Lipid Metabolism Research Articles

Dietary Oryzanol (Ory) Improved the Survival and Growth of Large Yellow Croaker (Larimichthys crocea) Larvae via Promoting Activities of Digestive Enzymes, Antioxidant Capacity, and Lipid Metabolism

A feeding study lasting 30 days was carried out to determine the effects of dietary Oryzanol (Ory) on the survival, growth, antioxidant capacity, peptic enzymes, as well as lipid metabolism of Larimichthys crocea larvae (11.87 ± 0.59 mg) using four different Ory concentrations in microfeed formulations (0, 20, 40, and 80 mg/kg), all preserving isolipidic (18.25% crude lipid) and isonitrogenous (52.08% crude protein) conditions. Results revealed that larvae given 40 and 80 mg/kg Ory revealed markedly higher survival rates; in particular, the 80 mg/kg Ory larvae exhibited a considerably higher specific growth rate than the control. Furthermore, the 80 mg/kg dietary Ory resulted in increased peptic enzyme activity, indicating heightened digestive capabilities of larvae. Meanwhile, Ory supplementation at 20, 40, and 80 mg/kg also increased antioxidant enzyme activities and reduced malondialdehyde levels, indicating an enhanced antioxidant capacity. Moreover, the incorporation of 20 and 40 mg/kg Ory demonstrated efficacy in enhancing the lipid metabolism of the larvae. This was evident in the reduction of triglyceride and total cholesterol levels in the larval visceral mass, attributed to the downregulation of genes that participate in lipid synthesis, and the upregulation of genes associated with lipid catabolism. Overall, the study suggests that the addition of Ory (ranging from 40 to 80 mg/kg) significantly improves both survival and developmental aspects, possibly mediated by enhanced digestion and antioxidative effects, alongside the induction of lipid metabolism in Larimichthys crocea larvae.

Mitochondrial respiration is lower in the intrauterine growth-restricted fetal sheep heart.

Fetuses affected by intrauterine growth restriction have an increased risk of developing heart disease and failure in adulthood. Compared with controls, late gestation intrauterine growth-restricted (IUGR) fetal sheep have fewer binucleated cardiomyocytes, reflecting a more immature heart, which may reduce mitochondrial capacity to oxidize substrates. We hypothesized that the late gestation IUGR fetal heart has a lower capacity for mitochondrial oxidative phosphorylation. Left (LV) and right (RV) ventricles from IUGR and control (CON) fetal sheep at 90% gestation were harvested. Mitochondrial respiration (states 1-3, LeakOmy, and maximal respiration) in response to carbohydrates and lipids, citrate synthase (CS) activity, protein expression levels of mitochondrial oxidative phosphorylation complexes (CI-CV), and mRNA expression levels of mitochondrial biosynthesis regulators were measured. The carbohydrate and lipid state 3 respiration rates were lower in IUGR than CON, and CS activity was lower in IUGR LV than CON LV. However, relative CII and CV protein levels were higher in IUGR than CON; CV expression level was higher in IUGR than CON. Genes involved in lipid metabolism had lower expression in IUGR than CON. In addition, the LV and RV demonstrated distinct differences in oxygen flux and gene expression levels, which were independent from CON and IUGR status. Low mitochondrial respiration and CS activity in the IUGR heart compared with CON are consistent with delayed cardiomyocyte maturation, and CII and CV protein expression levels may be upregulated to support ATP production. These insights will provide a better understanding of fetal heart development in an adverse in utero environment. KEY POINTS: Growth-restricted fetuses have a higher risk of developing and dying from cardiovascular diseases in adulthood. Mitochondria are the main supplier of energy for the heart. As the heart matures, the substrate preference of the mitochondria switches from carbohydrates to lipids. We used a sheep model of intrauterine growth restriction to study the capacity of the mitochondria in the heart to produce energy using either carbohydrate or lipid substrates by measuring how much oxygen was consumed. Our data show that the mitochondria respiration levels in the growth-restricted fetal heart were lower than in the normally growing fetuses, and the expression levels of genes involved in lipid metabolism were also lower. Differences between the right and left ventricles that are independent of the fetal growth restriction condition were identified. These results indicate an impaired metabolic maturation of the growth-restricted fetal heart associated with a decreased capacity to oxidize lipids postnatally.

