The therapeutic landscape of citrin deficiency.

Citrin deficiency (CD) is a recessive, liver disease caused by sequence variants in the SLC25A13 gene encoding a mitochondrial aspartate-glutamate transporter. CD manifests as different age-dependent phenotypes and affects crucial hepatic metabolic pathways including malate-aspartate-shuttle, glycolysis, gluconeogenesis, de novo lipogenesis and the tricarboxylic acid and urea cycles. Although the exact pathophysiology of CD remains unclear, impaired use of glucose and fatty acids as energy sources due to NADH shuttle defects and PPARα downregulation, respectively, indicates evident energy deficit in CD hepatocytes. The present review summarizes current trends on available and potential treatments for CD. Baseline recommendation for CD patients is dietary management, often already present as a self-selected food preference, that includes protein and fat-rich food, and avoidance of excess carbohydrates. At present, liver transplantation remains the sole curative option for severe CD cases. Our extensive literature review indicated medium-chain triglycerides (MCT) as the most widely used CD treatment in all age groups. MCT can effectively improve symptoms across disease phenotypes by rapidly supplying energy to the liver, restoring redox balance and inducing lipogenesis. In contrast, sodium pyruvate restored glycolysis and displayed initial preclinical promise, with however limited efficacy in adult CD patients. Ursodeoxycholic acid, nitrogen scavengers and L-arginine treatments effectively address specific pathophysiological aspects such as cholestasis and hyperammonemia and are commonly administered in combination with other drugs. Finally, future possibilities including restoring redox balance, amino acid supplementation, enhancing bioenergetics, improving ureagenesis and mRNA/DNA-based gene therapy are also discussed.

Impaired GK-GKRP interaction rather than direct GK activation worsens lipid profiles and contributes to long-term complications: a Mendelian randomization study.

BACKGROUND: Glucokinase (GK) plays a key role in glucose metabolism. In the liver, GK is regulated by GK regulatory protein (GKRP) with nuclear sequestration at low plasma glucose level. Some GK activators (GKAs) disrupt GK-GKRP interaction which increases hepatic cytoplasmic GK level. Excess hepatic GK activity may exceed the capacity of glycogen synthesis with excess triglyceride formation. It remains uncertain whether hypertriglyceridemia associated with some GKAs in previous clinical trials was due to direct GK activation or impaired GK-GKRP interaction. METHODS: Using publicly available genome-wide association study summary statistics, we selected independent genetic variants of GCKR and GCK associated with fasting plasma glucose (FPG) as instrumental variables, to mimic the effects of impaired GK-GKRP interaction and direct GK activation, respectively. We applied two-sample Mendelian Randomization (MR) framework to assess their causal associations with lipid-related traits, risks of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular diseases. We verified these findings in one-sample MR analysis using individual-level statistics from the Hong Kong Diabetes Register (HKDR). RESULTS: Genetically-proxied impaired GK-GKRP interaction increased plasma triglycerides, low-density lipoprotein cholesterol and apolipoprotein B levels with increased odds ratio (OR) of 14.6 (95% CI 4.57-46.4) per 1 mmol/L lower FPG for MASLD and OR of 2.92 (95% CI 1.78-4.81) for coronary artery disease (CAD). Genetically-proxied GK activation was associated with decreased risk of CAD (OR 0.69, 95% CI 0.54-0.88) and not with dyslipidemia. One-sample MR validation in HKDR showed consistent results. CONCLUSIONS: Impaired GK-GKRP interaction, rather than direct GK activation, may worsen lipid profiles and increase risks of MASLD and CAD. Development of future GKAs should avoid interfering with GK-GKRP interaction.

Inhibitors of apolipoprotein C3, triglyceride levels, and risk of pancreatitis: a systematic review and meta-analysis.

