HMG-CoA Research Articles

Low LDL cholesterol and risk of bacterial and viral infections – observational and Mendelian randomisation studies

Abstract Aims Low levels of low-density-lipoprotein(LDL) cholesterol may be associated with risk of infectious disease. We tested the hypothesis that low LDL cholesterol due to genetic variation in the LDLR, PCSK9, and HMGCR genes, and a polygenic LDL cholesterol score is associated with risk of infectious diseases in the general population. Methods and results Using observational and Mendelian randomisation designs, we examined associations of low plasma LDL cholesterol with risk of bacterial and viral infections in 119,805 individuals from the Copenhagen General Population Study/Copenhagen City Heart Study, 468,701 from the UK Biobank, and up to 376,773 from the FinnGen Research Project. Observationally, low LDL cholesterol concentrations were associated with risk of hospitalisation for both bacterial and viral infections. In genetic analyses, a 1 mmol/L lower LDL cholesterol was associated with lower plasma PCSK9(-0.55 nmol/L[95%CI: -1.06–-0.05], p=0.03), leucocyte count(-0.42 x109/L[-0.61–-0,24]; p<0.001), and high-sensitivity C-reactive protein(-0.44 mg/L[-0.79–-0.09]; p=0.014). Using an LDLR, HMGCR, and PCSK9 score, a 1 mmol/L lower LDL cholesterol was associated with risk ratios of 0.91(95%CI: 0.86–0.97; p=0.002) for unspecified bacterial infection, of 0.92(0.87–0.97; p=0.004) for diarrhoeal disease, and of 1.15(1.03-1.29; p=0.012) for unspecified viral infections and 1.64(1.13-2.39; p=0.009) for HIV/AIDS. Using a polygenic LDL cholesterol score largely showed similar results and in addition a lower risk of 0.85(0.76-0.96; p=0.006) for bacterial pneumonia and 0.91(0.82-0.99; p=0.035) for sepsis. Conclusion Genetically low LDL cholesterol concentrations were associated with lower concentration of markers of inflammation, and lower risk of hospitalisation for unspecified bacterial infections, infectious diarrhoeal diseases, bacterial pneumonia, and sepsis; and higher risk of viral infections and HIV/AIDS.

Features of the management tactics of a patient with menopausal metabolic syndrome

The aim of the study was to study the features of the management tactics of a patient with menopausal metabolic syndrome. We examined the results of the examination and treatment of patient M, 55 years old, diagnosed with grade 1 obesity (BMI 30 kg/m2). Impaired glucose tolerance. Dyslipidemia. Menopausal syndrome. Arterial hypertension 1 st degree. The patient was recommended moderate physical activity, with calorie restriction up to 1400 kcal, and a hypocholesterolemic diet. A drug was prescribed, which is a combination of estradiol 1.0 mg with drosperinone 2.0 mg, HMG-CoA reductase inhibitor 5 mg per day, orlistat with an improved safety profile 120 mg 3 times a day after meals, metformin 1000 mg. The complex treatment was carried out for 6 months with a follow-up examination after 6 months. The patient’s hot flashes stopped, sleep returned to normal, night sweats and headache did not bother her. After 6 months, the weight decreased to the initial body weight. The body mass index after 6 months was 25 kg/m2, which is the norm. The waist circumference after 6 months was 74 cm. Blood pressure stably corresponded to 120/70 mm Hg. Taking antihypertensive drugs was not required. Total cholesterol after 6 months was 4.8 mmol/l. The patient was recommended to continue treatment with subsequent examination annually. Thus, menopausal metabolic syndrome can be considered as one of the variants of the manifestation of menopausal syndrome, which requires an integrated approach to diagnosis and therapy. Individually selected menopausal hormone therapy, being an effective means of relieving the manifestations of menopausal syndrome, also contributes to a positive effect on the components of the metabolic syndrome in this age period. This clinical case demonstrates the need for an individual integrated approach to the management of patients of this age period, with the inclusion of MGT drug, which most effectively has a therapeutic effect due to its pharmacological characteristics.