The associations between pre-conception urinary phthalate concentrations, the serum metabolome, and live birth among women undergoing assisted reproduction

BackgroundPhthalates are ubiquitous endocrine disruptors. Past studies have shown an association between higher preconception urinary concentrations of phthalate metabolites and lower fertility in women; however, the biological mechanisms remain unclear. Our exploratory study aimed to understand the metabolites and pathways associated with maternal preconception phthalate exposure and examine if any may underline the association between phthalate exposure and live birth using untargeted metabolomics. MethodsParticipants (n = 183) were part of the Environment and Reproductive Health (EARTH) study, a prospective cohort that followed women undergoing in vitro fertilization (IVF) at the Massachusetts General Hospital Fertility Center (2005–2016). On the same day, women provided a serum sample during controlled ovarian stimulation, which was analyzed for metabolomics using liquid chromatography coupled with high-resolution mass spectrometry and two chromatography columns, and a urine sample, which was analyzed for 11 phthalate metabolites using targeted approaches. We used multivariable generalized linear models to identified metabolic features associated with urinary phthalate metabolite concentrations and live birth, followed by enriched pathway analysis. We then used a meet-in-the-middle approach to identify overlapping pathways and features. ResultsMetabolic pathway enrichment analysis revealed 43 pathways in the C18 negative and 32 pathways in the HILIC positive columns that were significantly associated (p < 0.05) with at least one of the 11 urinary phthalate metabolites or molar sum of di-2-ethylhexyl phthalate metabolites. Lipid, amino acid, and carbohydrate metabolism were the most common pathways associated with phthalate exposure. Five pathways, tryptophan metabolism, tyrosine metabolism, biopterin metabolism, carnitine shuttle, and vitamin B6 metabolism, were also identified as being associated with at least one phthalate metabolite and live birth following IVF. ConclusionOur study provides further insight into the metabolites and metabolomics pathways, including amino acid, lipid, and vitamin metabolism that may underlie the observed associations between phthalate exposures and lower fertility in women.

Bile Acids and Bilirubin Role in Oxidative Stress and Inflammation in Cardiovascular Diseases

Bile acids (BAs) and bilirubin, primarily known for their role in lipid metabolism and as heme catabolite, respectively, have been found to have diverse effects on various physiological processes, including oxidative stress and inflammation. Indeed, accumulating evidence showed that the interplay between BAs and bilirubin in these processes involves intricate regulatory mechanisms mediated by specific receptors and signaling pathways under certain conditions and in specific contexts. Oxidative stress plays a significant role in the development and progression of cardiovascular diseases (CVDs) due to its role in inflammation, endothelial dysfunction, hypertension, and other risk factors. In the cardiovascular (CV) system, recent studies have suggested that BAs and bilirubin have some opposite effects related to oxidative and inflammatory mechanisms, but this area of research is still under investigation. This review aims to introduce BAs and bilirubin from a biochemical and physiological point of view, emphasizing their potential protective or detrimental effects on CVDs. Moreover, clinical studies that have assessed the association between BAs/bilirubin and CVD were examined in depth to better interpret the possible link between them.

Epoxygenase Cyp2c44 regulates hepatic lipid metabolism and insulin signaling by controlling FATP2 localization and activation of the DAG/PKCδ axis.

Cytochrome P450 epoxygenase Cyp2c44, a murine epoxyeicosatrienoic acid (EET) producing enzyme, promotes insulin sensitivity and Cyp2c44(-/-) mice show hepatic insulin resistance. Because insulin resistance leads to hepatic lipid accumulation and hyperlipidemia, we hypothesized that Cyp2c44 regulates hepatic lipid metabolism. Standard chow diet (SD) fed male Cyp2c44(-/-) mice had significantly decreased EET levels and increased hepatic and plasma lipid levels compared to wild-type mice. We showed increased hepatic plasma membrane localization of the FA transporter 2 (FATP2) and total unsaturated fatty acids and diacylglycerol levels. Cyp2c44(-/-) mice had impaired glucose tolerance and increased hepatic plasma membraneassociated PKCδ and phosphorylated IRS-1, two negative regulators of insulin signaling. Surprisingly, SD and high fat diet fed (HFD) Cyp2c44(-/-) mice had similar glucose tolerance and hepatic plasma membrane PKCδ levels, suggesting that SD-fed Cyp2c44(-/-) mice have reached their maximal glucose intolerance. Inhibition of PKCδ resulted in decreased IRS-1 serine phosphorylation and improved insulin-mediated signaling in Cyp2c44(-/-) hepatocytes. Finally, Cyp2c44(-/-) HFD-fed mice treated with the analog EET-A showed decreased hepatic plasma membrane FATP2 and PCKDδ levels with improved glucose tolerance and insulin signaling. In conclusion, loss of Cyp2c44 with concomitant decreased EET levels leads to increased hepatic FATP2 plasma membrane localization, diacylglycerol accumulation, and PKCδ-mediated attenuation of insulin signaling. Thus, Cyp2c44 acts as a regulator of lipid metabolism by linking it to insulin signaling.

