Lipids in Health and Disease最新文献

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.

Pancreatic neoplasm, a highly aggressive and often fatal cancer, poses challenges due to late detection and nonspecific symptoms. Therefore, both early diagnosis and appropriate therapeutic approaches are necessary to augment the condition of these patients. Cancer cells undergo metabolic deregulation, which enables their proliferation, survival, and invasion. As a result, it is crucial to focus on the metabolic pathways in prevalent cancers and explore treatment strategies that target these pathways to control tumor growth effectively. This is particularly relevant in cancers like pancreatic cancer, which undergo numerous metabolic alterations. The ketogenic regimen, characterized by low carbohydrate and protein contents and high-fat sources, does not involve caloric restriction. This allows for the induction of ketogenesis and an increase in ketone bodies, while insulin and glucose levels remain low even after meals. This unique metabolic state may influence the tumor microenvironment. Given the lack of unanimous agreement on the precise role and mechanism of the ketogenic diet, this review aims to clarify the diagnostic value and accuracy of ketone bodies in various types of pancreatic tumors and explore the potential anti-cancer effects of the ketogenic diet when used alone or in conjunction with chemotherapy, also to determine the potential of the ketogenic diet to be used as adjuvant therapy. The outcomes of this study are instrumental in enhancing our understanding of the benefits and drawbacks associated with employing this diet for the management and diagnosis of pancreatic cancer.

Background: Lipid-lowering therapy (LLT) plays a central role in managing atherosclerotic cardiovascular disease (ASCVD) risk, but its underuse is reported in over 40% of the qualified population in the United States. Studies on factors, particularly actionable factors associated with guideline-directed LLT are limited.

Methods: This study evaluated participants from the Multi-Ethnic Study of Atherosclerosis (MESA) on their qualification for LLT at exam 5 (2010-2012) according to the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guideline on cholesterol management. Participants were categorized as on-LLT or off-LLT at the following exam (2016-2018). Multi-variable relative risk (RR) models were used to analyze between LLT usage and factors prior to 2013, including age, gender, race/ethnicity, education level and medical insurance, income, smoking, body mass index (BMI), diabetes, hypertension, and presence of coronary artery calcium (CAC).

Results: Among the 2114 participants qualified for LLT at exam 5 with an average age of 70.7, 1,129 (53.4%) were on LLT while 985 (46.6%) were off LLT at exam 6. Black participants were less likely to be on LLT compared to the reference white participants (RR 0.80, 95% confidence interval CI 0.71-0.90). Higher BMI showed borderline significant association with LLT. Comorbidities of diabetes and hypertension were positively associated with LLT use (RR 1.39 and 1.23, 95% CI 1.27-1.52 and 1.10-1.36, respectively). CAC score > 0 as an indicator of subclinical ASCVD was strongly associated with LLT too, independent of other demographic or comorbidity factors (RR 1.38, 95% CI 1.21-1.56).

Conclusions: This study identifies key factors influencing LLT use among MESA participants. Black participants were less likely to be on LLT, highlighting healthcare disparities. CAC presence was strongly associated with LLT use, suggesting that CAC measurement could be an actionable factor to improve adherence to LLT guidelines.

Background: In clinical practice, psoriasis is a prevalent chronic inflammatory cutaneous disease featured with the development of red plaque with silvery scales, which considerably affects cutaneous health and quality of life of those afflicted.

Objective: This research aimed to examine the association between the body roundness index (BRI) and psoriasis, using data sourced from the National Health and Nutrition Examination Survey (NHANES).

Methods: Our study used a cross-sectional design, including 8,479 adults, of whom 234 were diagnosed with psoriasis. Multivariable logistic regression was used to analyze the relationship between BRI and psoriasis, with stepwise adjustments for covariables.

Results: Results from multivariable logistic regression analyses indicated a significant positive relationship between BRI and the risk of developing psoriasis; specifically, after comprehensive adjustment for covariables, per 1 unit increase in BRI was linked to an 11% rise in psoriasis risk (OR = 1.11, 95% CI = 1.05-1.17). Furthermore, psoriasis patients exhibited higher average BRI compared to non-psoriasis patients and a greater prevalence of comorbidities such as hypertension and smoking.

Conclusion: These findings suggest that higher BRI is positively correlated with the risk of psoriasis in the adult population in the US. BRI could potentially act as a practical anthropometric index for more accurately predicting the risk of developing psoriasis.