Antioxidant Peptides from Miiuy Croaker Swim Bladders: Ameliorating Effect and Mechanism in NAFLD Cell Model through Regulation of Hypolipidemic and Antioxidant Capacity

In this work, the hypolipidemic and antioxidative capacity of FSGLR (S7) and GIEWA (S10) from miiuy croaker swim bladders was explored systematically in an oleic acid (OA)-induced nonalcoholic fatty liver disease (NAFLD) model of HepG2 cells. Moreover, the hypolipidemic activity of S7 and S10 and their antioxidative abilities were preliminarily investigated in combination with molecular docking technology. The results indicated that S7 and S10 could decrease the amount of lipid accumulation and the content of triglycerides (TG) and total cholesterol (TC) in the OA-induced NAFLD cell model in a dose-dependent manner. In addition, S7 and S10 exhibited better bile salt binding, pancreatic lipase (PL) inhibition, and cholesterol esterase (CE) inhibition capacities. The hypolipidemic mechanisms of S7 and S10 were connected with the downregulation of the mRNA expression levels of adipogenic factors, including sterol-regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), sterol-regulatory element-binding protein (SREBP)-2, hydroxymethylglutaryl-CoA reductase (HMGR), and fatty acid synthase (FAS) (p < 0.01), and the upregulation of the mRNA expression of β-oxidation-related factors, including carnitine palmitoyltransferase 1 (CPT-1), acyl-CoA oxidase 1 (ACOX-1), and peroxisome proliferator-activated receptor α (PPARα). Moreover, FSGLR (S7) and GIEWA (S10) could significantly protect HepG2 cells against OA-induced oxidative damage, and their antioxidant mechanisms were related to the increased activity of intracellular antioxidant proteases (superoxide dismutase, SOD; glutathione peroxidase, GSH-PX; catalase, CAT) to remove excess reactive oxygen species (ROS) and decrease the production of malondialdehyde (MDA). The presented findings indicate that the hypolipidemic and antioxidant functions and mechanisms of S7 and S10 could make them potential hypolipidemic and antioxidant candidates for the treatment of NAFLD.

Therapeutic potential of 2S-hesperidin against the hepatotoxic effects of dichlorvos in rats.

Dichlorvos (DDVP) is an organophosphate insecticide that enhances food production and repels disease vectors. However, it provokes cytotoxicity. 2S-hesperidin (2S-HES) is a potent antioxidant, anti-inflammatory, and anti-lipidemic flavanone. Regardless, the 2S-HES impact on DDVP-occupied hepatic injury remains fuzzy. We evaluated the therapeutic potential of 2S-HES in a rat model of DDVP-elicited hepatic intoxication. Forty-two rats were randomly allotted to seven groups (n=6/condition): control, DDVP (8mgkg⁻1day⁻1), DDVP with 2S-HES (50 and 100mgkg⁻1day⁻1), DDVP with atropine, and 2S-HES alone (50 and 100mgkg⁻1day⁻1). DDVP was administered orally for 7 days, followed by 14 days of 2S-HES chemotherapy. 2S-HES intervention partially mitigated DDVP-triggered alterations in leakage enzymes (ALT, AST, ALP, LDH-5), total protein, albumin, globulin, bilirubin, electrolytes, ion-transporters, lipid profiles, and HMG-CoA reductase. Furthermore, 2S-HES partially reversed DDVP-provoked increases in hepatic H₂O₂, NO, and malondialdehyde; transposed DDVP-mediated decreased liver GSH amount and activities of GST, SOD, catalase, and GPx; attenuated DDVP-triggered upregulated NF-κB-p65 and caspase-3; and abated DDVP-engendered repressed interleukin-10 mRNA expression. Cytoarchitectural analyses authenticated the 2-HES reduction in DDVP-evoked hepatocellular vacuolation. Altogether, 2S-HES elicited promising alternative or adjunctive therapy for partially mitigating DDVP-incited hepatic injury by attenuating leakage enzymes, ionoregulatory disruptions, ion pump inhibition, dyslipidemias, oxidative stress, inflammation, and apoptosis.

Embelin Elevates Endoplasmic Reticulum Calcium Levels and Blocks the Sterol Regulatory Element-Binding Protein 2 Mediated Proprotein Convertase Subtilisin/Kexin Type 9 Expression and Improves the Low-Density Lipoprotein Receptor Mediated Lipid Clearance on Hepatocytes.