Transcriptomic Insights into Host Metabolism and Immunity Changes after Parasitization by Leptopilina myrica

Parasitoids commonly manipulate their host’s metabolism and immunity to facilitate their offspring survival, but the mechanisms remain poorly understood. Here, we deconstructed the manipulation strategy of a newly discovered parasitoid wasp, L. myrica, which parasitizes D. melanogaster. Using RNA-seq, we analyzed transcriptomes of L. myrica-parasitized and non-parasitized Drosophila host larvae. A total of 22.29 Gb and 23.85 Gb of clean reads were obtained from the two samples, respectively, and differential expression analysis identified 445 DEGs. Of them, 304 genes were upregulated and 141 genes were downregulated in parasitized hosts compared with non-parasitized larvae. Based on the functional annotations in the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, we found that the genes involved in host nutrition metabolism were significantly upregulated, particularly in carbohydrate, amino acid, and lipid metabolism. We also identified 30 other metabolism-related DEGs, including hexokinase, fatty acid synthase, and UDP-glycosyltransferase (Ugt) genes. We observed that five Bomanin genes (Boms) and six antimicrobial peptides (AMPs) were upregulated. Moreover, a qRT-PCR analysis of 12 randomly selected DEGs confirmed the reproducibility and accuracy of the RNA-seq data. Our results provide a comprehensive transcriptomic analysis of how L. myrica manipulates its host, laying a solid foundation for studies on the regulatory mechanisms employed by parasitoid wasps in their hosts.

Anti-diabetic, anti-pancreatic lipase, and anti-protein glycation potential of Irvingia gabonensis stem bark extracts: in vitro and in silico studies.

Diabetes mellitus is a chronic metabolic disorder that affects glucose, lipid, and protein metabolism. Targeting these metabolic derangements can optimize the therapeutic strategies for this disease. Utilizing in vitro and in silico models, this study investigated the ability of aqueous and ethanol extracts of Irvingia gabonensis to inhibit α-amylase, α-glucosidase, pancreatic lipase, and protein glycation. High-performance liquid chromatography (HPLC) was used to identify the compounds found in the stem bark of I. gabonensis. In silico analysis determined the binding mode and mechanism of interactions between the enzymes and phytochemicals. With an IC50 value of 11.47µg/ml, the aqueous extract demonstrated higher inhibitory efficacy against α-amylase compared to the ethanol extract (IC50 19.88µg/ml). However, the ethanol extract had stronger inhibitory activities against α-glucosidase, pancreatic lipase, and protein glycation compared to the aqueous extract (IC50 values of 3.05, 32.85, 0.0014 versus 25.72, 332.42, 0.018µg/ml respectively). Quercetin ranked highest in binding energy with α-amylase (-6.6kcal/mol), α-glucosidase (-6.6kcal/mol), and pancreatic lipase (-5.6kcal/mol). This was followed by rhamnetin (6.5, 6.5, and 6.1kcal/mol respectively). Hydrogen bonding, hydrophobic interactions, and pi-pi stacking are forces responsible for the binding of quercetin and rhamnetin to these enzymes. Molecular dynamics simulation showed that the lead phytochemicals formed stable and energetically stabilized complexes with the target proteins. This study showed that the extracts of I. gabonensis stem bark had significant in vitro anti-diabetic, anti-pancreatic lipase, and anti-protein glycation activities. The strong binding affinities of some of the identified compounds could be responsible for the inhibitory potential of the extracts. I. gabonensis stem bark could be further explored as a natural remedy for the treatment of diabetes mellitus and its complications.

