Lipids in Health and Disease最新文献

Background: Research has identified a link between the triglyceride-glucose index (TyG-i) and the risk of mortality in severely ill patients. However, it remains uncertain if the TyG-i affects mortality by influencing heart rate (HR).

Methods: This study enrolled 3,509 severely ill participants from the Medical Information Mart for Intensive Care (MIMIC-IV) database who had triglyceride, glucose, and HR data upon entering the ICU. Cox regression models were applied to estimate the effect of the TyG-i and HR on 28-day all-cause mortality (ACM) and 28-day in-hospital mortality (IHM). Additionally, Kaplan-Meier (K-M) survival analysis was employed to explore outcome variations among different patient groups. The association of the TyG-i with HR, Sequential Organ Failure Assessment (SOFA) score, and Simplified Acute Physiology Score (SAPS) II was explored through linear regression analysis. Subgroup analysis explored potential interactions among patient characteristics, while sensitivity analysis gauged the robustness of the findings. Additionally, mediation analysis was conducted to assess whether elevated HR acts as an intermediary factor linking the TyG-i to both 28-day ACM and 28-day IHM.

Results: During the 28-day follow-up, 586 cases (16.7%) died from all causes, and 439 cases (12.5%) died during hospitalisation. Cox results showed that individuals with a heightened TyG-i and elevated HR had the highest 28-day ACM (Hazard Ratio 1.70, P-value below 0.001) and 28-day IHM (Hazard Ratio 1.72, P-value below 0.001) compared to those with a reduced TyG-i and HR. The K-M curves showed that individuals with low TyG-i and low HR had the lowest incidence of 28-day ACM and 28-day IHM. The linear analysis results evidenced that the TyG-i was independently connected to HR (beta = 3.05, P-value below 0.001), and the TyG-i was also independently associated with SOFA score (beta = 0.39, P-value below 0.001) and SAPS II (beta = 1.79, P-value below 0.001). Subgroup analysis revealed a significant association in participants without hypertension, the interaction of an elevated TyG-i and HR strongly correlated with a higher 28-day death risk (interaction P-value below 0.05). Furthermore, HR mediated 29.5% of the connection between the TyG-i and 28-day ACM (P-value = 0.002), as well as 20.4% of the connection between the TyG-i and 28-day IHM (P-value = 0.002).

Conclusion: For severely ill patients, the TyG-i is distinctly correlated with HR, and elevated levels of both are strongly connected to greater 28-day ACM and 28-day IHM risks, especially in patients without hypertension. Furthermore, elevated HR mediates the connection between the TyG-i and 28-day mortality.

Lipid uptake by white adipose tissue (WAT) is critically important for storage of excess energy and to protect peripheral tissues from ectopic lipid deposition. When WAT becomes dysfunctional (i.e., with obesity), it is characterized by impaired lipid uptake and increased lipolysis which, together, promote whole-body dyslipidemia. Omega-3 polyunsaturated fatty acids (N-3 PUFA) are widely studied for their triacylglycerol (TAG)-lowering properties and cardiometabolic health benefits. One potential mechanism underlying these benefits is the modification of WAT lipid uptake; however, there are gaps in our understanding regarding the specific mechanisms by which N-3 PUFA function. Evidence to date suggests that N-3 PUFA promote TAG clearance by increasing lipoprotein lipase (LPL) activity and the abundance of fatty acid transporters. Specifically, N-3 PUFA have been shown to increase LPL activity through increased gene transcription and modifications of endogenously produced LPL regulators such as apolipoprotein C-II/III and angiopoietin-like proteins. This review presents and discusses the available in vitro and in vivo research to provide a comprehensive overview of N-3 PUFA regulation of WAT lipid uptake in healthy and obese contexts. Additionally, we highlight areas where more research is necessary to better understand the contribution of increased WAT lipid uptake in relation to the TAG-lowering properties associated with N-3 PUFA.