Cardiovascular diseases (CVDs) continue to be one of the leading causes of morbidity and mortality worldwide, with a significant increase in recent years. Atherosclerosis, the pathological basis and prime reason for CVDs is primarily driven by dysregulated lipid metabolism and inflammation. Recently, proprotein convertase subtilisin kexin9 (PCSK9) has been evolved to be highly implicated in the circulatory low-density lipoprotein cholesterol levels by its modulatory effects on the low-density lipoprotein receptor (LDLR) mediated clearance. Even though not economical, the therapies targeting PCSK9 demonstrated appreciable levels of efficiency in managing hyperlipidaemic conditions. Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone) is a naturally occurring para-benzoquinone isolated from dried berries of Embelia ribes, which possess several effects in maintaining the cholesterol homeostasis. In this study, we have analysed the role of embelin in sterol regulatory element-binding protein 2 (SREBP2) mediated PCSK9 expression in cultured hepatocytes. The study showed that the embelin treatment attenuates the endoplasmic reticulum (ER) stress-induced reactive oxygen species levels and ER stress markers on cultured hepatocytes. The treatment of embelin modulates the mRNA and protein level expression of SREBP2 and its downstream targets like PCSK9, LDLR, and HMG-CoA reductase (HMGCR). Interestingly the Ca2+ levels and the calcium binding protein of ER were significantly increased with embelin treatment. The work revealed a putative mechanism of embelin in lowering PCSK9 levels by boosting ER Ca2+ levels, thereby blocking SREBP2 nuclear translocation. Further, this reduces LDLR degradation and increases receptor-mediated circulatory lipid clearance. The study summarized the potential clinical applications of embelin in addressing the cardio vascular diseases.

Uncovering The Pharmacological Mechanism of Ficus elastica as Anti-hyperlipidemia Candidate: LC-HRMS, Network Pharmacology, In vitro and In vivo Studies

Hyperlipidemia is a major risk factor for cardiovascular diseases. While conventional treatments exist, there is a growing interest in natural remedies with fewer side effects. Ficus elastica has promising medicinal properties, yet its potential as an anti-hyperlipidemic agent remains unexplored. This study aimed to investigate the anti-hyperlipidemic effects of F. elastica using an integrated approach of LC-HRMS-based chemical bioinformatics and in vitro/in vivo experimental validation. The anti-hyperlipidemic potential of F. elastica and its mechanism of action were screened using integrative computational network pharmacology followed by in vitro HMG-CoA reductase inhibition and in vivo lipid-lowering activity in a hyperlipidemia rat model. Network pharmacology analysis identified STAT3, HSP90AA1, and TLR4 as potential core targets involved in lipid and atherosclerosis-related KEGG pathways. Molecular docking simulations revealed high-affinity interactions between F. elastica compounds and the identified targets, notably compound 41 and compound 61. In vitro assay demonstrated that ethanolic extract of F. elastica inhibited HMG-CoA reductase with an IC50 of 297.73 µg/mL. In vivo experiment using a hyperlipidemic rat model showed significant reductions in total cholesterol, triglycerides, and increased HDL levels. The reduction of triglycerides and elevation of HDL level after F. elastica ethanolic extract supplementation is similar to the effect from supplementation of simvastatin. These findings suggest that F. elastica ethanolic extract possesses notable anti-hyperlipidemic properties, likely mediated through multiple molecular targets and pathways. The study highlights the potential of F. elastica ethanolic extract as a promising candidate for anti-hyperlipidemic therapy and underscores the efficacy of integrating computational and experimental approaches in natural product research.

Understanding statin intolerance: Challenges, mechanisms, and management strategies

Statins are among the most commonly prescribed drugs for the treatment and prevention of cardiovascular diseases (CVD), such as coronary artery disease and stroke. They function by blocking HMG-CoA reductase that produces cholesterol, which lowers the levels of low-density lipoprotein (LDL) cholesterol. But despite its demonstrated ability to lower cardiovascular risk, a sizable portion of individuals develop adverse effects that result in statin intolerance. Statin intolerance is a frequent cause of statin cessation or noncompliance. It is linked to fewer clinical benefits and less-than-ideal cardiovascular risk management. This review article explores the concept of statin intolerance, including its occurrence, causes, symptoms, diagnosis, and treatment options.

Associations between lipid-lowering drugs and urate and gout outcomes: a Mendelian randomization study

