Associations of polychlorinated biphenyls exposure, lifestyle, and genetic susceptibility with dyslipidemias: Evidence from a general Chinese population.

Polychlorinated biphenyls (PCBs) are endocrine-disrupting chemicals that have been associated with various adverse health conditions. Herein we explored the associations of PCBs with dyslipidemia and further assessed the modification effect of genetic susceptibility and lifestyle factors. Six serum PCBs (PCB-28, 101, 118, 138, 153, 180) were determined in 3845 participants from the Wuhan-Zhuhai cohort. Dyslipidemia, including hyper-total cholesterol (HyperTC), hyper-triglyceride (HyperTG), hyper-low density lipoprotein cholesterol (HyperLDL-C), and hypo-high density lipoprotein cholesterol (HypoHDL-C) were determined, and lipid-specific polygenic risk scores (PRS) and healthy lifestyle score were constructed. We found that all six PCB congeners were positively associated with the prevalence of dyslipidemias, and ΣPCB level was associated with HyperTC, HyperTG, and HyperLDL-C in dose-response manners. Compared with the lowest tertiles of ΣPCB, the odds ratios (95% confidence intervals) in the highest tertiles were 1.490 (1.258, 1.765) for HyperTC, 1.957 (1.623, 2.365) for HyperTG, and 1.569 (1.316, 1.873) for HyperLDL-C, respectively. Compared with those with low ΣPCB, healthy lifestyle, and low genetic risk, participants with high ΣPCB, unfavorable lifestyle, and high genetic risk had the highest odds of HyperTC, HyperTG, and HyperLDL-C. Our study provided evidence that high PCB exposure exacerbated the association of genetic risk and unhealthy lifestyle with dyslipidemia.

Monoclonal antibodies for dyslipidemia in adults: a focus on vulnerable patients groups.

INTRODUCTION: Dyslipidemia significantly contributes to atherosclerotic cardiovascular disease (ASCVD). Patients with lipid-rich vulnerable plaques are particularly susceptible to cardiovascular complications. Despite available lipid-lowering therapies (LLTs), challenges in effective lipid management remain. AREAS COVERED: This article reviews monoclonal antibody (mAb) therapy in dyslipidemia, particularly focusing on vulnerable plaques and patients. We have reviewed the definitions of vulnerable plaques and patients, outlined the efficacy of traditional LLTs, and discussed in-depth the mAbs targeting PCSK9. We extensively discuss the potential mechanisms, intracoronary imaging, and clinical evidence of PCSK9mAbs in vulnerable plaques and patients. A brief overview of promising mAbs targeting other targets such as ANGPTL3 is also provided. EXPERT OPINION: Research consistently supports the potential of mAb therapies in treating adult dyslipidemia, particularly in vulnerable patients. PCSK9mAbs are effective in regulating lipid parameters, such as LDL-C and Lp(a), and exhibit anti-inflammatory and anti-thrombotic properties. These antibodies also maintain endothelial and smooth muscle health, contributing to the stabilization of vulnerable plaques and reduction in adverse cardiovascular events. Future research aims to further understand PCSK9 and other targets like ANGPTL3, focusing on vulnerable groups. Overall, mAbs are emerging as a promising and superior approach in dyslipidemia management and cardiovascular disease prevention.

Risk Factors for Relapse and/or Prolonged Glucocorticoid Therapy in Polymyalgia Rheumatica: Multicenter Study in 185 Patients.

BACKGROUND: In polymyalgia rheumatica (PMR) relapses and long-term GC dependency are common. We assessed risk factors for higher relapse rate and/or prolonged glucocorticoid therapy in PMR patients. METHODS: A multicenter and observational study (chart review) of PMR patients seen between 2006 and 2021 who had at least a 3-month follow-up period after starting GCs was performed. Results were expressed as median and interquartile range 25th-75th or mean ± standard deviation for numerical variables and percentage for categorical ones. Relapse versus nonrelapse groups were compared using Cox proportional analysis. Hazards ratios (HRs) with 95% confidence intervals (CIs) are reported. In all cases, a p value <0.05 was considered to indicate statistical significance. RESULTS: We included 185 patients (69.1% female). The median follow-up time was 17.1 months (interquartile range, 6.8-34.7). Incidence of relapses was 1.2 per 100 persons/month. In univariate analysis, PMR patients with a previous history of dyslipidemia had a lower risk of relapse (HR, 0.55; 95% CI, 0.33-0.94; p = 0.03); high-dose GC (HR, 2.35; 95% CI, 1.42-3.87; p = 0.001) and faster GC dose reduction had higher risk of relapse (HR, 3.04; 95% CI, 1.77-5.21; p = 0.001). In multivariate analysis, a previous history of dyslipidemia had a lower risk of relapse (HR, 0.54; 95% CI, 0.32-0.92; p = 0.023), and high dose of GC (HR, 2.46; 95% CI, 1.49-4.08; p = 0.001) remained the only risk factors for relapse. CONCLUSIONS: Lower doses of corticosteroids and a slow rate of reduction are critical to avoid relapse in PMR. Risk factors for higher relapse rate rely on therapy more than clinical characteristics of the patients at the time of diagnosis of PMR.

