Independent relationship between sleep apnea-specific hypoxic burden and glucolipid metabolism disorder: a cross-sectional study.

OBJECTIVES: Obstructive sleep apnea (OSA) is associated with abnormal glucose and lipid metabolism. However, whether there is an independent association between Sleep Apnea-Specific Hypoxic Burden (SASHB) and glycolipid metabolism disorders in patients with OSA is unknown. METHODS: We enrolled 2,173 participants with suspected OSA from January 2019 to July 2023 in this study. Polysomnographic variables, biochemical indicators, and physical measurements were collected from each participant. Multiple linear regression analyses were used to evaluate independent associations between SASHB, AHI, CT90 and glucose as well as lipid profile. Furthermore, logistic regressions were used to determine the odds ratios (ORs) for abnormal glucose and lipid metabolism across various SASHB, AHI, CT90 quartiles. RESULTS: The SASHB was independently associated with fasting blood glucose (FBG) (ß = 0.058, P = 0.016), fasting insulin (FIN) (ß = 0.073, P < 0.001), homeostasis model assessment of insulin resistance (HOMA-IR) (ß = 0.058, P = 0.011), total cholesterol (TC) (ß = 0.100, P < 0.001), total triglycerides (TG) (ß = 0.063, P = 0.011), low-density lipoprotein cholesterol (LDL-C) (ß = 0.075, P = 0.003), apolipoprotein A-I (apoA-I) (ß = 0.051, P = 0.049), apolipoprotein B (apoB) (ß = 0.136, P < 0.001), apolipoprotein E (apoE) (ß = 0.088, P < 0.001) after adjustments for confounding factors. Furthermore, the ORs for hyperinsulinemia across the higher SASHB quartiles were 1.527, 1.545, and 2.024 respectively, compared with the lowest quartile (P < 0.001 for a linear trend); the ORs for hyper-total cholesterolemia across the higher SASHB quartiles were 1.762, 1.998, and 2.708, compared with the lowest quartile (P < 0.001 for a linear trend) and the ORs for hyper-LDL cholesterolemia across the higher SASHB quartiles were 1.663, 1.695, and 2.316, compared with the lowest quartile (P < 0.001 for a linear trend). Notably, the ORs for hyper-triglyceridemia{1.471, 1.773, 2.099} and abnormal HOMA-IR{1.510, 1.492, 1.937} maintained a consistent trend across the SASHB quartiles. CONCLUSIONS: We found SASHB was independently associated with hyperinsulinemia, abnormal HOMA-IR, hyper-total cholesterolemia, hyper-triglyceridemia and hyper-LDL cholesterolemia in Chinese Han population. Further prospective studies are needed to confirm that SASHB can be used as a predictor of abnormal glycolipid metabolism disorders in patients with OSA. TRIAL REGISTRATION: ChiCTR1900025714 { http://www.chictr.org.cn/ }; Prospectively registered on 6 September 2019; China.

Prevalence of plasma lipid disorders with an emphasis on LDL cholesterol in selected countries in the Asia-Pacific region.

Cardiovascular disease (CVD) is a major cause of mortality and morbidity within the Asia-Pacific region, with the prevalence of CVD risk factors such as plasma lipid disorders increasing in many Asian countries. As members of the Cardiovascular RISk Prevention (CRISP) in Asia network, the authors have focused on plasma lipid disorders in the six countries within which they have clinical experience: Indonesia, Malaysia, Philippines, Thailand, Vietnam, and Australia. Based on country-specific national surveys, the prevalence of abnormal levels of total cholesterol, low- and high-density lipoprotein cholesterol (LDL-C and HDL-C, respectively), and triglycerides (TG) are reported. An important caveat is that countries have used different thresholds to define plasma lipid disorders, making direct comparisons difficult. The prevalence of abnormal lipid levels was as follows: high total cholesterol (30.2-47.7%, thresholds: 190-213 mg/dL); high LDL-C (33.2-47.5%; thresholds: 130-135 mg/dL); low/abnormal HDL-C (22.9-72.0%; thresholds: 39-50 mg/dL); and high/abnormal TG (13.9-38.7%; thresholds: 150-177 mg/dL). Similarities and differences between country-specific guidelines for the management of plasma lipid disorders are highlighted. Based on the authors' clinical experience, some of the possible reasons for suboptimal management of plasma lipid disorders in each country are described. Issues common to several countries include physician reluctance to prescribe high-dose and/or high-intensity statins and poor understanding of disease, treatments, and side effects among patients. Treatment costs and geographical constraints have also hampered disease management in Indonesia and the Philippines. Understanding the factors governing the prevalence of plasma lipid disorders helps enhance strategies to reduce the burden of CVD in the Asia-Pacific region.