In recent years, novel apoC3 inhibitor therapies for the treatment of hypertriglyceridemia have been developed and assessed through phase II and III clinical trials. The objective of this study was to perform an updated meta-analysis on the impact of new apoC3 inhibitor drugs on triglyceride and apoC3 levels, as well as on the incidence of pancreatitis. We conducted a meta-analysis of randomized, placebo-controlled studies assessing the effects of apoC3 inhibitors therapy (antisense oligonucleotides and small interfering RNA) on triglyceride levels, apoC3 levels, and the occurrence of acute pancreatitis. This meta-analysis was performed according to PRISMA guidelines. The random-effects model was performed. Nine randomized clinical trials (n = 717 patients) were considered eligible for this systematic review. ApoC3 inhibitor drugs were consistently associated with decreased triglyceride levels (MD -57.0%; 95% CI -61.9 to -52.1, I2 82%) and lowered apoC3 values (MD -76; 95% CI -80.1 to -71.8, I2 77%) when compared to placebo. Furthermore, the use of apoC3 inhibitor drugs demonstrated a reduction in the risk of acute pancreatitis (OR 0.11; 95% CI 0.04 to 0.27, I2 0%). The present updated meta-analysis of randomized clinical trials demonstrated that the utilization of apoC3 inhibitors in patients with hypertriglyceridemia correlated with reduced apoC3 and triglyceride levels, along with a decreased risk of acute pancreatitis compared to the placebo.

Medium-chain triglycerides combined with DHA improve cognitive function by inhibiting neurocyte apoptosis of the brain in SAMP8 mice.

Medium-chain triglycerides (MCTs) and docosahexaenoic acid (DHA, Cn-3, 22:6) are essential in improving cognitive function and protecting neurocytes. This study explored the effects of the combined intervention of MCTs and DHA on inhibiting neurocyte apoptosis of the brain and improving cognitive function in senescence-accelerated mouse-prone 8 (SAMP8). Four-month-old male SAMP8 mice were randomly divided into four treatment groups (12 mice/group): DHA, MCT, DHA + MCT, and control groups, which intervened for seven months. Twelve age-matched male senescence-accelerated mouse resistant 1 (SAMR1) was used as the natural aging group. TUNEL assay and HE staining were used to assess neurocyte apoptosis and damage in the brain of mice. Moreover, the cognitive function was analyzed using the Morris water maze (MWM) and open field (OF) tests. The results showed that the cognitive function of 11-month-old SAMP8 mice decreased with age, and further pathological examination revealed the damaged neurocyte structure, karyopyknosis, cell atrophy, and even apoptosis. MCTs combined with DHA supplementation could increase octanoic acid (C8:0), decanoic acid (C10:0), and DHA levels in the serum, inhibit neurocyte apoptosis, improve neurocyte damage, moreover delay age-related cognitive decline after seven-month treatment. Furthermore, combining MCTs and DHA was significantly more beneficial than MCTs or DHA alone. In conclusion, MCTs combined with DHA could delay cognitive decline by inhibiting neurocyte apoptosis of the brain in SAMP8 mice.

The Importance of Metabolic Factors in Endometrial Cancer: Evaluating the Utility of the Triglyceride-to-Glycemia Index and Triglyceride-to-High-Density Lipoprotein Ratio As Biomarkers.

Introduction Endometrial cancer (EC) is the most common gynecological malignancy in developed countries worldwide. Its incidence is rising, making it a significant public health concern. The relationship between lipids, hyperglycemia, and anthropometric risk factors in the development of EC has gained increasing attention in recent years. Understanding the role of dyslipidemia as a part of metabolic syndrome is crucial for developing effective prevention and treatment strategies for EC. We investigate the association between dyslipidemia, hyperglycemia, and EC. This study aims to elucidate the potential contribution of altered lipid profiles and chronic hyperglycemia to endometrial carcinogenesis. By analyzing patients with benign and malignant endometrial pathologies, we seek to identify novel biomarkers and unravel the underlying mechanisms by which these metabolic factors influence the risk of developing EC. Material and methods Our retrospective unicentric study included 390 patients (192 diagnosed with EC and 198 with endometrial hyperplasia), in which we compared the clinical and biochemical characteristics, with a particular focus on lipid profiles and glycemic indices sampled 24-48 hours before surgery. The data obtained from the medical records were analyzed using statistical methods to compare selected metabolic factors between EC and endometrial hyperplasia. Results Our analysis revealed statistically significant differences in metabolic health and lipid profiles between patients diagnosed with EC and those with endometrial hyperplasia. The EC group exhibits trends towards higher levels of triglycerides (TG) and glycated hemoglobin, alongside a higher BMI. Notably, high-density lipoprotein cholesterol levels were lower in the EC group. Conclusion Although the triglycerides-to-fasting blood glucose index and the triglycerides-to-high-density lipoprotein cholesterol ratio did not demonstrate sufficient discriminatory power for predicting myometrial invasion depth in this study, further exploration of cost-effective emerging biomarkers warrants investigation in future studies.