ObjectiveGout is a common inflammatory arthritis and lipid metabolism plays a crucial role in urate and gout. Potential associations between urate and gout and lipid-lowering drugs have been revealed in observational studies. However, the effects of lipid-lowering drugs on urate and gout remain controversial. The aim of this study was to investigate the genetic association between lipid-lowering drugs and urate and gout.MethodsIn this study, two genetic proxies were employed to approximate lipid-lowering drug exposure: expression quantitative trait loci (eQTL) associated with drug-target genes and genetic variations proximal to or within genes targeted by these drugs, which are linked to low-density lipoprotein cholesterol (LDL-C) levels. The study’s exposures encompassed genetic variants within drug target genes (HMGCR, PCSK9, NPC1L1), each representing distinct lipid-lowering mechanisms. Causal effects were estimated using the inverse variance weighting (IVW) method, while the Summary Data-based Mendelian Randomization (SMR) method, leveraging pooled data, was applied to compute effect estimates. These estimates were further refined through various approaches including MR-Egger, the weighted median method, simple and weighted models, and leave-one-out analyses to conduct sensitivity analyses.ResultThe analytical outcomes utilizing the IVW method indicated that inhibitors of HMGCR were correlated with an elevated risk of developing gout (IVW: OR [95%CI] = 1.25 [1.03, 1.46], p=0.0436), while PCSK9 inhibitors were linked to heightened levels of urate (IVW: OR [95%CI] = 1.06 [1.01,1.10], p=0.0167). Conversely, no significant correlation between NPC1L1 inhibitors and the levels of urate or the risk of gout was established. Furthermore, the SMR analysis failed to identify significant associations between the expression levels of the HMGCR, PCSK9, and NPC1L1 genes and the risk of gout or elevated urate levels (SMR method: all P values >0.05). Sensitivity analyses further confirmed the robustness of these results, with no significant heterogeneity or pleiotropy found.ConclusionThis study furnishes novel causal evidence supporting the potential genetic correlation between the use of lipid-lowering drugs and the incidence of gout as well as urate levels. The findings indicate that inhibitors targeting HMGCR may elevate the risk associated with the development of gout, while inhibitors targeting PCSK9 are likely to increase urate concentrations.

Renal Impairment Caused by Statins in Rats Can Be Restored by Thymoquinone.

Atorvastatin (ATO) is an HMG-CoA reductase inhibitor used to lower blood cholesterol, but it causes renal injury in high doses. Thymoquinone (TQ), is a natural antioxidant that has been shown to protect the kidney through its anti-inflammatory, antioxidant, & antiapoptotic, effects. The current study aimed to investigate whether posttreatment TQ could reverse ATOinduced renal injury, and the possible mechanism of action by which TQ produced such an effect. Forty adult male rats were divided into 4 groups: (control; TQ-treated; ATO-treated; ATO plus TQ-treated). Blood and kidney tissue samples were tested for kidney functions, oxidative stress and apoptosis markers, and morphometric analyses of the histopathological and ultrastructural evaluations. Statistical analyses were done using JASP, Shapiro-Wilk, and Levene's test. ANOVA and Kruskal-Wallis tests were done to determine differences between groups. The significance level was set at p<.05. The ATO-treated group showed abnormal outcome measures including kidney functions, oxidative stress and apoptotic markers, and morphometric analyses of the histopathological and ultrastructural findings. Post-treatment TQ improved all outcome measures. Posttreatment TQ could reverse oxidative stress-induced renal injury produced by highdose ATO, suggesting a potential clinical application in patients with renal insufficiency with hypercholesterolemia.

P1338 Defining the preclinical changes of microbial composition, gut barrier function, and subclinical inflammatory markers associated with future risk of ulcerative colitis

Abstract Background Ulcerative colitis (UC) is a chronic inflammatory condition of the rectum and colon with a complex aetiology involving genetic, immune, and microbial factors. Less is known about the pre-disease phase of UC compared to Crohn’s disease (CD). Investigating the preclinical biomarkers that precede the development of UC may provide insights into its pathogenesis. Methods Participants were recruited as part of the CCC-GEM project, a prospective cohort study following healthy first-degree relatives (FDR) of patients with CD. Baseline gut inflammation was assessed using faecal calprotectin (FCP), with a cut-off of 100ug/g, while baseline gut permeability was assessed by the fractional urinary excretion ratio of lactulose-to-mannitol (LMR). Baseline faecal microbiome composition was analyzed using 16s rRNA sequences, and functional pathways were inferred using PICRUSt2. Cox proportional hazards models were used to assess the association of baseline variables with UC onset, adjusting for age, sex, and family clustering. Significance was determined using p-values and false discovery rate-adjusted q-values. Results Among 3,596 FDRs, 16 developed UC during a median follow-up of 6.88 years. FDRs with elevated baseline FCP had a 3.1-fold higher risk (p=0.02) of developing UC, while no significant association was observed between baseline LMR and UC onset. The relative abundance of genus Bilophila (HR=0.33 per SD, q=0.010) and Bifidobacteria (HR=0.16, q=0.02) were associated with UC risk, but lost significance after adjusting for FCP. Interestingly, the relative abundances of genera Alistipes (HR=0.15, q=0.0007), Phascolarctobacterium (HR=0.08, q=0.027), Christensenellaceae R.7 group (HR=8.37, q=0.02) and Angelakisella (HR=5.28, q=0.004) remained significantly associated with risk of UC even after adjusting for FCP. Thirty-seven pathways, predominantly involved in specific metabolic processes such as carbohydrates, lipid, or folate metabolism, were also associated with UC risk. Fur example, pathways involving hydroxymethylglutaryl-CoA reductase (HR=0.44, q=0.03), choline monooxygenase (HR=0.22, q=0.005), and 3-phenylpropionate/trans-cinnamate dioxygenase (HR=4.70, q=0.001) remained significantly associated with UC risk even after adjusting for FCP. Conclusion We report that elevated FCP, but not LMR, was significantly associated with future risk of UC. Furthermore, specific microbial taxa and functional pathways exhibited strong associations with future risk of UC, independent of FCP. These microbial signatures were distinct from the previously reported pre-CD microbial changes, suggesting a unique gut microbial contribution to the development of UC. References Raygoza Garay JA, Turpin W, Lee S-H, et al. Gastroenterology 2023;165:670–681.