A systematic review and meta-analysis of tolerability, cardiac safety and efficacy of inclisiran for the therapy of hyperlipidemic patients.

BACKGROUND: Dyslipidaemia is a crucial risk factor for cardiovascular morbidity and mortality. A short interfering RNA called inclisiran diminishes circulating levels of PCSK9 and LDL-C by hindering PCSK9 translation in the liver. METHODS: RCTs were electronically searched on PubMed, Cochrane Central, and Clinicaltrials.gov to assess the safety and efficacy of inclisiran. Cochrane Review Manager 5 was used to conduct the pooled analysis. Risk of bias was assessed and GRADE pro-GDT was utilized, respectively, to estimate the methodological quality and overall quality of evidence. RESULTS: Of 218 records screened, four studies were included with 2203 participants in inclisiran and 1949 participants in the placebo group. Inclisiran was related to non-significant elevated risk of total adverse events[RR = 1.05(0.98,1.12), p = 0.16; I2 = 53%], non-serious adverse events[RR = 1.09(0.97,1.22),p = 0.15;I2 = 61%] and all-cause mortality[RR = 1.01(0.60,1.70),p = 0.97;I2 = 0%] whereas a lower risk of serious adverse events[RR = 0.94(0.70,1.25),p = 0.67;I2 = 73%], cardiac disorders [RR = 0.87(0.66,1.15),p = 0.33;I2 = 42%] and Major adverse cardiovascular events(MACE)[RR = 0.79(0.62,1.00),p = 0.05; I2 = 0%] as compared to placebo. Inclisiran was also linked to a substantial decline in the percentage of LDL-C, PCSK9, total cholesterol, and Apo B. CONCLUSION: The pooled analysis of the existing evidence shows that inclisiran showed reduced risk of MACE along with excellent efficacy in managing dyslipidemia. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifiers are NCT03399370, NCT03397121, NCT03400800, and NCT02597127.

Elevated cholesterol levels have been found to be associated with a high risk of heart disease and associated deaths. There are various classes of drugs used to control high low-density lipoprotein cholesterol (LDL-C) levels in blood yet appropriate control and patient compliance, to regular cholesterol-lowering drugs have been an issue. Inclisiran, a novel drug for reducing the LDL-C levels in serum can be given every six months as an effective therapy to minimize the levels of LDL-C in serum. This study was designed to assess the safety and effectiveness of inclisiran in patients with hyperlipidemia. Inclisiran was found to have a non-significant elevated risk of total adverse events, non-serious adverse events, and all-cause mortality. The majority of the adverse events seem to be non-serious and tolerable. There was an observed non-significant lower risk of serious adverse events, cardiac disorders, and significantly reduced risk of major adverse cardiovascular events when compared to placebo. Inclisiran was also linked to a significant decline in the percentage of LDL-C, PCSK9, total cholesterol, and Apo B in patients with hyperlipidemia. With the evidence available at present, inclisiran seems an efficacious and well-tolerated therapeutic strategy to manage elevated cholesterol and LDL-C levels. However, long-term, large cardiovascular outcome trials are required to conclude on the drug's cardiovascular and overall safety.

Long-term exposure to PM1 is associated with increased prevalence of metabolic diseases: evidence from a nationwide study in 123 Chinese cities.