HDL Cholesterol Efflux Capacity is Impaired in Severe Short-Term Hypothyroidism Despite Increased HDL Cholesterol.

CONTEXT: Severe hypothyroidism has profound effects on lipoprotein metabolism including high-density lipoprotein (HDL) cholesterol elevations but effects on HDL function metrics are unknown. OBJECTIVE: To determine the impact of severe short-term hypothyroidism on HDL particle characteristics, HDL cholesterol efflux capacity (CEC), and HDL antioxidative capacity. DESIGN: Observational study with variables measured during severe short-term hypothyroidism (median TSH 81 mU/L) and after 20 weeks of thyroid hormone supplementation (median TSH 0.03 mU/L) (Netherlands Trial Registry ID 7228). SETTING: University hospital setting in The Netherlands. PATIENTS: Seventeen patients who had undergone a total thyroidectomy for differentiated thyroid carcinoma. MAIN OUTCOME MEASURES: HDL particle characteristics (nuclear magnetic resonance spectrometry), CEC (human THP-1-derived macrophage foam cells and apolipoprotein B-depleted plasma), and HDL anti-oxidative capacity (inhibition of low-density lipoprotein oxidation). RESULTS: During hypothyroidism plasma total cholesterol, HDL cholesterol and apolipoprotein A-I were increased (P ≤ 0.001). HDL particle concentration was unchanged, but there was a shift in HDL subclasses toward larger HDL particles (P < 0.001). CEC was decreased (P = 0.035), also when corrected for HDL cholesterol (P < 0.001) or HDL particle concentration (P = 0.011). HDL antioxidative capacity did not change. CONCLUSION: During severe short-term hypothyroidism CEC, an important antiatherogenic metric of HDL function, is impaired. HDL cholesterol and larger HDL particles are increased but HDL particle concentration is unchanged. Combined, these findings suggest that HDL quality and quantity are not improved, reflecting dysfunctional HDL in hypothyroidism.

The Presence of Serum TgAb Suggests Lower Risks for Glucose and Lipid Metabolic Disorders in Euthyroid General Population From a National Survey.

Purpose: The expressions of antibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) are very common in the sera of patients with autoimmune thyroid diseases (AITD). The relationship between thyroid autoantibodies and the occurrence of glucose and lipid metabolic disorders remains unclear. This study was performed to investigate the correlation between the presence of serum TPOAb/TgAb and those metabolic disorders in euthyroid general population. Methods: The data of this study were derived from the Thyroid Disease, Iodine status, and Diabetes National epidemiological (TIDE) survey from all 31 provinces of mainland China. A total of 17,964 euthyroid subjects including 5,802 males (4,000 with TPOAb-TgAb- and 1,802 with TPOAb+/TgAb+) and 12,162 females (8,000 with TPOAb-TgAb- and 4,162 with TPOAb+/TgAb+) were enrolled in this study. The blood glucose and lipid levels were compared between individuals with TPOAb-TgAb- and those with TPOAb+TgAb-, TPOAb-TgAb+, TPOAb+TgAb+. Results: Both fasting blood glucose (FBG) concentration and the proportion of individuals with impaired FBG (IFG) showed the decreased trends in TPOAb-TgAb+ males as compared with TPOAb-TgAb- men. There were significantly lower FBG and higher HDL-C levels as well as tendencies toward decreased incidences of IGT and hypertriglyceridemia in TPOAb-TgAb+ females when compared with TPOAb-TgAb- women. Binary logistic regression analysis further showed that serum TgAb single positivity in males was an independent protective factor for IFG with an OR of 0.691 (95% CI, 0.503-0.949). For females, serum TgAb single positivity was an independent protective factor for hypertriglyceridemia with an OR of 0.859 (95% CI, 0.748-0.987). Trend test showed that with the increase of serum TgAb level, there were significant decreases in the prevalence of IFG among the men with TSH ≤ 2.5 mIU/L and that of hypertriglyceridemia in the women, especially among non-obese females. Conclusion: Serum TgAb single positivity may imply a reduced risk of IFG in euthyroid men and that of hypertriglyceridemia in euthyroid women. The mechanisms for the independent protective roles of TgAb await further investigation.