Influence of Oral Contraceptives on Lipid Profile and Trajectories in Healthy Adolescents-Data From the EVA-Tyrol Study.

PURPOSE: Oral contraception is one of the most popular contraceptive methods both in adults and adolescents. However, the effects of oral contraception on lipids in adolescents are not well studied. METHODS: Lipid profiles were measured and contraceptive use was assessed in 14- to 19-year-old female participants of the prospective population-based Early Vascular Ageing-Tyrol Study between 2015 and 2018, twice on average 22 months apart. RESULTS: For this analysis, data from 828 young women with a median age of 17.0 years were available. Of them, 317 (38%) used oral contraceptives (OCs). OC users had a slightly higher systolic and diastolic blood pressure and larger changes over time and were more likely to use cigarettes than nonusers. Total cholesterol (179.6 vs. 162.4 mg/dL), low-density lipoprotein-cholesterol (106.4 vs. 94.6 mg/dL), and triglycerides (104.0 vs. 67.0 mg/dL) were significantly higher in OC users after multivariable adjustment in linear regression models. No difference in high-density lipoprotein-cholesterol between the two groups was found. In 558 females, follow-up data were available. Those who initiated OC use had on average 15.4 mg/dL higher low-density lipoprotein-cholesterol and 36.2 mg/dL higher triglyceride level changes between baseline and follow-up than never users. Duration of OC use did not show a significant association with lipid levels and changes. DISCUSSION: We showed an independent association between OC use and blood lipids as well as lipid trajectories over time in a large cohort of healthy adolescents. These changes are especially relevant to consider in adolescents with other risk factors for dyslipidemia or other cardiovascular risk factors.

Efficacy of AI-Guided (GenAISTM) Dietary Supplement Prescriptions versus Traditional Methods for Lowering LDL Cholesterol: A Randomized Parallel-Group Pilot Study.

Emerging evidence suggests that personalized dietary supplement regimens can significantly influence lipid metabolism and cardiovascular risk. The efficacy of AI-guided dietary supplement prescriptions, compared with standard physician-guided prescriptions, remains underexplored. In a randomized, parallel-group pilot study, 70 patients aged 40-75 years with LDL-C levels between 70 and 190 mg/dL were enrolled. Participants were randomized to receive either AI-guided dietary supplement prescriptions or standard physician-guided prescriptions for 90 days. The primary endpoint was the percent change in LDL-C levels. Secondary endpoints included changes in total cholesterol, HDL-C, triglycerides, and hsCRP. Supplement adherence and side effects were monitored. Sixty-seven participants completed the study. The AI-guided group experienced a 25.3% reduction in LDL-C levels (95% CI: -28.7% to -21.9%), significantly greater than the 15.2% reduction in the physician-guided group (95% CI: -18.5% to -11.9%; p < 0.01). Total cholesterol decreased by 15.4% (95% CI: -19.1% to -11.7%) in the AI-guided group compared with 8.1% (95% CI: -11.5% to -4.7%) in the physician-guided group (p < 0.05). Triglycerides were reduced by 22.1% (95% CI: -27.2% to -17.0%) in the AI-guided group versus 12.3% (95% CI: -16.7% to -7.9%) in the physician-guided group (p < 0.01). HDL-C and hsCRP changes were not significantly different between groups. The AI-guided group received a broader variety of supplements, including plant sterols, omega-3 fatty acids, red yeast rice, coenzyme Q10, niacin, and fiber supplements. Side effects were minimal and comparable between groups. AI-guided dietary supplement prescriptions significantly reduce LDL-C and triglycerides more effectively than standard physician-guided prescriptions, highlighting the potential for AI-driven personalization in managing hypercholesterolemia.

Association between Serum Lipids and Asthma in Adults-A Systematic Review.