Lipids, lipid-lowering drug target genes and pancreatic cancer: a Mendelian randomization study.

Pancreatic cancer (PC) is a malignant tumor with a low survival rate. Lipid modifiers show potential for PC therapy, but evidence is lacking. This Mendelian randomization (MR) study aimed to explore the relationship between lipid traits, and lipid-lowering drug target genes with PC risk. Genetic instrumental variables associated with lipid traits and lipid-lowering drug target genes were used to perform MR analyses of PC risk. MR estimation was based on genome-wide association study data from two large sample sets, and the MR results were meta-analyzed to assess their impact on PC risk. To ensure the reliability of lipid-modifying drug targets, we conducted a Summary Data-based Mendelian Randomization (SMR) analysis. Additionally, a two-step MR analysis was employed to explore potential mediating effects. In two independent datasets, HMG-CoA reductase (HMGCR) inhibition was statistically associated with a lower risk of PC (OR 0.50, [95% CI 0.25-1.00]; p = 0.0453). The results were further supported by SMR analysis, which showed a similar association (OR 0.51, [95% CI 0.28-0.96]; p = 0.0369). Mediation analysis revealed that 11.69% of the protective effect of HMGCR inhibitors on PC is mediated through lower BMI levels. No significant effect of lipid traits and the other eight lipid-lowering drug targets on PC risk was found. This study suggests that HMGCR may be a potential drug target for the treatment or prevention of PC, providing important insights into the use of lipid-targeted drugs in PC therapy.

Biological Effects of Calceolarioside A as a Natural Compound: Anti-Ovarian Cancer, Anti-Tyrosinase, and Anti-HMG-CoA Reductase Potentials with Molecular Docking and Dynamics Simulation Studies.

One kind of hydroxycinnamic acid is calceolarioside A. Plantago coronopus, Cassinopsis madagascariensis, and other organisms for whom data are available are known to have this naturally occurring compound. IC50 values of Calceolarioside A for ovarian cell lines (NIH-OVCAR-3, ES-2, UACC-1598, Hs832.Tc, TOV-21G, UWB1.289) were 24.42, 13.50, 9.31, 14.90, 20.07, and 16.18µM, respectively. IC50 values were 19.83 and 73.48µM for tyrosinase and HMG-CoA reductase enzymes. The chemical activities of Calceolarioside A against HMG-CoA reductase and tyrosinase were assessed by conducting the molecular docking study, MM/GBSA calculation, and molecular dynamics (MD) simulation. The anticancer activities of this compound were evaluated against some ovarian cancer cells, such as NIH-OVCAR-3, ES-2, UACC-1598, Hs832.Tc, TOV-21G, and UWB1.289 cell lines. The chemical activities of Calceolarioside A against some of the expressed surface receptor proteins (folate receptor, CD44, EGFR, Formyl Peptide Receptor-Like 1, M2 muscarinic receptor, and estrogen receptors) were investigated using computational methods. The results exhibited the interplay among atoms. The compound formed robust associations with both the enzymes and receptors. Calceolarioside A can hinder the functioning of these enzymes and the proliferation of malignant cells.