Familial combined hypolipidemia: angiopoietin-like protein-3 deficiency.

PURPOSE OF REVIEW: Angiopoietin-like protein-3 (ANGPTL3) is emerging as a key player in lipoprotein transport with an expanding role on fatty acid and glucose metabolism. Its deficiency is associated with a favorable metabolic profile. The present review will highlight the recent understanding of metabolic and cardiovascular consequences of ANGPTL3 inactivation by considering both genetic and pharmacological investigations. RECENT FINDINGS: Experimental studies have further illustrated the complex interplay between ANGPTL3 and ANGPTL4-8 in orchestrating lipid transport in different nutritional status. Individuals with familial combined hypolipidemia due to homozygous loss-of-function mutations in ANGPTL3 gene showed improved metabolism of triglyceride-rich lipoproteins during fasting and postprandial state and increased fatty acid oxidation and insulin sensitivity. Moreover, mendelian randomizations studies demonstrated that partial ANGPTL3 deficiency associates with reduced risk of atherosclerotic cardiovascular events and, eventually, diabetes mellitus. Finally, inactivation of ANGPTL3, using either a specific mAb or antisense oligonucleotide, was reported to reduce plasma levels of atherogenic lipoprotein in humans and improve hepatic fat infiltration in animal models. SUMMARY: Human and animal studies have further dissected the complex role of ANGPTL3 in the regulation of energy substrate metabolism. Moreover, genetic and pharmacological investigations have convincingly indicated that the inactivation of ANGPTL3 may be a very promising strategy to treat atherogenic metabolic disorders.

High-Performance Liquid Chromatography-Mass Spectrometry-Based Lipid Metabolite Profiling of Acromegaly.

CONTEXT: Metabolic disorders, especially dysregulated lipid metabolism, increase the risk of cardiovascular mortality in acromegaly. Previous studies measuring plasma macromolecular lipids have yielded conflicting results. PURPOSE: To explore the plasma lipid metabolite profiles by metabolomics analysis and identify potential metabolites associated with cardiac function in acromegaly. METHODS: Plasma was obtained from 80 newly diagnosed, untreated patients with acromegaly and 80 healthy controls. Echocardiography was performed. Based on the results of an oral glucose tolerance test (OGTT), patients were categorized into 2 groups: normal glucose tolerance (NGT, n = 28) and impaired glucose tolerance or diabetes mellitus (IGT/DM, n = 52). High-performance liquid chromatography-mass spectrometry (HPLC-MS)-based metabolomics analysis was conducted. Data were processed by principal components analysis (PCA), orthogonal partial least square-discriminant analysis (OPLS-DA), and MetaboAnalyst 4.0. Associations between metabolic substances and cardiovascular parameters were also explored. RESULTS: Metabolomics uncovered a distinct metabolic pattern between acromegaly and healthy controls, and perturbed pathways mainly include glycerophospholipid metabolism, sphingolipid metabolism, as well as linoleic acid metabolism. Collective analysis showed that phosphatidylethanolamine (PE) (22:6/16:0) was positively correlated with LV mass, while lysophosphatidylcholine (LysoPC) (16:0) was positively correlated with fractional shortening (FS) and left ventricle ejection fraction (LVEF). CONCLUSION: Patients with acromegaly have distinct lipid metabolite profiling, while PE (22:6/16:0) and LysoPC (16:0) are correlated with cardiac structure and function, which may contribute to the risk of cardiovascular complications.

Inclisiran-New hope in the management of lipid disorders?