(1) Background: Asthma is a syndrome found in both adults and children, characterized by airflow obstruction caused by the inflammation of the airways. In recent years, an increasing number of studies have found that lipid metabolism influences both the development and symptomatology of asthma. Lipid metabolism plays an important role both in the occurrence of exacerbations and in the reduction of lung inflammation. Our study aimed to identify any type of association between patients diagnosed with asthma and their serum lipids, including HDL-cholesterol, LDL-cholesterol, total cholesterol, and triglycerides in adults. (2) Methods: To find articles for our review, we searched two platforms: PubMed and Google Scholar. A total of 309 articles from two platforms were analyzed. Finally, 12 papers were selected from the initial pool of identified articles. (3) Results: The positive correlation between triglycerides, total cholesterol, low-density lipoprotein-cholesterol (LDL-cholesterol), and asthma has been demonstrated in several studies. Moreover, it appears that there is an association between biomarkers of type 2 inflammation and HDL and serum triglycerides in people with atopic status. Regarding the nutrition of asthmatic patients, the greatest impact on the development of the disease seems to be the consumption of fruit and vegetables. Several studies show that a predominantly vegan diet is associated with better control of the disease and a decrease in the number of pro-inflammatory cytokines. (4) Conclusions: Studies show a positive correlation between total cholesterol, triglyceride, and LDL-cholesterol levels and asthma and a negative correlation between HDL-cholesterol and asthma. Increased cholesterol values would lead to the stimulation of pro-inflammatory processes and the secretion of cytokines involved in these processes. The most successful diets for asthma patients seem to be those in which the consumption of fruit, vegetables, and high-fiber foods is increased because all of these food groups are rich in vitamins, antioxidants, and minerals.

The association between the size of adipocyte-derived extracellular vesicles and fasting serum triglyceride-glucose index as proxy measures of adipose tissue insulin resistance in a rat model of early-stage obesity.

Introduction: Obesity is a complex disease that predisposes individuals to cardiometabolic alterations. It leads to adipose tissue (AT) dysfunction, which triggers insulin resistance (IR). This suggests that people with obesity develop local IR first and systemic IR later. AT secretes extracellular vesicles, which may be physiopathologically associated with the development of IR. Our aim was to evaluate the effect of a high-fat diet on different parameters of adiposity in a rat model of early-stage obesity and to determine if these parameters are associated with markers of systemic IR. In addition, we sought to explore the relationship between fasting blood measures of IR (Triglycerides/High Density Lipoprotein-cholesterol [TAG/HDL-c] and Triglycerides-Glucose Index [TyG Index]) with the size of adipocyte-derived extracellular vesicles (adEV). Methods: We used a model of diet-induced obesity for ten weeks in Wistar rats exposed to a high-fat diet. Final weight gain was analyzed by Dual X-ray absorptiometry. Visceral obesity was measured as epididymal AT weight. IR was evaluated with fasting TyG Index & TAG/HDL-c, and adEV were isolated from mature adipocytes on ceiling culture. Results: In the high-fat diet group, glucose and triglyceride blood concentrations were higher in comparison to the control group (Log2FC, 0.5 and 1.5 times higher, respectively). The values for TyG Index and adEV size were different between the control animals and the high-fat diet group. Multiple linear regression analyses showed that adEV size can be significantly associated with the TyG Index value, when controlling for epididymal AT weight. Conclusion: Our results show that lipid and glucose metabolism, as well as the size and zeta potential of adEV are already altered in early-stage obesity and that adEV size can be significantly associated with liver and systemic IR, estimated by TyG Index.

An exploratory study on lipidomic profiles in a cohort of individuals with posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) can develop after trauma exposure. Some studies report that women develop PTSD at twice the rate of men, despite greater trauma exposure in men. Lipids and their metabolites (lipidome) regulate a myriad of key biological processes and pathways such as membrane integrity, oxidative stress, and neuroinflammation in the brain by maintaining neuronal connectivity and homeostasis. In this study, we analyzed the lipidome of 40 adults with PTSD and 40 trauma-exposed non-PTSD individuals (n = 20/sex/condition; 19-39 years old). Plasma samples were analyzed for lipidomics using Quadrupole Time-of-Flight (QToF) mass spectrometry. Additionally, ~ 90 measures were collected, on sleep, and mental and physical health indices. Poorer sleep quality was associated with greater PTSD severity in both sexes. The lipidomics analysis identified a total of 348 quantifiable known lipid metabolites and 1951 lipid metabolites that are yet unknown; known metabolites were part of 13 lipid subclasses. After adjusting for BMI and sleep quality, in women with PTSD, only one lipid subclass, phosphatidylethanolamine (PE) was altered, whereas, in men with PTSD, 9 out of 13 subclasses were altered compared to non-PTSD women and men, respectively. Severe PTSD was associated with 22% and 5% of altered lipid metabolites in men and women, respectively. Of the changed metabolites, only 0.5% measures (2 PEs and cholesterol) were common between women and men with PTSD. Several sphingomyelins, PEs, ceramides, and triglycerides were increased in men with severe PTSD. The correlations between triglycerides and ceramide metabolites with cholesterol metabolites and systolic blood pressure were dependent upon sex and PTSD status. Alterations in triglycerides and ceramides are linked with cardiac health and metabolic function in humans. Thus, disturbed sleep and higher body mass may have contributed to changes in the lipidome found in PTSD.