Impact of protein intake from a caloric-restricted diet on liver lipid metabolism in overweight and obese rats of different sexes

In addition to being linked to an excess of lipid accumulation in the liver, being overweight or obese can also result in disorders of lipid metabolism. There is limited understanding regarding whether different levels of protein intake within an energy-restricted diet affect liver lipid metabolism in overweight and obese rats and whether these effects differ by gender, despite the fact that both high protein intake and calorie restriction can improve intrahepatic lipid. The purpose of this study is to explore the effects and mechanisms of different protein intakes within a calorie-restricted diet on liver lipid metabolism, and to investigate whether these effects exhibit gender differences. The Sprague-Dawley rats, which were half female and half male, were used to construct a rat model of overweight and obesity attributed to a high-fat diet. They were then split up into five groups: the normal control (NC) group, the model control (MC) group, the calorie-restricted low protein (LP) group, the calorie-restricted normal protein (NP) group, and the calorie-restricted high protein (HP) group. Body weight was measured weekly. Samples of plasma and liver were obtained after eight weeks and analyzed for glucose, triglycerides, cholesterol, and hormones in the plasma as well as the liver fat and factors involved in the liver’s synthesis and degradation. For the male rats, compared to the HP group, the weight of liver fat in the LP and NP group was significantly higher (P < 0.05). However, for the female rats, there was no significant variation among the three calorie-restricted groups (P > 0.05). There was no significant variation in the concentration of total cholesterol (TC), very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) among the three male calorie-restricted groups (P > 0.05), while the TC and VLDL concentrations in the female LP and NP group were significantly higher compared to those in the HP group (P < 0.05). Moreover, the trend of expression in the signaling pathways of adiponectin/phosphorylated AMP-activated protein kinase (p-AMPK) and adiponectin/peroxisome proliferators-activated receptor alpha (PPARα) in the liver was consistent with that of the liver fat content, and leptin acted in the same way as adiponectin. Compared with the three calorie-restricted groups, the expressions of nuclear sterol-regulatory element-binding protein-2 (nSREBP-2) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) involved in cholesterol synthesis and low-density lipoprotein receptor (LDLR) and cholesterol 7-alpha hydroxylase (CYP7A1) involved in cholesterol clearance in the MC group were significantly lower (P < 0.05). A 40% energy restriction can significantly reduce the body weight, body fat, liver fat, and the blood concentration of TG in both male and female overweight and obese rats, but it can significantly increase the blood concentration of TC in overweight and obese male rats. At the same time of 40% calorie restriction, increasing dietary protein intake to twice the normal protein intake has a stronger effect on promoting hepatic triglyceride oxidation and reducing liver fat content in the male overweight and obese rats by increasing the levels of adiponectin and leptin in the blood, and can also significantly reduce the plasma cholesterol concentration in the female overweight and obese rats through inhibiting cholesterol synthesis most likely by increasing glucagon level in the blood.

Potential antihyperlipidemic effects of myrcenol and curzerene in high-fat fed rats

The study evaluated the anti-hyperlipidemic effects of myrcenol and curzerene on a high fat diet induced hyperlipidemia rat model. Thirty male albino rats were fed on a high-fat diet for four months. The HFD-induced hyperperlipidemia rats were treated with rosuvastatin (10 mg/kg), curzerene (130 mg/kg) and myrcenol (100 mg/kg) for four weeks. Blood samples were collected for further analysis. Aorta and heart were harvested for histopathological evaluation. Hepatic lipase and HMG-CoA reductase were determined by ELISA. FST and Y-maze tests were performed to assess the stress level in hyperlipidemia rats. The phytochemical compounds (Curzerene and Myrcenol) and the standard drug (Rosuvastatin) resulted in decreased body weight as well as reduced levels of LDL, TG, TC, AST and ALT as compared to the diseased group. Additionally, the treated groups displayed improved HDL levels and less depressed behavior. The ELISA results revealed that the Curzerene and myrcenol had significantly increased the protein concentration of hepatic lipase than the diseased group whereas both compounds significantly lowered the HMG-CoA reductase concentrations compared to the diseased group. The findings suggested that myrcenol and curzerene had the potential to be therapeutic agents for managing hyperlipidemia and reducing the risk of heart-related conditions associated with high lipid levels.

Effects of HMG CoA reductase (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. Statins inhibit HMGCR activity to generate their cholesterol-lowering effects and are known to cause multiple types of adverse effects on skeletal muscle, while the antibodies associated with anti-HMGCR myopathy specifically target this enzyme. 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.

Icariin improves learning and memory function by enhancing HRD1-mediated ubiquitination of amyloid precursor protein in APP/PS1 mice.