Background: Remnant Cholesterol (RC) has emerged as a significant risk factor for cardiovascular disease. However, the factors influencing RC levels remain incompletely understood. This research investigates smoking-a major modifiable risk factor-to elucidate its impact on RC levels and examine the mediating role of inflammation in this relationship.

Methods: Using NHANES data from 1999 to 2018, this study analyzed the association between serum cotinine levels (a biomarker of smoking intensity) and RC in 8,829 participants aged 20 years and older. Through complex sampling design and adjustment for multiple covariables, we examined both linear and nonlinear relationships using linear regression models, restricted cubic splines (RCS), and subgroup analyses. Additionally, mediation analyses evaluated the role of inflammatory markers-neutrophils (NEU), monocytes (MON), lymphocytes (LYM), and platelets (PLT)-in this association.

Results: The high cotinine exposure group demonstrated significantly elevated RC levels (β = 2.256, 95% CI: 1.401-3.112, p < 0.001) compared to the no/minimal exposure group. This positive association was particularly pronounced in females (p for interaction < 0.05). Restricted cubic spline analysis demonstrated a nonlinear, N-shaped relationship (p for nonlinearity < 0.05), with RC levels reaching their peak at cotinine concentrations of approximately 172 ng/mL. In the mediation analysis, inflammatory markers showed significant mediating effects: NEU (28%), LYM (14.1%), PLT (9.5%), and MON (6.9%) of the total effect.

Conclusion: A significant positive association exists between cotinine and RC levels, moderated by sex. Inflammatory markers, particularly NEU, partially mediate this association.

Background: Obesity and overweight, as determined by the body mass index (BMI), are harmful to metabolic health. However, the BMI can not reflect body composition or fat distribution. The fat-free mass index (FFMI) and the fat mass index (FMI) can provide more information on body composition. The aim of the observational research was to determine whether the FMI and the FFMI are significantly associated with the risk of developing diabetes and prediabetes.

Methods: The investigators included data for 10,085 National Health and Nutrition Examination Survey (2011-2018) participants aged over 20 years who underwent dual-energy X-ray absorptiometry (DXA). The FFMI and the FMI were determined based on total fat mass and lean mass measured by DXA. Diabetes and prediabetes status were determined by medical history and laboratory examination. Logistic regression analyses were performed to explore the correlations between the FMI/FFMI and the risk of developing diabetes/prediabetes. Restricted cubic spline analysis was used to explore underlying nonlinear associations.

Results: In the present study, 1,135 patients were diagnosed with diabetes, 3,258 had prediabetes, and 5,692 were classified as control participants. The FFMI (odds ratio (OR) = 1.10, 95% confidence interval (CI) = 1.04-1.16) and the FMI (OR = 1.08, 95% CI = 1.04-1.12) were independently related to an increased risk of developing diabetes. Moreover, the FFMI (OR 1.08, 95% CI 1.02-1.16) and the FMI (OR 1.07, 95% CI 1.02-1.13) also independently correlated with a rising risk of developing prediabetes. The restricted cubic spline (RCS) outcomes suggested that the associations are approximately linear.

Conclusions: Both the FMI and the FFMI significantly correlated with the danger of developing diabetes and prediabetes, and the correlations are approximately linear.

Background: Lysophosphatidic acid (LPA) is a lipid mediator with diverse biological functions through its receptors on the cell membrane. As one of the six LPA receptors, LPA receptor 3 (LPAR3) is highly expressed in mouse kidneys, but its physiological function in the kidney has been poorly explored.

Methods: Wild-type (WT) and Lpar3^-/- mice were used to investigate the renal physiological function of LPAR3 under hypoxia. The expression levels of LPA receptors in the kidneys of WT mice with or without exposure to hypoxia (8% O₂) were detected by RT‒qPCR. RNA sequencing analysis was performed to identify differences in gene expression profiles between the hypoxic kidneys of WT and Lpar3^-/- mice. The effects of LPAR3 deficiency and treatment with the LPAR1/3 inhibitor Ki16425 or the LPAR3 selective agonist 2S-OMPT on erythropoietin (EPO) production in the kidneys of hypoxic mice were determined by RT‒qPCR and ELISAs. The mechanism of LPAR3-mediated regulation of EPO expression was further studied in vivo with mouse models and in vitro with cultured human cells.