Exposure to particulate matter (PM) has been linked to metabolic diseases. However, the effects of PM with an aerodynamic diameter ≤ 1.0 µm (PM1) on metabolic diseases remain unclear. This study is aimed at assessing the associations of PM1 with metabolic disease risk and quantifying the concentration-response (C-R) relationship of PM1 with metabolic disease risk. A national cross-sectional study was conducted, including 12,495 middle-aged and older adults in 123 Chinese cities. The two-year average concentration of PM1 was evaluated using satellite-based spatiotemporal models. Metabolic diseases, including abdominal obesity, diabetes, hypertension, dyslipidemia, and metabolic syndrome, were identified based on physical examination, blood standard biochemistry examination, and self-reported disease histories. Generalized linear models and C-R curves were used to evaluate the associations of PM1 with metabolic diseases. A total of 12,495 participants were included in this study, with a prevalence of 45.73% for abdominal obesity, 20.22% for diabetes, 42.46% for hypertension, 41.01% for dyslipidemia, and 33.78% for metabolic syndrome. The mean ± standard deviation age of participants was 58.79 ± 13.14 years. In addition to dyslipidemia, exposure to PM1 was associated with increased risks of abdominal obesity, diabetes, hypertension, and metabolic syndrome. Each 10 µg/m3 increase in PM1 concentrations was associated with 39% (odds ratio (OR) = 1.39, 95% confidence interval (CI) 1.33, 1.46) increase in abdominal obesity, 18% (OR = 1.18, 95%CI 1.12, 1.25) increase in diabetes, 11% (OR = 1.11, 95%CI 1.06, 1.16) increase in hypertension, and 25% (OR = 1.25, 95%CI 1.19, 1.31) in metabolic syndrome, respectively. C-R curves showed that the OR values of abdominal obesity, diabetes, hypertension, and metabolic syndrome were increased gradually with the increase of PM1 concentrations. Subgroup analysis indicated that exposure to PM1 was associated with increased metabolic disease risks among participants with different lifestyles and found that solid fuel users were more susceptible to PM1 than clean fuel users. This national cross-sectional study indicated that exposure to higher PM1 might increase abdominal obesity, diabetes, hypertension, and metabolic syndrome risk, and solid fuel use might accelerate the adverse effects of PM1 on metabolic syndrome risk. Further longitudinal cohort studies are warranted to establish a causal inference between PM1 exposure and metabolic disease risk.

Activation of the PERK-CHOP signaling pathway during endoplasmic reticulum stress contributes to olanzapine-induced dyslipidemia.

Olanzapine (OLZ) is a widely prescribed antipsychotic drug with a relatively ideal effect in the treatment of schizophrenia (SCZ). However, its severe metabolic side effects often deteriorate clinical therapeutic compliance and mental rehabilitation. The peripheral mechanism of OLZ-induced metabolic disorders remains abstruse for its muti-target activities. Endoplasmic reticulum (ER) stress is implicated in cellular energy metabolism and the progression of psychiatric disorders. In this study, we investigated the role of ER stress in the development of OLZ-induced dyslipidemia. A cohort of 146 SCZ patients receiving OLZ monotherapy was recruited, and blood samples and clinical data were collected at baseline, and in the 4th week, 12th week, and 24th week of the treatment. This case-control study revealed that OLZ treatment significantly elevated serum levels of endoplasmic reticulum (ER) stress markers GRP78, ATF4, and CHOP in SCZ patients with dyslipidemia. In HepG2 cells, treatment with OLZ (25, 50 µM) dose-dependently enhanced hepatic de novo lipogenesis accompanied by SREBPs activation, and simultaneously triggered ER stress. Inhibition of ER stress by tauroursodeoxycholate (TUDCA) and 4-phenyl butyric acid (4-PBA) attenuated OLZ-induced lipid dysregulation in vitro and in vivo. Moreover, we demonstrated that activation of PERK-CHOP signaling during ER stress was a major contributor to OLZ-triggered abnormal lipid metabolism in the liver, suggesting that PERK could be a potential target for ameliorating the development of OLZ-mediated lipid dysfunction. Taken together, ER stress inhibitors could be a potentially effective intervention against OLZ-induced dyslipidemia in SCZ.

High-salt diet induces dyslipidemia through the SREBP2/PCSK9 pathway in dahl salt-sensitive rats.