Effectiveness and safety of PCSK9 inhibitors in children with family hypercholesterolemia

Familial hypercholesterolemia (CGHS) is a monogenic disease with a predominantly autosomal dominant type of inheritance, accompanied by a significant increase in the level of low-density lipoprotein cholesterol in the blood, and as a result, premature development and progressive course of atherosclerosis, usually at a young age. One of the common causes of the disease is a mutation in the PCSK9 gene. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the main link in the regulation of blood lipid metabolism due to its direct participation in the degradation of LDL receptors. Currently, only evolocumab is used as PCSK9 inhibitors in children over 12 years of age in the Russian Federation, which has proven the safety and steady reduction of LDL cholesterol in pediatric patients with HES. Another representative of this pharmacological group is alirocumab, which is currently indicated only for people over the age of 18, due to the lack of evidence in children.

Codonopsis pilosula-derived glycopeptide dCP1 promotes the polarization of tumor-associated macrophage from M2-like to M1 phenotype

The majority of the immune cell population in the tumor microenvironment (TME) consists of tumor-associated macrophages (TAM), which are the main players in coordinating tumor-associated inflammation. TAM has a high plasticity and is divided into two main phenotypes, pro-inflammatory M1 type and anti-inflammatory M2 type, with tumor-suppressive and tumor-promoting functions, respectively. Considering the beneficial effects of M1 macrophages for anti-tumor and the high plasticity of macrophages, the conversion of M2 TAM to M1 TAM is feasible and positive for tumor treatment. This study sought to evaluate whether the glycopeptide derived from simulated digested Codonopsis pilosula extracts could regulate the polarization of M2-like TAM toward the M1 phenotype and the potential regulatory mechanisms. The results showed that after glycopeptide dCP1 treatment, the mRNA relative expression levels of some M2 phenotype marker genes in M2-like TAM in simulated TME were reduced, and the relative expression levels of M1 phenotype marker genes and inflammatory factor genes were increased. Analysis of RNA-Seq of M2-like TAM after glycopeptide dCP1 intervention showed that the gene sets such as glycolysis, which is associated with macrophage polarization in the M1 phenotype, were significantly up-regulated, whereas those of gene sets such as IL-6-JAK-STAT3 pathway, which is associated with polarization in the M2 phenotype, were significantly down-regulated. Moreover, PCA analysis and Pearson's correlation also indicated that M2-like TAM polarized toward the M1 phenotype at the transcriptional level after treatment with the glycopeptide dCP1. Lipid metabolomics was used to further explore the efficacy of the glycopeptide dCP1 in regulating the polarization of M2-like TAM to the M1 phenotype. It was found that the lipid metabolite profiles in dCP1-treated M2-like TAM showed M1 phenotype macrophage lipid metabolism profiles compared with blank M2-like TAM. Analysis of the key differential lipid metabolites revealed that the interconversion between phosphatidylcholine (PC) and diacylglycerol (DG) metabolites may be the central reaction of the glycopeptide dCP1 in regulating the conversion of M2-like TAM to the M1 phenotype. The above results suggest that the glycopeptide dCP1 has the efficacy to regulate the polarization of M2-like TAM to M1 phenotype in simulated TME.

Association of Di(2-ethylhexyl) Terephthalate and Its Metabolites with Nonalcoholic Fatty Liver Disease: An Epidemiology and Toxicology Study.

As an alternative plasticizer to conventional phthalates, di(2-ethylhexyl) terephthalate (DEHTP) has attracted considerable concerns, given its widespread detection in the environment and humans. However, the potential toxicity, especially liver toxicity, posed by DEHTP remains unclear. In this study, based on the 2017-2018 National Health and Nutrition Examination Survey, two metabolites of DEHTP, i.e., mono(2-ethyl-5-hydroxyhexyl) terephthalate (MEHHTP) and mono(2-ethyl-5-carboxypentyl) terephthalate (MECPTP), were found to be present in the urine samples of nearly all representative U.S. adults. Moreover, a positive linear correlation was observed between the concentrations of the two metabolites and the risk of nonalcoholic fatty liver disease (NAFLD) in the population. Results of weighted quantile sum and Bayesian kernel machine regression indicated that MEHHTP contributed a greater weight to the risk of NAFLD in comparison with 12 conventional phthalate metabolites. In vitro experiments with hepatocyte HepG2 revealed that MEHHTP exposure could increase lipogenic gene programs, thereby promoting a dose-dependent hepatic lipid accumulation. Activation of liver X receptor α may be an important regulator of MEHHTP-induced hepatic lipid disorders. These findings provide new insights into the liver lipid metabolism toxicity potential of DEHTP exposure in the population.