Drugs reducing plasma concentrations of apolipoprotein B-containing lipoproteins have been demonstrated to reduce the risk of cardiovascular disease (CVD) in both primary and secondary prevention. Despite the demonstrated efficacy of statins and ezetimibe on low-density lipoprotein (LDL) concentration and long-term CVD risk, a large number of patients do not achieve their therapeutic goals. The introduction of monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) protein was a milestone in the treatment of lipid disorders, as their administration leads to unprecedentedly low LDL cholesterol concentrations. Inclisiran represents an entirely new mechanism of PSCK9 protein inhibition in hepatocytes, targeting the messenger RNA for PCSK9. Its administration is necessary only every 3 to 6 months, which is an essential advantage over statin and monoclonal antibody therapy. The infrequent administration regimen can increase the number of patients who maintain their therapeutic goals, especially in patients struggling to comply with daily or biweekly pharmacotherapy. Preclinical studies and Phase I and Phase II clinical trials of inclisiran have demonstrated its tolerability and efficacy in promoting long-term reduction of both PCSK9 protein and LDL cholesterol. The efficacy and safety of inclisiran will continue to be assessed in ongoing and forthcoming trials on larger patient groups. If the results of these trials reflect previously published data, they will add further evidence that inclisiran might be a revolutionary new tool in the pharmacologic management of plasma lipids. This review summarizes the currently available literature data on inclisiran with respect to its mechanism of action, effectiveness, and safety as a lipid-lowering drug for CVD prevention.

Crohn's disease and ulcerative colitis are associated with different lipid profile disorders: a nationwide population-based study.

BACKGROUND: The relationships between lipid profiles and IBD remain elusive. AIM: To determine the association of IBD with serum lipid profiles. METHODS: A nationwide population-based study was performed using claims data from the Korean National Healthcare Insurance service. A total of 9 706 026 subjects undergoing medical check-ups in 2009 were enrolled and followed up until 2016. Individuals who developed Crohn's disease (CD) or ulcerative colitis (UC) were identified during follow-up. Adjusted hazard ratio (aHR) by age, sex, body mass index, cigarette smoking, alcohol drinking, exercise, income and underlying comorbidities was calculated to define the impact of serum lipid profiles on developing IBD. RESULTS: During a median follow-up of 7.3 years, IBD was detected in 7,058 (0.07%) individuals. Compared with the highest quartile of serum total cholesterol (TC) levels, lower TC levels were associated with higher incidence of CD (aHR: Q1, 2.52; Q2, 1.52; Q3, 1.27), but not UC. Lower serum LDL-C levels were associated with higher incidence of CD (aHR: Q1, 1.92; Q2, 1.47; Q3, 1.22), but not UC. Moreover, lower serum HDL-C levels were associated with higher incidence of CD (aHR: Q1, 2.49; Q2, 1.90; Q3, 1.43), but not UC. In contrast, lower serum triglyceride levels were associated with higher incidence of UC (aHR: Q1, 1.22; Q2, 1.19; Q3, 1.19), but not CD. CONCLUSIONS: Low serum TC, LDL-C and HDL-C levels were associated with CD. Low serum triglyceride levels were related to UC.

Evaluation of serum free fatty acids in chronic renal failure: evidence from a rare case with undetectable serum free fatty acids and population data.

BACKGROUND: Free fatty acid (FFA) accumulation in proximal tubules plays a fundamental role in the progress of kidney disease. Here, we reported a rare case with undetectable serum FFAs and further evaluated the changes of serum FFAs in patients with chronic renal failure (CRF). METHODS: We analyzed the clinical data of a rare case and 574 CRF patients. The mRNA expression of lipoprotein lipase (LPL), hepatic lipase (HL) and fatty acid synthase (FASN) were determined in the rare case and 30 age-matched healthy males with qPCR. RESULTS: This rare case had serious proteinuria, hyperglycemia, lipid disorders and bilateral renal glomerular filtration dysfunction. Compared with healthy males, this case showed a 1.49-fold increase of LPL expression (P < 0.01), a 3.38-fold reduction of HL expression (P < 0.001), and no significant change of FASN expression (P > 0.05). In total, 21.6% of CRF patients showed abnormal FFAs. Biochemical parameters such as blood urea nitrogen (BUN) and creatinine (CREA) significantly differed among groups with low-, normal- or high-level-FFAs. Moreover, serum FFAs was found to be associated with BUN. FFAs decreased in the group with higher BUN (> 17.4 mmol/L) and in the group with lower estimated glomerular filtration rate (eGFR) (< 15 mL/min/1.73m2). CONCLUSIONS: The proteinuria, HL low expression and renal function failure may contribute to the FFA reduction, which might imply that the renal function is severely damaged.

The biochemical and genetic diagnosis of lipid disorders.