A high-salt diet is known to increase serum cholesterol levels; however, the underlying mechanism of salt-induced dyslipidemia in patients with salt-sensitivity remains poorly understood. We aimed to investigate whether high-salt diet (HSD) can induce dyslipidemia and elucidate the underlying mechanism of salt-induced dyslipidemia in Dahl salt-sensitive (SS) rats. Metabolomic and biochemical analyses revealed that the consumption of an HSD (8 % NaCl) significantly increased the serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in SS rats. The enzyme-linked immunosorbent assay demonstrated an increase in circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, accompanied by a decrease in hepatic low-density lipoprotein receptor (LDLR) levels due to HSD consumption. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis revealed that HSD consumption activated sterol regulatory element-binding protein-2 (SREBP2) expression in the liver and kidney, resulting in upregulation of PCSK9 at the transcriptional level in the liver and at the translational level in the kidney, ultimately increasing circulating PCSK9 levels. The combined effects of HSD on the liver and kidney contributed to the development of hypercholesterolemia. Furthermore, an in vitro assay confirmed that high-salt exposure led to an increase in the protein expression of SREBP2 and PCSK9 secretion, thereby reducing low-density lipoprotein (LDL) uptake. This study, for the first time, shows that an HSD induces dyslipidemia through activation of the SREBP2/PCSK9 pathway, providing new insights into the prevention and treatment of dyslipidemia in patients with salt sensitivity.

Bempedoic acid: new evidence and recommendations on use.

PURPOSES OF REVIEW: Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity worldwide. Recognizing the importance of dyslipidemia treatment in the prevention of cardiovascular events has become a part of standard clinical practice. Desired values of LDL cholesterol (LDL-C) have become lower and lower in the last few decades, as evidenced by the most recent guidelines. Therefore, efforts to lower LDL cholesterol concentrations with conventional therapies and combinations of lipid-lowering therapy may not be successful in a high proportion of patients. RECENT FINDINGS: Bempedoic acid is a novel agent, first in-class ATP Citrate Lyase (ACL) inhibitor, which targets biosynthesis of the cholesterol in the liver. Considering the results of phase 3 studies, it has been approved for sole use for dyslipidemia treatment for patients who are statin-intolerant or in combination with statin-ezetimibe for those suffering from familial hypercholesterolemia or ASCVD and unable to reach targeted LDL-C values. SUMMARY: Bempedoic acid has proven beneficial for further reduction of LDL cholesterol for targeted groups of patients. It is not only efficient but also a well tolerated, affordable, and available agent whose place in lipid-lowering management is yet to be fully understood with new data collected from ongoing clinical research. In this review we suggest the place of bempedoic acid in lipid-lowering management.

Association of hair polychlorinated biphenyls and multiclass pesticides with obesity, diabetes, hypertension and dyslipidemia in NESCAV study.

Obesity, diabetes, hypertension and dyslipidemia are well-established risk factors for cardiovascular diseases (CVDs), and have been associated with exposure to persistent organic pollutants. However, studies have been lacking as regards effects of non-persistent pesticides on CVD risk factors. Here, we investigated whether background chronic exposure to polychlorinated biphenyls (PCBs) and multiclass pesticides were associated with the prevalence of these CVD risk factors in 502 Belgian and 487 Luxembourgish adults aged 18-69 years from the Nutrition, environment and cardiovascular health (NESCAV) study 2007-2013. We used hair analysis to evaluate the chronic internal exposure to three PCBs, seven organochlorine pesticides (OCs) and 18 non-persistent pesticides. We found positive associations of obesity with hexachlorobenzene (HCB), ß-hexachlorocyclohexane (ß-HCH) and chlorpyrifos, diabetes with pentachlorophenol (PCP), fipronil and fipronil sulfone, hypertension with PCB180 and chlorpyrifos, and dyslipidemia with diflufenican and oxadiazon, among others. However, we also found some inverse associations, such as obesity with PCP, diabetes with γ-HCH, hypertension with diflufenican, and dyslipidemia with chlorpyrifos. These results add to the existing evidence that OC exposure may contribute to the development of CVDs. Additionally, the present study revealed associations between CVD risk factors and chronic environmental exposure to currently used pesticides such as organophosphorus and pyrethroid pesticides.

Association between blood arsenic concentration and dyslipidemia: Mediating effect of lipid peroxidation in the elderly.