Metabolic pathways and antimicrobial peptide resistance in bacteria.

Antimicrobial resistance is a pressing concern that poses a significant threat to global public health, necessitating the exploration of alternative strategies to combat drug-resistant microbial infections. Recently, antimicrobial peptides (AMPs) have gained substantial attention as possible replacements for conventional antibiotics. Because of their pharmacodynamics and killing mechanisms, AMPs display a lower risk of bacterial resistance evolution compared with most conventional antibiotics. However, bacteria display different mechanisms to resist AMPs, and the role of metabolic pathways in the resistance mechanism is not fully understood. This review examines the intricate relationship between metabolic genes and AMP resistance, focusing on the impact of metabolic pathways on various aspects of resistance. Metabolic pathways related to guanosine pentaphosphate (pppGpp) and guanosine tetraphosphate (ppGpp) [collectively (p)ppGpp], the tricarboxylic acid (TCA) cycle, haem biosynthesis, purine and pyrimidine biosynthesis, and amino acid and lipid metabolism influence in different ways metabolic adjustments, biofilm formation and energy production that could be involved in AMP resistance. By targeting metabolic pathways and their associated genes, it could be possible to enhance the efficacy of existing antimicrobial therapies and overcome the challenges exhibited by phenotypic (recalcitrance) and genetic resistance toward AMPs. Further research in this area is needed to provide valuable insights into specific mechanisms, uncover novel therapeutic targets, and aid in the fight against antimicrobial resistance.

Loss of YhcB results in overactive fatty acid biosynthesis.

Loss of the Escherichia coli inner membrane protein YhcB results in pleomorphic cell morphology and clear growth defects. Prior work suggested that YhcB was directly involved in cell division or peptidoglycan assembly. We found that loss of YhcB is detrimental in genetic backgrounds in which lipopolysaccharide (LPS) or glycerophospholipid (GPL) synthesis is altered. The growth defect of ΔyhcB could be rescued through inactivation of the Mla pathway, a system responsible for the retrograde transport of GPLs that are mislocalized to the outer leaflet of the outer membrane. Interestingly, this rescue was dependent upon the outer membrane phospholipase PldA that cleaves GPLs at the bacterial surface. Since the freed fatty acids resulting from PldA activity serve as a signal to the cell to increase LPS synthesis, this result suggested that outer membrane lipids are imbalanced in ΔyhcB. Mutations that arose in ΔyhcB populations during two independent suppressor screens were in genes encoding subunits of the acetyl coenzyme A carboxylase complex, which initiates fatty acid biosynthesis (FAB). These mutations fully restored cell morphology and reduced GPL levels, which were increased compared to wild-type bacteria. Growth of ΔyhcB with the FAB-targeting antibiotic cerulenin also increased cellular fitness. Furthermore, genetic manipulation of FAB and lipid biosynthesis showed that decreasing FAB rescued ΔyhcB filamentation, whereas increasing LPS alone could not. Altogether, these results suggest that YhcB may play a pivotal role in regulating FAB and, in turn, impact cell envelope assembly and cell division.IMPORTANCESynthesis of the Gram-negative cell envelope is a dynamic and complex process that entails careful coordination of many biosynthetic pathways. The inner and outer membranes are composed of molecules that are energy intensive to synthesize, and, accordingly, these synthetic pathways are under tight regulation. The robust nature of the Gram-negative outer membrane renders it naturally impermeable to many antibiotics and therefore a target of interest for antimicrobial design. Our data indicate that when the inner membrane protein YhcB is absent in Escherichia coli, the pathway for generating fatty acid substrates needed for all membrane lipid synthesis is dysregulated which leads to increased membrane material. These findings suggest a potentially novel regulatory mechanism for controlling the rate of fatty acid biosynthesis.

The switch triggering the invasion process: Lipid metabolism in the metastasis of hepatocellular carcinoma.