Bariatric Surgery Effect on the Crosstalk of PAI-1 and PCSK9 to Regulate the Metabolic Changes in Patients with Obesity.

BACKGROUND: Adiposity favors several metabolic disorders with an exacerbated chronic pro-inflammatory status and tissue damage, with high levels of plasminogen activator inhibitor type 1 (PAI-1) and proprotein convertase subtilisin/kexin type 9 (PCSK9). OBJECTIVE: To demonstrate the influence of bariatric surgery on the crosstalk between PAI-1 and PCSK9 to regulate metabolic markers. METHODS: Observational and longitudinal study of 190 patients with obesity and obesity-related comorbidities who underwent bariatric surgery. We measured, before and after bariatric surgery, the anthropometric variables and we performed biochemical analysis by standard methods (glucose, insulin, triglycerides [TG], total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C] and TG/HDL-C ratio, PAI-1 and PCSK9 were measured by ELISA). RESULTS: PAI-1 levels decreased significantly after bariatric surgery, and were positively correlated with lipids, glucose, and TG, with significance on PCSK9 and TG/HDL-C alleviating the insulin resistance (IR) and inducing a state reversal of type 2 diabetes (T2D) with a significant decrease in body weight and BMI (p <0.0001). Multivariate regression analysis predicted a functional model in which PAI-1 acts as a regulator of PCSK9 (p <0.002), TG (p <0.05), and BMI; at the same time, PCSK9 modulates LDL-C HDL-C and PAI-1. CONCLUSIONS: After bariatric surgery, we found a positive association and crosstalk between PAI-1 and PCSK9, which modulates the delicate balance of cholesterol, favoring the decrease of circulating lipids, TG, and PAI-1, which influences the glucose levels with amelioration of IR and T2D, demonstrating the crosstalk between fibrinolysis and lipid metabolism, the two main factors involved in atherosclerosis and cardiovascular disease in human obesity.

Low serum HDL-cholesterol is associated with increased risk of the subcortical small vessel type of dementia.

Background: There are conflicting results whether serum lipid pattern is related to the amount of white matter hyperintensities (WMHs) on magnetic resonance imaging. Little is known of the associations between lipid concentrations and the subsequent risk of the subcortical small vessel type of dementia (SSVD), in which WMHs are a prominent manifestation. Here, we determined whether lipid levels are associated with the risk of SSVD, Alzheimer's disease (AD), or mixed dementia (combined AD and SSVD). Methods: This was a longitudinal, prospective study of 329 patients with subjective or objective mild cognitive impairment at baseline. The statistical analyses included Cox proportional hazards regression with adjustments for age, gender, education, body mass index, current smoking, hypertension, diabetes mellitus, and APOE ε4 genotype. Results: During the follow-up (mean 4.1 years), 80 patients converted to dementia [SSVD, n = 15 (5 %); AD, n = 39 (12 %); and mixed dementia, n = 26 (8 %)]. Serum high-density lipoprotein cholesterol (HDL, per SD increase) was inversely associated with the risk of SSVD, whereas triglycerides (TG), low-density lipoprotein cholesterol (LDL)/HDL ratio, and TG/HDL ratio were positively associated with SSVD risk. Furthermore, the lowest HDL tertile was associated with a sevenfold, and the highest tertile of TG/HDL ratio with a threefold, increase in SSVD risk. There were no associations with the risk of AD or mixed dementia after adjustment for covariates. Conclusion: In a memory clinic population, low HDL and high TG/HDL ratio were independent risk factors of SSVD, but not of AD or mixed dementia.