BACKGROUND: The earlier investigations have revealed heavy metals exposure is implicated in the pathogenesis of dyslipidemia. The goal was to evaluated the relationship of blood arsenic (As) concentration with dyslipidemia in the elderly through a cross-sectional study. METHODS: The entire 360 elderly population were selected. Fasting blood specimens, demographic information, and clinical characteristics were obtained. The concentration of blood As was detected using ICP-MS. Serum 8-iso-PGF2α, a biomarker of lipid peroxidation, was measured by ELISA. RESULTS: Pearson correlative analysis hinted there were strong relationships of blood As with liver function indices in the elderly. Besides, blood As was positively associated with total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C), and apolipoprotein A-I (ApoA I). Further multivariate linear and logistic regression suggested that the incidences of TC and LDL-C elevation were upregulated with the rising tertiles of blood As. Blood As was positively related with the prevalence of dyslipidemia (OR=3.609; 95%CI: 1.353, 6.961). Additionally, serum 8-iso-PGF2α was dramatically and positively linked to the levels of blood As and lipid profiles. Mediation analyses verified that 8-iso-PGF2α partially mediated the correlations between blood As with TC (36.63%) and LDL-C (34.03%). CONCLUSION: Blood As concentration is positively related to lipid profiles in the elderly. Higher blood As concentration elevates the prevalence of dyslipidemia. Lipid peroxidation partially mediates the correlation of As exposure with dyslipidemia.

Blood glucose level and serum lipid profiles among people living with HIV on dolutegravir-based versus efavirenz-based cART; a comparative cross-sectional study.

BACKGROUND: Antiretroviral therapy-linked metabolic abnormalities have become a growing concern among people living with HIV. There is limited data regarding the effects of dolutegravir-based treatment on blood glucose levels and serum lipid profiles in people living with HIV in Ethiopia. Thus, this study aimed to assess blood glucose levels and serum lipid profiles among people living with HIV on dolutegravir-based versus efavirenz-based therapy. METHOD AND MATERIALS: An institutional-based comparative cross-sectional study was conducted from 30 June 2021 to 30 August 2021. A total of 128 participants (64 in the dolutegravir-based group and 64 in the efavirenz-based group) were enrolled in the study. The Chi-square, independent t-test, Mann-Whitney U-test, and logistic regression were used as appropriate statistical tests using SPSS Version 26.0 for this study. A p-value of <0.05 was considered statistically significant. RESULT: The prevalence of hyperglycemia and dyslipidemia were 17.2% (11/64) and 79.7% (51/64) in the dolutegravir group, and 9.4% (6/64) and 75% (48/64) in the efavirenz group, respectively. The efavirenz group had significantly higher mean values of total cholesterol (190.73 ± 44.13 vs. 175.27 ± 37.67 mg/dl, p = 0.035) and high-density lipoprotein (47.53 ± 14.25 vs. 40.92 ± 13.17 mg/dl, p = 0.007) than the dolutegravir group. For a Kg/m2 increase in BMI and for each month's increase in the duration of HIV, the patients were 66% (AOR = 1.66, 95% CI: 1.13, 2.44), and 13% (AOR = 1.13, 95% CI: 1.03, 1.23) more likely to have hyperglycemia, respectively. In contrast, female patients were 3.04 times more likely to have dyslipidemia (AOR = 3.03, 95% CI: 1.14, 8.05) as compared to male patients, and with an increase in CD4 cell count of 1 cell/mm3, the odds of dyslipidemia increased by 0.3% (AOR = 1.003, 95% CI: 1.001, 1.006). CONCLUSION: Efavirenz-based therapy resulted in higher mean values of total cholesterol and high-density lipoprotein as compared with dolutegravir-based therapy. It is important to consider and evaluate high-density lipoprotein levels in HIV patients on dolutegravir-based therapy, and total cholesterol levels in people living with HIV on efavirenz-based therapy.

The long-term use of ART is thought to be one of the potential causes of metabolic abnormalities such as dysregulation of glucose and lipid metabolism.The burden of DTG-based cART-related metabolic abnormalities in resource-limited settings has not been well characterized.This study aimed to address these gaps by assessing blood glucose levels and serum lipid profiles among people living with HIV on DTG-based versus EFV-based regimens and identifying factors associated with hyperglycemia and dyslipidemia.

Synergism of mechanisms underlying early-stage changes in retina function in male hyperglycemic db/db mice in the absence and presence of chemically-induced dyslipidemia.