Results: LPAR3 is the major LPA receptor in mouse kidneys, and its expression is significantly upregulated under hypoxic conditions. RNA sequencing analysis revealed that, compared with WT mice, Lpar3^-/- mice presented a significant decrease in hypoxia-induced EPO expression in the kidney, together with reduced plasma EPO levels and lower hematocrit and hemoglobin levels. Hypoxic renal EPO expression in WT mice was diminished by the administration of the LPAR1/3 inhibitor Ki16425 and increased by 2S-OMPT, a selective agonist of LPAR3. Hypoxia-induced HIF-2α accumulation in mouse kidneys was impaired by LPAR3 deficiency. Further studies revealed that the PI3K/Akt pathway participated in the regulation of HIF-2α accumulation and EPO expression by LPAR3 under hypoxic conditions.

Conclusions: Our study revealed the role of LPAR3 in promoting the HIF-2α‒EPO axis in hypoxic mouse kidneys, suggesting that the LPA receptor may serve as a novel potential pharmaceutical target to regulate renal EPO production in hypoxia-related situations, such as chronic kidney disease and altitude disease.

Background: Congenital diarrheas and enteropathies (CODEs) caused by diacylglycerol transferase 1 (DGAT1) mutations often cause disease within 2 weeks after birth. If not treated properly, the disease can be life-threatening; therefore, early diagnosis and rational treatment strategies are essential. This study was conducted to improve the understanding of congenital diarrhea caused by DGAT1 deficiency.

Methods: Clinical data from five congenital diarrhea infant cases caused by DGAT1 deficiency were analyzed. Infants were prospectively provided with a nutritional intervention with a low-fat amino acid formula for special medical purposes (FSMP). Their gastrointestinal symptoms and nutritional complications before and after interventions were compared.

Results: Due to poor weight gain and gastrointestinal symptoms after birth, infants were treated by our clinical nutritionist. Genetic testing confirmed a compound heterozygous mutation in DGAT1. Neither hydrolyzed nor high-medium chain triglyceride (MCT) formula significantly alleviated diarrheal symptoms; however, a low-fat amino acid diet rapidly relieved symptoms and significantly improved nutritional status, with infants showing better tolerance to dietary fat content with age.

Conclusions: Infants with DGAT1 deficiency can be diagnosed by genetic testing. A low-fat amino acid FSMP formula and diet can quickly relieve diarrhea, vomiting, and other symptoms, and also improve infant growth and development.

Trial registration: Ethical approval was obtained from the Medical Ethics Committee of the Children's Hospital of Fudan University (reference code: No.(2022)405).

Background: Some research indicates that unsaturated fatty acids (UFAs) in the diet could enhance reproductive outcomes in infertile women. However, other research holds different views, possibly due to differences in the conversion rates of UFAs from various foods and bioavailability in the body. Therefore, this research examined the link between serum UFAs and infertility issues.

Methods: This research included reproductive-age women participating in the 2013-2014 American National Health and Nutrition Examination Survey (NHANES). Serum levels of four UFAs, including palmitoleic acid (16:1n-7), vaccenic acid (18:1n-7), oleic acid (18:1n-9), and linoleic acid (18:2n-6) were measured through gas chromatography-mass spectrometry. Infertility data was collected by affirmative responses to targeted questionnaire items. Associations between serum UFA levels and infertility were evaluated utilizing Poisson regression models and smooth curve fitting methods. Sensitivity analysis was also conducted.