PURPOSE OF REVIEW: To examine recent advances in our knowledge on the diagnosis of lipid disorders. RECENT FINDINGS: Fasting values above the 99th percentile for direct LDL-cholesterol (LDL-C), lipoprotein(a), and triglycerides are greater than 225 mg/dl, greater than 160 mg/dl, and greater than 500 mg/dl (>5.82, >394, and >5.65 mmol/l), respectively, whereas such values for plasma lathosterol, ß-sitosterol, and cholestanol are greater than 8.0, 8.0, and 5.0 mg/l (>0.021, 0.019, and 0.013 mmol/l), respectively. Values below the first percentile for LDL-C are less than 40 mg/dl (<1.03 mmol/l) and for HDL-cholesterol (HDL-C) less than 25 mg/dl (<0.65 mmol/l) in men and less than 30 mg/dl (<0.78 mmol/l) in women, respectively. The above values can predispose to premature CVD, pancreatitis, neurologic disease, and kidney failure, and may be associated with monogenic lipid disorders. In the absence of secondary causes including diabetes or kidney, liver, or thyroid disease, consideration should be given to sequencing the following genes: ABCA1, ABCG5, ABCG8, APOA1, APOA5, APOB, APOC2, APOE, CETP, CYP27A1, GPIHBP1, LCAT, LDLR, LDLRAP1, LIPA, LIPC, LMF1, LPL, MTTP, PCSK9, SCARB1, and STAP1. SUMMARY: Recent data indicate that secondary causes and a wider range of conditions need to be considered in identifying the underlying causes of hypercholesterolemia, hypertriglyceridemia, hyperalphalipoproteinemia, hypobetalipoproteinemia, and HDL deficiency. Identifying such disorders allows for a more precise assessment of prognosis and the formulation of optimal therapy.

The evolution of genetic-based risk scores for lipids and cardiovascular disease.

PURPOSE OF REVIEW: With improved next-generation sequencing technology, open-access genetic databases and increased awareness of complex trait genetics, we are entering a new era of risk assessment in which genetic-based risk scores (GRSs) will play a clinical role. We review the concepts underlying polygenic models of disease susceptibility and challenges in clinical implementation. RECENT FINDINGS: Polygenic risk scores are currently used in genetic research on dyslipidemias and cardiovascular disease (CVD). Although the underlying principles for constructing polygenic scores for lipids are established, the lack of consensus on which score to use is indicated by the large number - about 50 - that have been published. Recently, large-scale polygenic scores for CVD appear to afford superior risk prediction compared to small-scale scores. Despite the potential benefits of GRSs, certain biases towards ethnicity and sex need to be worked through. SUMMARY: We are on the verge of clinical application of GRSs to provide incremental information on dyslipidemia and CVD risk above and beyond traditional clinical variables. Additional work is required to develop a consensus of how such scores will be constructed and measured in a validated manner, as well as clinical indications for their use.

Prolonged effectiveness of 12-month exercise-plus-diet intervention in Japanese adults at risk of impaired glucose or lipid metabolism.

BACKGROUND AND OBJECTIVES: To investigate the prolonged effects of a 12-month exercise-plus-diet intervention in Japanese adults at risk of impaired glucose or lipid metabolism. METHODS AND STUDY DESIGN: A total of 180 participants were randomly divided into an intervention group (n=94), and a control group (n=86). An exercise-plus- diet intervention was conducted on the intervention group for 12 months. The effects were evaluated by questionnaire, physical examinations, and blood tests at baseline, 3 months, 12 months (the end of intervention), and 24 months (one year after the end of intervention). The control group took only the same examinations as the intervention group. RESULTS: At the end of the 12-month intervention, body weight, waist circumference, fasting glucose, HbA1c, triglycerides, and LDL-cholesterol were improved in the intervention group compared to the control group (all p<0.05). One year after the end of the intervention, body weight, waist circumference, fasting glucose, triglycerides, and LDL-cholesterol were still decreased in the intervention group compared to the control group (all p<0.05), especially among non-overweight participants. Among overweight persons, only body weight in the intervention group was lower than the control group. The personal behaviours of physical activity and diet in the intervention group were also improved. CONCLUSIONS: The 12-month exercise-plus-diet programs were found to be effective in improving glucose and lipid metabolism, as well as personal behaviour one year after completion of the intervention.

Type 2 Diabetes and Adiposity Induce Different Lipid Profile Disorders: A Mendelian Randomization Analysis.