The study was designed to quantify retina function in a spontaneous mutation mouse model of diabetes, in which sustained dyslipidemia was induced chemically. The goal of the study was to identify if dyslipidemia in the presence of hyperglycemia resulted in either a synergistic, or a merely additive, exacerbation of retinal and visual dysfunctions in diabetes. Two cohorts of mice, male C57BL/6 and C57BL/KsJ-db/db mice were divided into two groups each. One group of each strain received the triblock copolymer, poloxamer 407 (P-407), administered by intraperitoneal injection ("WT P-407" and "db/db P-407" groups) with saline as a control in the remaining two groups ("WT" and "db/db" groups). Blood glucose, total cholesterol (TC) and total triglyceride (TG) levels were quantified using enzyme-based colorimetric assays. Retina function was measured using electroretinography (ERG) and visual acuity was determined by behaviorally assessing parameters of the optomotor reflex. TC and TG levels were normal in both saline controls (WT) and db/db mice but were significantly elevated in the WT P-407 group (p < 0.01 for TC; p < 0.001 for TG), while levels of the same lipids were further elevated in the db/db P-407 group when compared to the WT P-407 group levels (p < 0.001 for both TC and TG). Behavioral assessment of the optomotor reflex indicated reduced visual acuity for the db/db P-407 group when compared to either the WT P-407 or the db/db groups (p < 0.001, p < 0.0001). ERG measurements of scotopic retina function showed a significant decline in the scotopic b-wave amplitude of the WT P-407 animals (p < 0.01) and a further reduction for the db/db P-407 group when compared to controls (p < 0.0001). Very significant, strong correlations between scotopic b-wave amplitude and implicit time to TC (r = - 0.8376, p = < 0.0001 and r = 0.7069, p = 0.0022, respectively) and TG levels (r = - 0.8554, p = < 0.0001 and r = 0.7150, p = 0.0019, respectively) were found. Dyslipidemia in the presence of hyperglycemia synergistically exacerbated the severity of retinal dysfunction in diabetes. P-407 administration significantly elevated plasma TC and TG levels in male wild-type (WT) and diabetic mice (db/db), but the resulting hyperlipidemia was more significantly pronounced in the diabetic mice. While elevated plasma lipid and blood glucose levels were individually correlated with a decline in retinal function, the combination of both exacerbated retinal dysfunction. This model of combined hyperglycemia and dyslipidemia can be used to dissect individual contributions of features of the metabolic syndrome to the pathogenesis of retinal dysfunction in diabetes.

CircFOXN2 alleviates glucocorticoid- and tacrolimus-induced dyslipidemia by reducing FASN mRNA stability by binding to PTBP1 during liver transplantation.

We aimed to examine impacts and functional mechanism of circular RNA forkhead box N2 (FOXN2) in tacrolimus (TAC)- and dexamethasone (Dex)-induced lipid metabolism disorders. RNA level and protein contents in TAC, Dex, or combined TAC- plus Dex-treated patients and Huh-7 cells were measured utilizing quantitative real-time (qRT)-PCR and western blotting assays measured the formation of lipid droplet. Total cholesterol (TC) and triglyceride (TG) levels were determined using corresponding commercial kits and Oil red O staining. RNA immunoprecipitation and RNA pull-down verified the binding relationship among circFOXN2, polypyrimidine tract binding protein 1 (PTBP1) and fatty acid synthase (FASN). Male C57BL/6 mice were used to establish a dyslipidemia mouse model to validate the discoveries at the cellular level. Dex treatment significantly promoted TAC-mediated increase of TC and TG in serum samples and Huh-7 cells. Moreover, circFOXN2 was reduced but FASN was elevated in TAC-treated Huh-7 cells, and these expression trends were markedly enhanced by Dex cotreatment. Overexpression of circFOXN2 could reverse the accumulation of TC and TG and the upregulation of FASN and sterol regulatory element binding transcription factor 2 (SREBP2) mediated by Dex and TAC cotreatment. Mechanistically, circFOXN2 reduced FASN mRNA stability by recruiting PTBP1. The protective roles of circFOXN2 overexpression on lipid metabolism disorders were weakened by FASN overexpression. In vivo finding also disclosed that circFOXN2 greatly alleviated the dysregulation of lipid metabolism triggered by TAC plus Dex. CircFOXN2 alleviated the dysregulation of lipid metabolism induced by the combination of TAC and Dex by modulating the PTBP1/FASN axis.NEW & NOTEWORTHY Collectively, our experiments revealed for the first time that circFOXN2 alleviated the Dex- and TAC-induced dysregulation of lipid metabolism by regulating the PTBP1/FASN axis. These findings suggested that circFOXN2 and FASN might be candidate targets for the treatment of Dex- and TAC-induced metabolic disorders.