Targeted metabolomics identifies accurate CSF metabolite biomarkers for the differentiation between COVID-19 with neurological involvement and CNS infections with neurotropic viral pathogens.

BACKGROUND: COVID-19 is primarily considered a respiratory tract infection, but it can also affect the central nervous system (CNS), which can result in long-term sequelae. In contrast to CNS infections by classic neurotropic viruses, SARS-CoV-2 is usually not detected in cerebrospinal fluid (CSF) from patients with COVID-19 with neurological involvement (neuro-COVID), suggesting fundamental differences in pathogenesis. METHODS: To assess differences in CNS metabolism in neuro-COVID compared to CNS infections with classic neurotropic viruses, we applied a targeted metabolomic analysis of 630 metabolites to CSF from patients with (i) COVID-19 with neurological involvement [n = 16, comprising acute (n = 13) and post-COVID-19 (n = 3)], (ii) viral meningitis, encephalitis, or myelitis (n = 10) due to herpes simplex virus (n = 2), varicella zoster virus (n = 6), enterovirus (n = 1) and tick-borne encephalitis virus (n = 1), and (iii) aseptic neuroinflammation (meningitis, encephalitis, or myelitis) of unknown etiology (n = 21) as additional disease controls. RESULTS: Standard CSF parameters indicated absent or low neuroinflammation in neuro-COVID. Indeed, CSF cell count was low in neuro-COVID (median 1 cell/µL, range 0-12) and discriminated it accurately from viral CNS infections (AUC = 0.99) and aseptic neuroinflammation (AUC = 0.98). 32 CSF metabolites passed quality assessment and were included in the analysis. Concentrations of differentially abundant (fold change ≥|1.5|, FDR ≤ 0.05) metabolites were both higher (9 and 5 metabolites) and lower (2 metabolites) in neuro-COVID than in the other two groups. Concentrations of citrulline, ceramide (d18:1/18:0), and methionine were most significantly elevated in neuro-COVID. Remarkably, triglyceride TG(20:1_32:3) was much lower (mean fold change = 0.09 and 0.11) in neuro-COVID than in all viral CNS infections and most aseptic neuroinflammation samples, identifying it as highly accurate biomarker with AUC = 1 and 0.93, respectively. Across all samples, TG(20:1_32:3) concentration correlated only moderately with CSF cell count (ρ = 0.65), protein concentration (ρ = 0.64), and Q-albumin (ρ = 0.48), suggesting that its low levels in neuro-COVID CSF are only partially explained by less pronounced neuroinflammation. CONCLUSIONS: The results suggest that CNS metabolite responses in neuro-COVID differ fundamentally from viral CNS infections and aseptic neuroinflammation and may be used to discover accurate diagnostic biomarkers in CSF and to gain insights into differences in pathophysiology between neuro-COVID, viral CNS infections and aseptic neuroinflammation.

Clinical characterization and mutation spectrum of patients with hypertriglyceridemia in a German outpatient clinic.

BACKGROUND: Severe hypertriglyceridemia (HTG) has predominantly multifactorial causes (MCS). Yet a small subset of patients have the monogenetic form (FCS). It remains a challenge to distinguish patients clinically, since decompensated MCS might mimic FCS´s severity. Aim of the current study was to determine clinical criteria that could sufficiently distinguish both forms as well as to apply the FCS score proposed by Moulin and colleagues. METHODS: We retrospectively studied 72 patients who presented with severe HTG in our clinic during a time span of seven years and received genetic testing. We classified genetic variants (ACMG-criteria), followed by genetic categorization into MCS or FCS. Clinical data were gathered from the medical records and the FCS score was calculated for each patient. RESULTS: Molecular genetic screening revealed eight FCS patients and 64 MCS patients. Altogether, we found 13 pathogenic variants of which four have not been described before. The FCS patients showed a significantly higher median triglyceride level compared to the MCS. The FCS score yielded a sensitivity of 75% and a specificity of 93.7% in our cohort, and significantly differentiated between the FCS and MCS group (p<0.001). CONCLUSIONS: In our cohort we identified several variables that significantly differentiated FCS from MCS. The FCS score performed similar to the original study by Moulin, thereby further validating the discriminatory power of the FCS score in an independent cohort.