Context: Type 2 diabetes and obesity often coexist, so it is difficult to judge whether diabetes or obesity induce certain types of hyperlipidemia due to mutual confounds and reverse causation. We used Mendelian randomization analyses to explore the causal relationships of diabetes and adiposity with lipid profiles. Design, Setting, and Main Outcome Measures: From 23 sites in East China, 9798 participants were enrolled during 2014 to 2016. We calculated two weighted genetic risk scores as instrumental variables for type 2 diabetes and body mass index (BMI). These scores were used to measure the causal relationships of diabetes and BMI with lipid profiles that included total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TGs). Results: The causal regression coefficients (ßIV) of genetically determined diabetes for the total cholesterol, LDL-C, and log10TG were 0.130 [95% confidence interval (CI): 0.020, 0.240; P = 0.014], 0.125 (96% CI: 0.041, 0.209; P = 0.001), and 0.019 (95% CI: -0.001, 0.039; P = 0.055), respectively. The ßIV for HDL-C was -0.008 (95% CI: -0.032. 0.016), which was not significant (P = 0.699). The causal regression coefficients of a genetically determined 10 kg/m2 increase in BMI for HDL-C and log10TG were -0.409 (96% CI: -0.698, -0.120; P = 0.004) and 0.227 (95% CI: 0.039, 0.415; P = 0.026), respectively. The ßIVs for TGs and LDL-C were not significant. Conclusions: This study has provided evidence for the biologically plausible causal effects of diabetes and adiposity by BMI on different elements of the lipid profile using Mendelian randomization analyses.

Liver and the defects of cholesterol and bile acids biosynthesis: Rare disorders many diagnostic pitfalls.

In recent decades, biotechnology produced a growth of knowledge on the causes and mechanisms of metabolic diseases that have formed the basis for their study, diagnosis and treatment. Unfortunately, it is well known that the clinical features of metabolic diseases can manifest themselves with very different characteristics and escape early detection. Also, it is well known that the prognosis of many metabolic diseases is excellent if diagnosed and treated early. In this editorial we briefly summarized two groups of inherited metabolic diseases, the defects of cholesterol biosynthesis and those of bile acids. Both groups show variable clinical manifestations but some clinical signs and symptoms are common in both the defects of cholesterol and bile acids. The differential diagnosis can be made analyzing sterol profiles in blood and/or bile acids in blood and urine by chromatographic techniques (GC-MS and LC-MS/MS). Several defects of both biosynthetic pathways are treatable so early diagnosis is crucial. Unfortunately their diagnosis is made too late, due either to the clinical heterogeneity of the syndromes (severe, mild and very mild) that to the scarcity of scientific dissemination of these rare diseases. Therefore, the delay in diagnosis leads the patient to the medical observation when the disease has produced irreversible damages to the body. Here, we highlighted simple clinical and laboratory descriptions that can potentially make you to suspect a defect in cholesterol biosynthesis and/or bile acids, as well, we suggest appropriate request of the laboratory tests that along with common clinical features can help to diagnose these defects.

Circulating acylcarnitine profile in human heart failure: a surrogate of fatty acid metabolic dysregulation in mitochondria and beyond.

Heart failure (HF) is associated with metabolic perturbations, particularly of fatty acids (FAs), which remain to be better understood in humans. This study aimed at testing the hypothesis that HF patients with reduced ejection fraction display systemic perturbations in levels of energy-related metabolites, especially those reflecting dysregulation of FA metabolism, namely, acylcarnitines (ACs). Circulating metabolites were assessed using mass spectrometry (MS)-based methods in two cohorts. The main cohort consisted of 72 control subjects and 68 HF patients exhibiting depressed left ventricular ejection fraction (25.9 ± 6.9%) and mostly of ischemic etiology with ≥2 comorbidities. HF patients displayed marginal changes in plasma levels of tricarboxylic acid cycle-related metabolites or indexes of mitochondrial or cytosolic redox status. They had, however, 22-79% higher circulating ACs, irrespective of chain length (P < 0.0001, adjusted for sex, age, renal function, and insulin resistance, determined by shotgun MS/MS), which reflects defective mitochondrial ß-oxidation, and were significantly associated with levels of NH2-terminal pro-B-type natriuretic peptide levels, a disease severity marker. Subsequent extended liquid chromatography-tandem MS analysis of 53 plasma ACs in a subset group from the primary cohort confirmed and further substantiated with a comprehensive lipidomic analysis in a validation cohort revealed in HF patients a more complex circulating AC profile. The latter included dicarboxylic-ACs and dihydroxy-ACs as well as very long chain (VLC) ACs or sphingolipids with VLCFAs (>20 carbons), which are proxies of dysregulated FA metabolism in peroxisomes. Our study identified alterations in circulating ACs in HF patients that are independent of biological traits and associated with disease severity markers. These alterations reflect dysfunctional FA metabolism in mitochondria but also beyond, namely, in peroxisomes, suggesting a novel mechanism contributing to global lipid perturbations in human HF.NEW & NOTEWORTHY Mass spectrometry-based profiling of circulating energy metabolites, including acylcarnitines, in two cohorts of heart failure versus control subjects revealed multiple alterations in fatty acid metabolism in peroxisomes in addition to mitochondria, thereby highlighting a novel mechanism contributing to global lipid perturbations in heart failure.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/acylcarnitines-in-human-heart-failure/.