One of the hallmark pathological characteristics of Alzheimer's disease (AD) is amyloid-β (Aβ) accumulated in brain, which is mainly derived from the proteolytic processing of amyloid-β protein precursor (AβPP). The ubiquitin-proteasome system is able to reduce Aβ generation by ubiquitination and degradation of AβPP. Icariin (ICA), a flavonoid isolated from Epimedium brevicornum Maxim., has been reported that it could regulate the metabolism of AβPP and reduce the Aβ level in AD in vivo and in vitro models. To investigate whether the effect of ICA on AβPP and Aβ is related to AβPP ubiquitination. We used in vivo and in vitro models to observe the effect of ICA on AβPP ubiquitination as well as to investigate the effect of HMG-CoA reductase degradation protein 1 (HRD1), an E3 ubiquitin-protein ligase, on the processing of AβPP ubiquitination. This study showed that ICA improved the cognitive abilities of APP/PS1 AD mice in Morris Water Maze and Y-maze tests, upregulated HRD1 expression, subsequently elevated the total ubiquitination and K48-linked polyubiquitination of AβPP level, as well as increased AβPP degradation. Moreover, silenced HRD1 gene abolished the aforementioned effects of ICA. Furthermore, ICA decreased the location of AβPP in the early endosome, where AβPP is cleaved into Aβ, evidenced by reducing the co-localization of AβPP and early endosome antigen 1 (EEA1). This study demonstrated that ICA increased AβPP degradation by upregulating HRD1 mediated ubiquitination.

PIN1 prolyl isomerase promotes initiation and progression of bladder cancer through the SREBP2-mediated cholesterol biosynthesis pathway.

Identities of functional pSer/Thr.Pro protein substrates of the PIN1 prolyl isomerase and its effects on downstream signaling in bladder carcinogenesis remain largely unknown. Phenotypically, we found that PIN1 positively regulated bladder cancer cell proliferation, cell motility and urothelium clearance capacity in vitro and controlled tumor growth and potential metastasis in vivo. Mechanistically, we observed a negative enrichment of SREBP2-driven cholesterol metabolism pathways and a decrease in free/total cholesterol levels in PIN1-knockout bladder cancer cells. Moreover, we showed that PIN1 interacted with SREBP2 following its phosphorylation by the JNK MAP kinase at Ser455, which lies near the Site-2 cleavage site that generates the active, nuclear-form of SREBP2. Therapeutically, a combination of the sulfopin PIN1 covalent inhibitor and the simvastatin HMGCoA reductase inhibitor suppressed cell proliferation in vitro and tumor growth in vivo synergistically. Together, these findings emphasize that PIN1 can act as a driver and potential therapeutic target in bladder cancer.

Combining In Vitro, In Vivo, and In Silico Approaches to Explore the Effect of Ceratonia siliqua and Ocimum basilicum Rich Phenolic Formula on Lipid Metabolism and Plasma Lipoprotein Oxidation in Mice Fed a High-Fat Diet: A Follow-Up Study.

Hyperlipidemia is a serious risk factor for cardiovascular diseases and liver steatosis. In this work, we explored the effect of an herbal formula (CBF) containing immature Ceratonia siliqua pods and Ocimum basilicum extracts on lipid metabolism disorders and lipoprotein-rich plasma (LRP) oxidation in mice. The phenolic composition was determined using HPLC-DAD analysis. The antioxidant activity was studied using various in vitro methods. Acute toxicity was evaluated in mice. Importantly, the effect of the CBF on lipid metabolism disorders was investigated in a high-fat diet (HFD) hyperlipidemia mouse model. An in silico study was carried out to predict underlying mechanisms. The HPLC analysis revealed gallic acid, cinnamic acid, and naringenin as major phenolics of the carob pod aqueous extract. Concerning the basil hydro-ethanolic extract, rosmarinic, chicoric, caftaric, and caffeic acids were the main phenolics. Accordingly, the CBF prevented LRP oxidation in a concentration-dependent manner. This formula is not toxic in mice (LD50 > 2000 mg/kg body weight). Moreover, animals administered the CBF at 200 mg/kg/day presented a significant decline in their body weight gain, adipose tissue weight, plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C) level, and glycaemia after 10 weeks' treatment. Accordingly, the CBF decreased the plasma atherogenic index and the LDL-C to HDL-C ratio and reduced the level of fats accumulated in the liver. The molecular docking study revealed that chicoric, rosmarinic, and caftaric acids, and naringenin bound particularly strongly to many proteins involved in the regulation of lipid and cholesterol metabolism. This includes the HMG-CoA reductase, PPARα/γ, PCSK9, Cyp7a1, and ATP-citrate lyase. The CBF could be a good source of natural supplements, functional foods, and pharmaceuticals effective in managing hyperlipidemia and oxidative stress and preventing their related cardiovascular disorders.