The clinical impact of estimating low-density lipoprotein cholesterol (LDL-C) using different equations in the general population.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is associated with atherosclerotic cardiovascular disease (ASCVD). Friedewald, Sampson, and Martin-Hopkins equations are used to calculate LDL-C. This study compares the impact of switching between these equations in a large geographically defined population. MATERIALS AND METHODS: Data for individuals who had a lipid panel ordered clinically between 2010 and 2019 were included. Comparisons were made across groups using the two-sample t-test or chi-square test as appropriate. Discordances between LDL measures based on clinically actionable thresholds were summarized using contingency tables. RESULTS: The cohort included 198,166 patients (mean age 54 years, 54% female). The equations perform similarly at the lower range of triglycerides but began to diverge at a triglyceride level of 125 mg/dL. However, at triglycerides of 175 mg/dL and higher, the Martin-Hopkins equation estimated higher LDL-C values than the Samson equation. This discordance was further exasperated at triglyceride values of 400 to 800 mg/dL. When comparing the Sampson and Friedewald equations, at triglycerides are below 175 mg/dL, 9% of patients were discordant at the 70 mg/dL cutpoint, whereas 42.4% were discordant when triglycerides are between 175 and 400 mg/dL. Discordance was observed at the clinically actionable LDL-C cutpoint of 190 mg/dL with the Friedewald equation estimating lower LDL-C than the other equations. In a high-risk subgroup (ASCVD risk score > 20%), 16.3% of patients were discordant at the clinical cutpoint of LDL-C < 70 mg/dL between the Sampson and Friedewald equations. CONCLUSIONS: Discordance at clinically significant LDL-C cutpoints in both the general population and high-risk subgroups were observed across the three equations. These results show that using different methods of LDL-C calculation or switching between different methods could have clinical implications for many patients.

Fenofibrate's impact on cardiovascular risk in patients with diabetes: a nationwide propensity-score matched cohort study.

BACKGROUND: The beneficial effects of fenofibrate on atherosclerotic cardiovascular disease (ASCVD) outcomes in patients with diabetes and statin treatment are unclear. We investigated the effects of fenofibrate on all-cause mortality and ASCVD in patients with diabetes, high triglyceride (TG) levels and statin treatment. METHODS: We performed a nationwide propensity-score matched (1:1) cohort study using data from the National Health Information Database in the Republic of Korea from 2010 to 2017. The study included 110,723 individuals with diabetes, TG levels ≥ 150 mg/dL, and no prior diagnoses of ASCVD who used statins and fenofibrate, and an equal matched number of similar patients who used statins alone (control group). The study outcomes included newly diagnosed myocardial infarction (MI), stroke, both (MI and/or stroke), and all-cause mortality. RESULTS: Over a mean 4.03-year follow-up period, the hazard ratios (HR) for outcomes in the fenofibrate group in comparison to the control group were 0.878 [95% confidence interval (CI) 0.827-0.933] for MI, 0.901 (95% CI 0.848-0.957) for stroke, 0.897 (95% CI 0.858-0.937) for MI and/or stroke, and 0.716 (95% CI 0.685-0.749) for all-cause death. These beneficial effects of fenofibrate were consistent in the subgroup with TG 150-199 mg/dL but differed according to low-density lipoprotein cholesterol (LDL-C) levels. CONCLUSION: In this nationwide propensity-score matched cohort study involving individuals with diabetes and TG ≥ 150 mg/dL, the risk of all-cause death and ASCVD was significantly lower with fenofibrate use in conjunction with statin treatment compared to statin treatment alone. However, this finding was significant only in individuals with relatively high LDL-C levels.

Is FSH combined with equine chorionic gonadotropin able to modify lipid metabolism in bovine superstimulated antral follicles?

