phospholipids (2-fold, 2.5-fold, 2.3 fold by flour and 60.5%, 34.2%, 54.7% by malt in liver, heart and kidneys respectively), activity of hormone sensitive lipase (27.6% and 22.7% by flour and malt respectively in adipose), HMG CoA reductase (56.7%, 28.8%, 2-fold by flour in liver, heart and kidneys respectively; 48%, 2-fold by malt in liver and kidneys respectively). Finger millets normalized sirtuin1 and lipid profile. Potential of flour was greater than malt in favorably regulating biochemical parameters.

Bempedoic acid: A new player in lipid-lowering

Elevated LDL cholesterol remains one of the most important cardiovascular risk factors. For this reason, great scientific efforts have been made in recent decades to reduce elevated LDL cholesterol levels. After statins, ezetrol, and PCSK9 inhibitors, bempedoic acid is a new promising option for the treatment of LDL-cholesterol. Bempedoic acid is an inhibitor of adenosine triphosphate citrate lyase (ACL), an enzyme that converts citrate to acetyl-CoA in the cytosol. The active ingredient thus attacks the above HMG-CoA reductase, the target of statins, in the mevalonate/cholesterol biosynthesis pathway. Bempedoic acid can be considered a prodrug that is converted intracellularly to ETC-1002-CoA by ACSVL1 (very long-chain acyl-CoA synthetase 1) via coenzyme A (CoA) activation. ACSVL1 is primarily expressed in the liver and not in skeletal muscle. Therefore, in contrast to statins, it is not associated with muscle pain, which is one of the great advantages of this drug.

PCB169 exposure aggravated the development of non-alcoholic fatty liver in high-fat diet-induced male C57BL/6 mice.

Polychlorinated biphenyls (PCBs) are lipophilic environmental toxicants. Epidemiological studies have established a link between PCBs and both metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). Multiple studies have reported that exposure to both PCB156 and PCB126 among the 12 dioxin-like PCBs leads to the development of NAFLD. However, studies to elucidate whether PCB169 induces the development of NAFLD by constructing in vivo models have not been reported. Therefore, we evaluated the effects of exposure to PCB169 (5 mg/kg-bw) on hepatic lipid metabolism in C57BL/6 mice from control diet and high-fat diet cohorts. The results showed that PCB169 exposure reduced body weight and intraperitoneal fat mass in mice on the control diet, but the liver lipid levels were significantly increased, exacerbating NAFLD in mice on a high-fat diet. Through transcriptomics studies, it was found that PCB169 exposure induced significant up-regulation of Pparγ, Fasn, and Aacs genes involved in hepatic lipogenesis, as well as remarkable up-regulation of Hmgcr, Lss, and Sqle genes involved in cholesterol synthesis. Additionally, there was notable down-regulation of Pparα and Cpt1 genes involved in lipid β-oxidation, leading to abnormal lipid accumulation in the liver. In addition, we found that PCB169 exposure significantly activated the Arachidonic acid metabolism, PPAR signaling pathway, Metabolism of xenobiotics by cytochrome P450, and Retinol metabolism pathways, and so on. Our study suggests that PCB169 can modify gene expression related to lipid metabolism, augument lipid accumulation in the liver, and further contribute to the development of NAFLD, thereby revealing the detrimental effects associated with PCB exposure on animal growth and metabolism.