Alchornea cordifolia leaf-extract ameliorates bisphenol A-induced obesity in male Wistar rats

BackgroundBisphenol-A (BPA), a chemical impregnated into plastic bottles which has been linked to obesity and its associated health problems, was used to induce obesity in this study. The cost and reported limitations and side effects of orthodox medications employed for weight management, have necessitated a shift in attention to medicinal plants, given their comparative advantage and the common belief amongst locals that plants are free from negative side effects. One plant that has found application for weight loss amongst the local population in Nigeria is Alchornea cordifolia which commonly grows in Africa and has been confirmed to possess numerous medicinal properties including anti-inflammatory, anti-diarrheal, hepaprotective, antiviral, and anti-diabetic effects.ObjectiveTo evaluate the obesity attenuation effect of Alchornea cordifolia ethanol extract (ACEE) and other associated macrovascular health risks in BPA-induced obesity rat model.MethodsThirty (30) young male Wistar rats (80–100 g) divided into five groups of six rats each, were administered BPA (50 mg/kg), once a day, p.o. for four weeks in order to induce obesity. Afterwards, obesity was confirmed using anthropometric indicators, and the animals were treated for another four weeks as follows: Group 1 (Normal control) received drug/extract reconstitution solvent, olive oil, Group 2 (obese control) received 50 mg/kg of BPA, Group 3 received a conventional anti-obesity drug, Orlistat (30 mg/kg), Group 4 received ACEE (500 mg/kg), and Group 5 received ACEE (1000 mg/kg). At the end of study, anthropometric indicators and relevant serum biochemical indicators were determined using standard procedures.ResultsThe results obtained showed that oral BPA administration caused obesity i.e. increased body weight, Lee’s Index and waist circumference, compared to the normal control (p < 0.05). Moreover, BPA treatment was found to alter measured serum biochemical indicators, (FBG, lipid profile, liver and kidney function indicators) and the lipid regulating enzymes (pancreatic lipase and HMG-CoA reductase activities), relative to the normal control (p < 0.05). However, upon 4-week ACEE oral treatment at 500 and 1000 mg/kg b.w., there was observed significant attenuation of the anthropometric indices, serum biochemical indices and lipid metabolizing enzymes studied (p < 0.05).ConclusionTogether, the results obtained from this study have scientifically validated the traditional use of Alchornea cordifolia leaves in body weight control, hence suggest that the leaves may possess natural products useful in the management of obesity and its related complications.

Multiomic Mendelian Randomization Study Investigating the Impact of PCSK9 and HMGCR Inhibition on Type 2 Diabetes Across Five Populations.

The prevalence of type 2 diabetes (T2D) varies among populations of different race/ethnicity. The influence of genetically-proxied lipoprotein cholesterol (LDL-C) lowering through proprotein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA Reductase (HMGCR) on T2D in non-European populations is not well established.A drug-target Mendelian randomization (MR) approach was used to assess the effects of PCSK9 and HMGCR inhibition on T2D risk and glycemic traits in five populations: East Asian (EAS), South Asian (SAS), Hispanic (HISP), African (AFR), and European (EUR). Our study did not find relationships between genetically-proxied PCSK9 inhibition and T2D risk in EAS (odds ratio [OR]=1.02, [0.95-1.10]), SAS (OR=1.05, [0.97-1.14]), HISP (OR=1.03, [0.94-1.12]), or EUR (OR=1.04, [0.98-1.11]). However, in AFR, primary analyses suggested an increased risk of T2D due to PCSK9 inhibition (OR=1.53, [1.058-2.22], P-value=0.024), although this was not supported in sensitivity analyses. Genetically-proxied HMGCR inhibition was associated with an increased risk of T2D in SAS (OR=1.44, [1.30-1.61], P-value=9.8×10-12), EAS (OR=1.36, [1.22-1.51], P-value=4.2×10-10), and EUR (OR=1.52, [1.21-1.90], P-value=3.3×10-4). These results were consistent across various sensitivity analyses, including colocalization, indicating a robust finding. The findings indicate a neutral impact of long-term PCSK9 inhibition on T2D and glycemic markers in most non-European populations, with a potential increased risk in AFR cohorts. By contrast, HMGCR inhibition increased the risk of T2D in South Asian, East Asian, and European cohorts, underscoring the need to consider diversity in genetic research on metabolic diseases.