The mediation role of blood lipids on the path from air pollution exposure to MAFLD: A longitudinal cohort study.

BACKGROUND & AIMS: Recent cross-sectional studies found that exposure to ambient air pollution (AP) was associated with an increased risk of metabolic dysfunction-associated fatty liver disease (MAFLD). The alternation of blood lipids may explain the association, but epidemiological evidence is lacking. We aimed to examine whether and to what extent the association between long-term exposure to AP and incident MAFLD is mediated by blood lipids and dyslipidemia in a prospective cohort. METHODS: We included 6350 participants from the China Multi-Ethnic Cohort (CMEC, baseline 2018-2019, follow-up 2020-2021). Three-year average (2016-2018) of AP (PM1, PM2.5, PM10, NO2), blood lipids (TC, LDL-C, HDL-C, TG with their combinations) and incident MAFLD for each individual were assessed chronologically. Linear and logistic regression was used to assess the associations among AP, blood lipids, and MAFLD, and the potential mediation effects of blood lipids were evaluated using causal mediation analysis. RESULTS: A total of 744 participants were newly diagnosed with MAFLD at follow-up. The odds ratios of MAFLD associated with a 10 µm increase in PM1, PM2.5, and NO2 were 1.35 (95 % CI: 1.14, 1.58), 1.34 (1.10, 1.65) and 1.28 (1.14, 1.44), respectively. Blood lipids are important mediators between AP and incident MAFLD. LDL-C (Proportion Mediated: 6.9 %), non-HDL (13.4 %), HDL-C (20.7 %), LDL/HDL (30.1 %), and dyslipidemia (6.5 %) significantly mediated the association between PM2.5 and MAFLD. For PM1, the indirect effects were similar to those for PM2.5, with a larger value for the direct effect, and the mediation proportion by blood lipids was less for NO2. CONCLUSION: Blood lipids are important mediators between AP and MAFLD, and can explain 5 %-30 % of the association between AP and incident MAFLD, particularly cholesterol-related variables, indicating that AP could lead to MAFLD through the alternation of blood lipids. These findings provided mechanical evidence of AP leading to MAFLD in epidemiological studies.

Association between urinary neonicotinoid insecticide levels and dyslipidemia risk: A cross-sectional study in Chinese community-dwelling elderly.

Experimental evidence has demonstrated that neonicotinoids (NEOs) exposure can cause lipid accumulation and increased leptin levels. However, the relationship between NEOs exposure and dyslipidemia in humans remains unclear, and the interactive effects of NEOs and their characteristic metabolites on dyslipidemia remain unknown. We detected 14 NEOs and their metabolites in urine samples of 500 individuals (236 and 264 with and without dyslipidemia, respectively) randomly selected from the baseline of the Yinchuan community-dwelling elderly cohort (Ningxia, China). The NEOs and their metabolites were widely detected in urine (87.2-99.6 %) samples, and the median levels ranged within 0.06-0.55 µg/g creatinine. The positive associations and dose-dependent relationships of thiacloprid, imidacloprid-olefin, and imidacloprid-equivalent total with dyslipidemia were validated using restricted cubic spline analysis. Mixture models revealed a positive association between the NEOs mixture and dyslipidemia risk, with urine desnitro-imidacloprid ranked as the top contributor. The Bayesian Kernel Machine Regression models showed that the NEOs mixtures were associated with increased dyslipidemia when the chemical mixtures were ≥ 25th percentile compared to their medians, and desnitro-imidacloprid and imidacloprid-olefin were the major contributors to the combined effect. Given the widespread use of NEOs and the dyslipidemia pandemic, further investigations are urgently needed to confirm our findings and elucidate the underlying mechanisms.

Vitamin D Receptor Activation Attenuates Olanzapine-Induced Dyslipidemia in Mice Through Alleviating Hepatic Endoplasmic Reticulum Stress.