The effect of maternal chromium status on lipid metabolism in female elderly mice offspring and involved molecular mechanism.

Maternal malnutrition leads to the incidence of metabolic diseases in offspring. The purpose of this project was to examine whether maternal low chromium could disturb normal lipid metabolism in offspring, altering adipose cell differentiation and leading to the incidence of lipid metabolism diseases, including metabolic syndrome and obesity. Female C57BL mice were given a control diet (CD) or a low chromium diet (LCD) during the gestational and lactation periods. After weaning, offspring was fed with CD or LCD. The female offspring were assessed at 32 weeks of age. Fresh adipose samples from CD-CD group and LCD-CD group were collected. Genome mRNA were analysed using Affymetrix GeneChip Mouse Gene 2.0 ST Whole Transcript-based array. Differentially expressed genes (DEGs) were analysed based on gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis database. Maternal low chromium irreversibly increased offspring body weight, fat-pad weight, serum triglyceride (TG) and TNF-α. Eighty five genes increased and 109 genes reduced in the offspring adipose of the maternal low chromium group. According to KEGG pathway and String analyses, the PPAR signalling pathway may be the key controlled pathway related to the effect of maternal low chromium on female offspring. Maternal chromium status have long-term effects of lipid metabolism in female mice offspring. Normalizing offspring diet can not reverse these effects. The potential underlying mechanisms are the disturbance of the PPAR signalling pathway in adipose tissue.

Cardiometabolic risk in first-episode schizophrenia (FES) patients with the earliest stages of both illness and antipsychotic treatment.

OBJECTIVE: It is well established that schizophrenia patients have high cardiovascular morbidity and mortality. However, the underlying risk factors in the earliest stages of both schizophrenia illness and antipsychotics treatment are less clear. This study aimed to characterize the metabolic features of those patients. METHODS: We performed a retrospective cohort study in a naturalistic setting, which included antipsychotic-naïve, first-episode schizophrenia (FES) inpatients with the baseline metabolic measurements and changes following a short term treatment with antipsychotic drugs. RESULTS: Although prevalence of hypertriglyceridemia, hypercholesterolemia, higher-LDL-C and hyperglycaemia in patients with FES were much lower than those of the general population (7.5% v.s. 14.9%, 9.2% v.s. 18.4%, 8.1% v.s. 14.9%, 8.6% v.s.18.3%, respectively), lower-HDL-C in patients with FES were much more prevalent than that of the general population (19.9% v.s. 6.4%). Despite significant metabolic risk profiles (as such lipid abnormalities and insulin resistance) increase, mean fasting glucose and glucosylated serum protein (GSP) were significantly decreased after the short term (median of 23days) antipsychotics exposure, compared to baseline. There is no significant difference of the metabolic profile change between monopharmacy and polypharmacy. CONCLUSION: These results indicated an early-onset nature of HDL-C abnormalities in drug-naïve FES patients. Lipids metabolism risk may develop early and quickly after antipsychotic exposure. Early monitoring is required for the purpose of early detection and hence prevention of the initial metabolic risk which may lead to diabetes mellitus and cardiovascular disease.

Association of apolipoprotein E polymorphism with plasma lipid disorders, independent of obesity-related traits in Vietnamese children.