Results: This study included 535 women, aged between 18 and 45. Poisson regression analysis, both adjusted and unadjusted for confounders, revealed no associations between palmitoleic acid, vaccenic acid, oleic acid, or linoleic acid and female infertility (all P > 0.05). However, four UFAs all showed non-linear relationships with infertility in smooth curve fitting analysis. Sensitivity analysis confirmed the stability of the findings.

Conclusion: This research established non-linear associations between serum UFAs and infertility in American women. Specifically, maintaining appropriate serum levels of these UFAs may lower infertility risk. These findings offer new insights and practical dietary recommendations for improving female fertility.

Background: Cellular carcinogenesis is often marked by the accumulation of lipid droplets (LDs) due to reprogrammed lipid metabolism. LDs are dynamic organelles that primarily store intracellular triacylglycerol (TAG) and cholesteryl esters (CEs). Transmembrane protein 68 (TMEM68), a potential modifier of human breast cancer risk and outcomes, functions as a diacylglycerol acyltransferase, synthesizing TAG. However, the specific roles of TMEM68 in breast cancer cells remain unclear.

Methods: Gene expression profiling interactive analysis and survival analysis were conducted. TMEM68 was overexpressed or knockdown in breast cancer cells to assess its impact on cell proliferation, migration and invasion. Targeted quantitative lipidomic analysis and quantitative polymerase chain reaction were used to profile lipid alterations and examine gene expression related to lipid metabolism following changes in TMEM68 levels.

Results: TMEM68 gene was upregulated in breast cancer patients and higher TMEM68 levels were associated with poorer survival outcomes. Overexpression of TMEM68 increased breast cancer cell proliferation and invasion, whereas knockdown had minimal or no impact on reducing proliferation and invasion. Altering TMEM68 levels resulted in corresponding changes in TAG levels and cytoplasmic LDs, with overexpression increasing both and knockdown decreasing them. Lipidomic analysis revealed that TMEM68 regulated TAG levels and altered diacylglycerol content in breast cancer cells. Additionally, TMEM68 influenced the metabolism of glycerophospholipids, CEs and acylcarnitines. TMEM68 also modified the expression of key genes encoding enzymes related to neutral lipid metabolism, including TAG and CEs.

Conclusions: TMEM68 is highly expressed in breast cancer and negatively correlated with survival. Its overexpression promotes breast cancer cell proliferation while knockdown has varied effects depending on TMEM68 levels. TMEM68 regulates intracellular TAG and LDs contents along with alterations in glycerophospholipids. These findings suggest that TMEM68 may drive breast cancer cells proliferation by modulating TAG and LD content.

Background: The year of 2023 displayed the highest average global temperatures since it has been recorded-the duration and severity of extreme heat are projected to increase. Rising global temperatures represent a major public health threat, especially to occupations exposed to hot environments, such as construction and agricultural workers, and first responders. Despite efforts of the scientific community, there is still a need to characterize the pathophysiological processes leading to heat related illness and develop biomarkers that can predict its onset.

Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics analysis was performed on plasma from male and female subjects who underwent exertional heat tolerance testing (HTT), consisting of a 2-h treadmill walk at 5 km/h with 2.0% incline at a controlled temperature of 40ºC. From HTT, heat tolerance was calculated using the physiological strain index (PSI).

Results: Nearly half of all 995 detected lipids from 27 classes were responsive to HTT. Lipid classes related to substrate utilization were predominantly affected by HTT, with a downregulation of triacylglycerols and upregulation of free fatty acids and acyl-carnitines (CARs). Even chain CAR 4:0, 14:0 and 16:1, suggested by-products of incomplete beta oxidation, and diacylglycerols displayed the highest correlation to PSI. PSI did not correlate with plasma lactate levels, suggesting that correlations between even chain CARs and PSI are related to metabolic efficiency versus physical exertion.

Conclusions: Overall, HTT displays a strong impact on the human plasma lipidome and lipid metabolic inefficiencies may underlie reduced heat tolerance.