In humans, the liver is a central metabolic organ with a complex and unique histological microenvironment. Hepatocellular carcinoma (HCC), which is a highly aggressive disease with a poor prognosis, accounts for most cases of primary liver cancer. As an emerging hallmark of cancers, metabolic reprogramming acts as a runaway mechanism that disrupts homeostasis of the affected organs, including the liver. Specifically, rewiring of the liver metabolic microenvironment, including lipid metabolism, is driven by HCC cells, propelling the phenotypes of HCC cells, including dissemination, invasion, and even metastasis in return. The resulting formation of this vicious loop facilitates various malignant behaviors of HCC further. However, few articles have comprehensively summarized lipid reprogramming in HCC metastasis. Here, we have reviewed the general situation of the liver microenvironment and the physiological lipid metabolism in the liver, and highlighted the effects of different aspects of lipid metabolism on HCC metastasis to explore the underlying mechanisms. In addition, we have recapitulated promising therapeutic strategies targeting lipid metabolism and the effects of lipid metabolic reprogramming on the efficacy of HCC systematical therapy, aiming to offer new perspectives for targeted therapy.

Phytosterol supplementation enhances the growth performance, feed utilization, antioxidant status and glucose metabolism of juvenile largemouth bass (Micropterus salmoides) fed a high-starch diet

IntroductionPrevious studies found that phytosterols could influence growth performance, feed utilization and lipid metabolism as well as improve the antioxidant capacity of animals.MethodsTo investigate the effects of dietary phytosterol supplementation on juvenile largemouth bass (Micropterus salmoides) fed a high-starch diet, a 56- day feedingtrial was conducted with four dietary feeds for juvenile largemouth bass: extruded floating feed isonitrogenous and isoenergetic diets were formulated to contain 10% and 15% α-starch; on the basis of a 15% α-starch diet, two other diets were formulated with supplementation of 0.1% and 0.5% phytosterol, respectively. After the feeding trials, the survival rate, weight gain and specific growth rate, feed conversion ratio, intraperitoneal fat ratio, feed intake, protein efficiency ratio and activities of three digestive enzymes, as well as the concentrations of nine plasma biochemical indices, hepatic enzyme activities and glycogen contents, were measured and calculated, and the data were statistically analyzed.ResultsThe results of the present study showed that the survival rate, weight gain and specificgrowthrates were significantly greater in plants fed high-starch diets supplemented with phytosterols. As the supplemental phytosterol concentration increased, the feed conversion ratio and intraperitoneal fat ratio significantly decreased; the protease and lipase levels in the pyloric zone markedly increased; the plasma cholesterol, triglyceride, glucose, malondialdehyde, aspartate transaminase and alanin transaminase levels significantly decreased; the glucokinase and pyruvate kinase levelsmarkedly increased; and the hepatic glycogen content significantly decreased.DiscussionIn summary, dietary phytosterol supplementation promoted the growth performance, feed utilization and antioxidant status of juvenile largemouth bass fed a highstarch diet; enhanced glucose utilization and metabolism; and alleviated the negative stimulation of glycemia stress in M. salmoide fed a high-starch diet.

Lipidomic studies revealing serological markers associated with the occurrence of retinopathy in type 2 diabetes