The involvement of vitamin D (VD) signaling in atypical antipsychotics (AAPs)-induced metabolic disturbances has been previously established. This study aims to elucidate the role of VD in maintaining endoplasmic reticulum (ER) homeostasis and its impact on AAPs-induced metabolic adverse effects. Female C57BL/6 mice receive either calcitriol or vehicle one week prior to co-treatment with olanzapine (OLZ) for an additional four weeks. Metabolic parameters, hepatic ER homeostasis, and the SREBPs pathway are assessed through biochemical assays and protein expression profiling. HepG2 cells are transfected with vitamin D receptor (VDR) siRNA for VDR knockdown. OLZ-treated HepG2 cells are exposed to calcitriol to examine its effects on SREBPs and the unfolded protein response (UPR) pathways. VDR activation by calcitriol reduces OLZ-induced hepatic ER stress, leading to decreased SREBPs activity and lipid accumulation. Conversely, the knockdown of VDR in HepG2 cells diminishes the protective effects of calcitriol against OLZ-induced ER stress and SREBPs activation. This resulted in sustained UPR activation, elevated cleaved SREBPs levels, and increased lipid accumulation. These findings highlight an essential role of VDR signaling in the beneficial effects of VD on OLZ-induced metabolic side effects. Targeting VDR to resolve ER stress is likely an applicable therapeutic strategy for AAPs-induced metabolic disturbances.

Is dyslipidemia a risk factor for trastuzumab-induced cardiotoxicity in breast cancer patients? A systematic review and meta-analysis.

INTRODUCTION: Breast cancer patients undergoing trastuzumab therapy have greater risk of cardiovascular disease. Risk factors for this effect have been proposed. However, the role of dyslipidemia is not completely understood. This systematic review aimed to explore the role of dyslipidemia in trastuzumab-induced cardiotoxicity. METHODS: The investigators searched MEDLINE, Scopus, and Web of Science up to October 25, 2020. A random-effects model was used to determine pooled estimates of the results. The primary endpoint was trastuzumab-induced cardiotoxicity in patients with and without dyslipidemia. RESULTS: A total of 39 studies were selected for inclusion in our systematic review assessing 21079 patients. One study demonstrated a statistically significant association between dyslipidemia and cardiotoxicity (OR=2.28, 95% CI 1.22-4.26, p=0.01). In all other studies, no such association was observed. Twenty-one studies including 6135 patients were eligible for meta-analysis. In this meta-analysis of unadjusted data, dyslipidemia was significantly associated with cardiotoxicity (OR=1.25, 95% CI 1.01-1.53, p=0.04, I2=0%), however, a subgroup analysis of studies reporting adjusted measures did not demonstrate a significant association (OR=0.89, 95% CI 0.73-1.10, p=0.28, I2=0%). CONCLUSION: This systematic review and meta-analysis did not demonstrate a significant association between dyslipidemia alone and the development of cardiotoxicity. In the absence of other relevant cardiovascular risk factors, review of lipid profile may not be obligatory, and management of patients could be performed without referral for cardio-oncology assessment. Further investigation of risk factors for trastuzumab-induced cardiotoxicity is required to confirm these results.

Impact of metformin on statin-associated myopathy risks in dyslipidemia patients.

A growing number of patients with metabolic disorders are receiving statin and antidiabetic therapies as comedications. A signal of increased risk of myotoxicity due to potential interactions between antidiabetics and statins has been detected in previous studies. To investigate the effects of metformin on myopathy risks when added to preexisting statin therapy in dyslipidemia patients, we performed a retrospective cohort study using the Korean national health insurance data in statin-treated dyslipidemia patients with or without concomitant metformin use. We compared the risk of myopathy in statin + metformin users against statin-only users. Hazard ratios (HRs) and 95% confidence intervals (CIs) have been calculated following propensity score (PS) matching between study groups and subsequent stratification per patient factors. We included 4092 and 8161 patients in PS-matched statin + metformin and statin-only groups, respectively. The risk of myopathy decreased when metformin was used together with statins (adjusted HR 0.84; 95% CI 0.71-0.99). In subgroup analyses per individual statin agent and in stratified risk analyses, no specific statin agents or patient factors were associated with statistically significant myopathy risk. This study found that a comedication with metformin was associated with decreased myopathy risk in statin-treated dyslipidemia patients compared to statin-only users. Our findings suggest that metformin may provide protective effects on potential muscle toxicities induced by statin therapy.