Lipid metabolism is essential for ensuring oocyte maturation and embryo development. ß-Oxidized fatty acids (FA) are a potent source of energy for cells, particularly for bovine somatic follicular cells. Superstimulatory protocols using follicle stimulating hormone (FSH) or FSH combined with equine chorionic gonadotropin (eCG) are capable of stimulating the follicular microenvironment and drive the expression of biomarker genes associated with lipid metabolism in the cumulus-oocyte complex (COC) for better embryo development. In this study, we assesed the effects of FSH and FSH/eCG protocols on the expression of genes related to lipid metabolism in bovine granulosa cells (GCs). Further, we measured triglyceride levels in follicular fluid (FF) obtained from both superstimulatd and non-superstimulated cows (synchronized cows). In summary, superstimulation with gonadotropins maintained the TG levels in bovine FF and ensured GCs mRNA abundance of ACSL1, ACSL3, ACSL6, SCD, ELOVL5, ELOVL6, FASN, FADS2, and SREBP1. We, however, found the abundance of CPTIB mRNA to be lower in GCs obtained from cows subjected to FSH/eCG protocols than synchronized cows. In conclusion, the findings of this study showed that ovarian superstimulation around the preovulatory phase has a mild impact on the lipid metabolism in GCs.

Maternal Hypertriglyceridemia in Gestational Diabetes: A New Risk Factor?

Elevated maternal triglycerides (TGs) have been associated with excessive fetal growth. However, the role of maternal lipid profile is less studied in gestational diabetes mellitus (GDM). We aimed to study the association between maternal lipid profile in the third trimester and the risk for large-for-gestational-age (LGA) newborns in women with GDM. We performed an observational and retrospective study of pregnant women with GDM who underwent a lipid profile measurement during the third trimester. We applied a logistic regression model to assess predictors of LGA. A total of 100 singleton pregnant women with GDM and third-trimester lipid profile evaluation were included. In the multivariate analysis, pre-pregnancy BMI (OR 1.19 (95% CI 1.03-1.38), p = 0.022) and hypertriglyceridemia (OR 7.60 (1.70-34.10), p = 0.008) were independently associated with LGA. Third-trimester hypertriglyceridemia was found to be a predictor of LGA among women with GDM, independently of glycemic control, BMI, and pregnancy weight gain. Further investigation is needed to confirm the role of TGs in excessive fetal growth in GDM pregnancies.

Association Between Baseline Serum Lipids and Severity of Dry Eye Symptoms in Acne Patients Treated with Isotretinoin.

BACKGROUND: Isotretinoin is a commonly prescribed medication for moderate-to-severe acne. Elevated triglycerides and total cholesterol, as well as eye dryness, are frequent side effects of isotretinoin.  Objective: This study aims to examine the association between serum baseline levels of triglycerides and total cholesterol with regards to the severity of dry eye symptoms in acne patients treated with isotretinoin. METHOD: The study was a retrospective review of acne patients treated with isotretinoin for at least four months at the dermatology clinics of Qassim University Medical City, Saudi Arabia. Thirty patients were included in the study as they met the inclusion criteria. Baseline levels of triglycerides and total cholesterol were reviewed for these patients. The Ocular Surface Disease Index (OSDI) questionnaire was sent and filled out by the study participants to assess the severity of eye dryness. RESULT: 30 patients were included in the study, with 16 (53.3%) females and 14 (46.7%) males. The average age of participants was 22.1 years. The duration of treatment was between 120 and 140 days in 13 (43.3%) participants and 140 and 180 days in 17 (56.7%) participants. The mean ± 1 standard deviation (SD) was reported for each of the three variables, with an Ocular Surface Disease Index (OSDI) score of 27.6 ± 19.2, a baseline total cholesterol of 4.4 ± 0.9 mmol/L, and a baseline triglyceride level of 0.83 ± 0.4 mmol/L. Using a multiple linear regression model, baseline triglycerides and total cholesterol were used as predictors of the OSDI score. There was a significant dependent interaction between baseline total cholesterol and triglycerides and their effect on the OSDI score, with a higher OSDI score at higher levels of both triglycerides and cholesterol and a lower OSDI score at lower levels of both triglycerides and cholesterol. The study result showed that, in acne patients treated with isotretinoin for at least four months, a higher baseline level of both triglycerides and total cholesterol is associated with worse dry eye symptoms compared to those with lower baseline levels. CONCLUSION:  The study concluded that baseline levels of triglycerides and total cholesterol are both significant predictors of the severity of dry eye symptoms in acne patients treated with isotretinoin. Despite study limitations due to the small sample size, we hope that, based on our findings, this will open the door to future studies with a larger sample size to further confirm our findings generalize the result, and apply it to clinical practice so that clinicians may identify those at higher risk of severe eye dryness before starting isotretinoin and subsequently be able to recommend specific measures to minimize symptoms of eye dryness.