PurposeThe duration of type 2 diabetes mellitus (T2DM) and blood glucose levels have a significant impact on the development of T2DM complications. However, currently known risk factors are not good predictors of the onset or progression of diabetic retinopathy (DR). Therefore, we aimed to investigate the differences in the serum lipid composition in patients with T2DM, without and with DR, and search for potential serological indicators associated with the development of DR.MethodsA total of 622 patients with T2DM hospitalized in the Department of Endocrinology of the First Affiliated Hospital of Xi’an JiaoTong University were selected as the discovery set. One-to-one case–control matching was performed according to the traditional risk factors for DR (i.e., age, duration of diabetes, HbA1c level, and hypertension). All cases with comorbid chronic kidney disease were excluded to eliminate confounding factors. A total of 42 pairs were successfully matched. T2DM patients with DR (DR group) were the case group, and T2DM patients without DR (NDR group) served as control subjects. Ultra-performance liquid chromatography–mass spectrometry (LC–MS/MS) was used for untargeted lipidomics analysis on serum, and a partial least squares discriminant analysis (PLS-DA) model was established to screen differential lipid molecules based on variable importance in the projection (VIP) > 1. An additional 531 T2DM patients were selected as the validation set. Next, 1:1 propensity score matching (PSM) was performed for the traditional risk factors for DR, and a combined 95 pairings in the NDR and DR groups were successfully matched. The screened differential lipid molecules were validated by multiple reaction monitoring (MRM) quantification based on mass spectrometry.ResultsThe discovery set showed no differences in traditional risk factors associated with the development of DR (i.e., age, disease duration, HbA1c, blood pressure, and glomerular filtration rate). In the DR group compared with the NDR group, the levels of three ceramides (Cer) and seven sphingomyelins (SM) were significantly lower, and one phosphatidylcholine (PC), two lysophosphatidylcholines (LPC), and two SMs were significantly higher. Furthermore, evaluation of these 15 differential lipid molecules in the validation sample set showed that three Cer and SM(d18:1/24:1) molecules were substantially lower in the DR group. After excluding other confounding factors (e.g., sex, BMI, lipid-lowering drug therapy, and lipid levels), multifactorial logistic regression analysis revealed that a lower abundance of two ceramides, i.e., Cer(d18:0/22:0) and Cer(d18:0/24:0), was an independent risk factor for the occurrence of DR in T2DM patients.ConclusionDisturbances in lipid metabolism are closely associated with the occurrence of DR in patients with T2DM, especially in ceramides. Our study revealed for the first time that Cer(d18:0/22:0) and Cer(d18:0/24:0) might be potential serological markers for the diagnosis of DR occurrence in T2DM patients, providing new ideas for the early diagnosis of DR.

SNPs in microRNA seed region and impact of miR-375 in concurrent regulation of multiple lipid accumulation-related genes

Bovine intramuscular fat (IMF), commonly referred to as marbling, is regulated by lipid metabolism, which includes adipogenesis, lipogenesis, glycerolipid synthesis, and lipolysis. In recent years, breeding researchers have identified single nucleotide polymorphisms (SNPs) as useful marker-assisted selection tools for improving marbling scores in national breeding programs. These included causal SNPs that induce phenotypic variation. MicroRNAs (miRNAs) are small highly conserved non-coding RNA molecules that bind to multiple non-coding regions. They are involved in post-transcriptional regulation. Multiple miRNAs may regulate a given target. Previously, three SNPs in the GPAM 3ʹ UTR and four miRNAs were identified through in silico assays. The aim of this study is to verify the binding ability of the four miRNAs to the SNPs within the 3ʹUTR of GPAM, and to identify the regulatory function of miR-375 in the expression of genes related to lipid metabolism in mammalian adipocytes. It was verified that the four miRNAs bind to the GPAM 3ʹUTR, and identified that the miR-375 sequence is highly conserved. Furthermore, it was founded that miR-375 upregulated the GPAM gene, C/EBPα, PPARγ and lipid metabolism-related genes and promoted lipid droplet accumulation in 3T3-L1 cells. In conclusion, these results suggest that miR-375 is a multifunctional regulator of multiple lipid metabolism-related genes and may aid in obesity research as a biomarker.

Discovery of Oral AMP-Activated Protein Kinase Activators for Treating Hyperlipidemia.

Activation of AMP-activated protein kinase (AMPK) is proposed to alleviate hyperlipidemia. With cordycepin and N6-(2-hydroxyethyl) adenosine (HEA) as lead compounds, a series of adenosine-based derivatives were designed, synthesized, and evaluated on activation of AMPK. Finally, compound V1 was identified as a potent AMPK activator with the lipid-lowering effect. Molecular docking and circular dichroism indicated that V1 exerted its activity by binding to the γ subunit of AMPK. V1 markedly decreased the serum low-density lipoprotein cholesterol levels in C57BL/6 mice, golden hamsters, and rhesus monkeys. V1 was selected as the clinical compound and concluded Phase 1 clinical trials. A single dose of V1 (2000 mg) increased AMPK activation in human erythrocytes after 5 and 12 h of treatment. RNA sequencing data suggested that V1 downregulated expression of genes involved in regulation of apoptotic process, lipid metabolism, endoplasmic reticulum stress, and inflammatory response in liver by activating AMPK.