BACKGROUND: The dyslipidemia associated with obesity plays a major role in the development of atherosclerosis and cardiovascular disease. Dyslipidemia in childhood can progress in adult stage. APOE is one of the most important genes that regulate plasma lipid transport and clearance. The study aimed to assess whether the common APOE polymorphism is associated with lipid profiles and dyslipidemia, and it could be modulated by obesity-related traits (body mass index, waist circumference, hip circumference, and waist-to-hip ratio) in Vietnamese children. METHODS: A case-control study was designed including 249 cases with dyslipidemia and 600 controls without dyslipidemia. Dyslipidemia is defined as elevated total or low-density lipoprotein (LDL) cholesterol levels, or low levels of high-density lipoprotein (HDL) cholesterol. Genotype for APOE polymorphism (rs7412 and rs429358) was determined by the polymerase chain reaction and restriction fragment length polymorphism method. The association of APOE genotypes with plasma lipid disorders was tested by binary logistic regression analysis, taking into account the confounding factors of age, sex, residence, province and obesity-related traits. RESULTS: In comparison with ε3/ε3 carriers, the ε4 carriers had the highest concentration of serum TC and LDL-C in cases and controls (P ≤ 0.001), while ε2 carriers had the lowest. Carriers without TT haplotype had higher serum TC than those with TT haplotype. The ε4 carriers had higher hypoalphalipoproteinemia risk than ε3/ε3 carriers (OR = 2.78, P = 0.02) before and after adjustment for age, gender, residence and obesity-related traits. CONCLUSIONS: The study suggested that the APOE genotype and haplotype significantly associated with plasma TC and LDL-C level in Vietnamese children. The association of APOE genotype with hypoalphalipoproteinemia was independent of obesity-related traits.

Endoplasmic Reticulum Stress May Play a Pivotal Role in Lipid Metabolic Disorders in a Novel Mouse Model of Subclinical Hypothyroidism.

Subclinical hypothyroidism (SCH) is becoming a global health problem due to its increasing prevalence and potential deleterious effects. However, the molecular mechanisms underlying the lipid metabolic disorders in SCH have not been fully clarified. Additionally, progress in elucidating the exact pathogenesis of SCH has been hampered by the lack of optimized mouse models. Methimazole (MMI) was applied to construct a noninvasive SCH mouse model. Eight-week-old C57BL/6 mice were administrated MMI through the drinking water. After 12 weeks, the MMI-treated mice showed the diagnostic criteria for SCH: increased serum thyrotropin (TSH) levels with constant thyroid hormone levels that persisted for approximately 8 weeks. Notably, SCH mice presented evident lipid metabolic disturbances, including dyslipidemia and hepatic lipid accumulation. Further analysis showed that hepatic endoplasmic reticulum stress (ER stress) was induced in the SCH mice or by the elevation of TSH in vitro, likely via the IRE1α/XBP-1 pathway. Interestingly, when we used 4-phenyl butyric acid to repress ER stress in SCH mice for 4 weeks, dyslipidemia and hepatic lipid accumulation were both significantly alleviated. Our findings indicate that an optimized SCH mouse model could be established using MMI, and ER stress may play a pivotal role in the lipid metabolic abnormalities in SCH.

[Clinical Application of Methods for the Qualitative Evaluation of Lipid Abnormalities].

Recent lifestyle and social environment changes in Japan have been accompanied by increasing incidencerates of metabolic disorders, such as dyslipidemia and diabetes. Therefore, the rates of cardiovascular disease due to the progression of atherosclerosis are also increasing, and cardiovascular disease remains the leading cause of death in Japan. In particular, dyslipidemia, represented by hypercholesterolemia, hypertriglyceridemia, and hypoalphalipoproteinemia, is closely related to the onset and progression of atherosclerosis. Total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol have been used as quantitative markers of lipids to evaluate cardiovascular risks. However, these markers are not sufficient to fully assess the risks. Therefore, we focused on qualitative markers that represent lipid abnormalities, and examined the utility of qualitative lipids evaluation as clinical markers of atherosclerotic disorders. Previously, we reported that HDL and LDL subclasses and sterol markers are clinically important for evaluating the pathogenesis and risks of cardiovascular disorders. Moreover, lipoprotein subclasses may be useful as therapeutic markers for cardiovascular disorders, and oxysterols may also be useful as diagnostic markers for dementing disorders and diseases of the central nervous system. These issues remain to befully elucidated in the future.