Unveiling the oral-gut connection: chronic apical periodontitis accelerates atherosclerosis via gut microbiota dysbiosis and altered metabolites in apoE−/− Mice on a high-fat diet

The aim of this study was to explore the impact of chronic apical periodontitis (CAP) on atherosclerosis in apoE−/− mice fed high-fat diet (HFD). This investigation focused on the gut microbiota, metabolites, and intestinal barrier function to uncover potential links between oral health and cardiovascular disease (CVD). In this study, CAP was shown to exacerbate atherosclerosis in HFD-fed apoE−/− mice, as evidenced by the increase in plaque size and volume in the aortic walls observed via Oil Red O staining. 16S rRNA sequencing revealed significant alterations in the gut microbiota, with harmful bacterial species thriving while beneficial species declining. Metabolomic profiling indicated disruptions in lipid metabolism and primary bile acid synthesis, leading to elevated levels of taurochenodeoxycholic acid (TCDCA), taurocholic acid (TCA), and tauroursodeoxycholic acid (TDCA). These metabolic shifts may contribute to atherosclerosis development. Furthermore, impaired intestinal barrier function, characterized by reduced mucin expression and disrupted tight junction proteins, was observed. The increased intestinal permeability observed was positively correlated with the severity of atherosclerotic lesions, highlighting the importance of the intestinal barrier in cardiovascular health. In conclusion, this research underscores the intricate interplay among oral health, gut microbiota composition, metabolite profiles, and CVD incidence. These findings emphasize the importance of maintaining good oral hygiene as a potential preventive measure against cardiovascular issues, as well as the need for further investigations into the intricate mechanisms linking oral health, gut microbiota, and metabolic pathways in CVD development.

Valine induces inflammation and enhanced adipogenesis in lean mice by multi-omics analysis

IntroductionThe branched-chain amino acids (BCAAs) are essential to mammalian growth and development but aberrantly elevated in obesity and diabetes. Each BCAA has an independent and specific physio-biochemical effect on the host. However, the exact molecular mechanism of the detrimental effect of valine on metabolic health remains largely unknown.Methods and resultsThis study showed that for lean mice treated with valine, the hepatic lipid metabolism and adipogenesis were enhanced, and the villus height and crypt depth of the ileum were significantly increased. Transcriptome profiling on white and brown adipose tissues revealed that valine disturbed multiple signaling pathways (e.g., inflammation and fatty acid metabolism). Integrative cecal metagenome and metabolome analyses found that abundances of Bacteroidetes decreased, but Proteobacteria and Helicobacter increased, respectively; and 87 differential metabolites were enriched in several molecular pathways (e.g., inflammation and lipid and bile acid metabolism). Furthermore, abundances of two metabolites (stercobilin and 3-IAA), proteins (AMPK/pAMPK and SCD1), and inflammation and adipogenesis-related genes were validated.DiscussionValine treatment affects the intestinal microbiota and metabolite compositions, induces gut inflammation, and aggravates hepatic lipid deposition and adipogenesis. Our findings provide novel insights into and resources for further exploring the molecular mechanism and biological function of valine on lipid metabolism.

Risk factors and lipid metabolism characteristics of early-onset male androgenetic alopecia: A pilot study.

Male androgenetic alopecia (MAA) is a multifactorial disease, with patients presenting at a younger age, which is a risk factor for many metabolic diseases. To explore the risk factors associated with early-onset of MAA and its metabolic characteristics. Forty patients with MAA and 45 healthy controls were collected. The serum levels of fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total testosterone (TT), uric acid (UA), and 25-hydroxyvitamin D (25(OH)D) were measured. Meanwhile, lipid metabolites were detected by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). 37.50% MAA patients had metabolic syndrome, compared to 17.78% in control group (p < 0.05). The levels of HDL-C, UA, and 25(OH)D were decreased in patients with MAA compared to healthy controls (p < 0.05). However, there was no significant difference in the level of TT between the two groups. Additionally, there were no significant differences in the levels of HDL-C, UA, 25(OH)D, and TT among different grades of hair loss (p > 0.05). The lipid profile of early-onset MAA differed significantly from healthy controls. In early-onset MAA, the levels of ceramide (Cer) and sphingomyelin (SM) were significantly lower. Cer(d38:5) and TG(15:0/18:1/18:1) may be the biomarkers. Low HDL-C, UA, and 25(OH)D may be the independent risk factors for early-onset MAA. Abnormal lipid metabolism was observed in early-onset MAA, wherein Cer and SM may serve as protective factors.