Altered Lipid Metabolism Research Articles

Abstract A076: Spatial genomic expression profiling reveals metastatic gene markers in mucinous cystic carcinoma of the pancreas and regional lymph nodes

Abstract Pancreatic cancer is a highly lethal disease characterized by low detectability in its early stages, leading to limited treatment options in advanced stages. Mucinous cystic carcinoma (MCC) is a rare subtype of pancreatic cancer that produces mucin. In this study, we investigated the genetic characteristics of MCC and its metastatic potential. Using spatial genomic analysis, we observed the upregulation of several genes in MCC, including CPA1 and CPB1, which encode carboxypeptidases produced by the pancreas. These genes were highly expressed in both the pancreatic tumor and regional lymph nodes, suggesting their potential as gene markers for the metastatic potential of MCC. Moreover, we observed co-localization and upregulation of genes encoding chymotrypsin-like-elastase in both the pancreatic tissue and lymph nodes, indicating their potential involvement in metastasis. Furthermore, we observed significant elevation in the expression of pancreatic enzymes encoded by PRSS1, PRSSA, CLPS, and PLAG2GA in both the pancreatic tissue and lymph nodes. The presence of PRSS1 and PRSSA in the lymph node suggests the presence of cancer cells in the lymphatic system, which in turn promotes tumor growth, invasion, and metastasis. Additionally, elevated expression of CLPS in the lymph nodes may be associated with altered lipid metabolism and the breakdown of fat molecules in the tumor microenvironment. This upregulation was accompanied by increased levels of SPARC, an extracellular matrix protein, in both tissues, emphasizing the correlation between metastatic potential and tumorigenesis. Notably, commonly observed tumor markers for pancreatic cancer, such as SMAD4, did not exhibit upregulation in our MCC case, indicating alternative mechanisms of tumor development in this particular subtype. Additionally, we noted heightened expression of the CA 19-9 antigen, a valuable marker for monitoring the progression of pancreatic cancer. In conclusion, our findings reveal the upregulation of several gene markers in this rare subtype of pancreatic cancer and regional lymph nodes. Understanding the expression patterns of these markers can aid in identifying potential therapeutic targets and detecting metastatic potential at an early stage for MCC. Citation Format: Chirag S. Gopinath, Arshia Ghodrati, Lusine Demirkhanyan, Manu Gnanamony, Joseph A. Norton, Sonia T. Orcutt, Christopher S. Gondi. Spatial genomic expression profiling reveals metastatic gene markers in mucinous cystic carcinoma of the pancreas and regional lymph nodes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A076.

Regulating Lipid Metabolism via Mitochondrial Dynamics in Tongue Squamous Cell Carcinoma Cancer Stem Cells.

Cancer stem cells (CSCs) are a sub-population of cancer cells present in many kinds of malignant tumors that have the potential for self-proliferation and differentiation. These cells have been demonstrated as the main cause of tumor recurrence and metastasis. Strong evidence indicates that CSCs prefer reprogrammed fatty acid β-oxidation over oxidative phosphorylation for sustaining energy supply. Although mitochondrial dynamics participate in the regulation of cancer stemness, the correlation between the inhibition of mitochondrial fission and the regulation of lipid metabolism in CSCs remains poorly understood. The human tongue squamous cell carcinoma (TSCC) cell lines CAL27 and SAS were used to obtain the CSCs by 3D Spheroid Culture. Then,western blot methods, RT-PCR and flow cytometry analysis were used to identify the TSCC CSCs. Next, Immunofluorescence method, transmission electron microscopy detection and western blot methods were used to evaluate the mitochondrial morphology and the quantity of lipid droplets (LDs). Lastly, lipidomic analysis was applied to explored the lipidomic alterations of TSCC CSCs with different mitochondrial morphology. Here, we show that the quantity of lipid droplets containing intracellular triglyceride (TG) can be decreased by regulating mitochondrial morphology. Lipidomic analysis using ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) also compared alterations in lipid metabolites in tongue squamous cell carcinoma (TSCC) CSCs, TSCC cells (non-CSCs), and CSCs with different mitochondrial morphology. Discriminant lipids of statistical significance were successfully annotated, including phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), sphingomyelins (SMs), triacylglycerols (TGs), phosphatidylglycerols (PGs), phosphatidylserines (PSs), lysophosphatidylcholines (LPCs), and lysophosphatidylethanolamines (LPEs). This study provides a deeper insight into the alterations of lipid metabolism associated with TSCC CSCs, non-CSCs and CSCs regulated by mitochondrial dynamics and thus serves as a guide toward novel targeted therapies.

New Advances in Rapid Pretreatment for Small Dense LDL Cholesterol Measurement Using Shear Horizontal Surface Acoustic Wave (SH-SAW) Technology.

Atherosclerosis is an inflammatory disease of the arteries associated with alterations in lipid and other metabolism and is a major cause of cardiovascular disease (CVD). LDL consists of several subclasses with different sizes, densities, and physicochemical compositions. Small dense LDL (sd-LDL) is a subclass of LDL. There is growing evidence that sd-LDL-C is associated with CVD risk, metabolic dysregulation, and several pathophysiological processes. In this study, we present a straightforward membrane device filtration method that can be performed with simple laboratory methods to directly determine sd-LDL in serum without the need for specialized equipment. The method consists of three steps: first, the precipitation of lipoproteins with magnesium harpin; second, the collection of effluent from a 100 nm filter; and third, the quantification of sd-LDL-ApoB in the effluent with an SH-SAW biosensor. There was a good correlation between ApoB values obtained using the centrifugation (y = 1.0411x + 12.96, r = 0.82, n = 20) and filtration (y = 1.0633x + 15.13, r = 0.88, n = 20) methods and commercially available sd-LDL-C assay values. In addition to the filtrate method, there was also a close correlation between sd-LDL-C and ELISA assay values (y = 1.0483x - 4489, r = 0.88, n = 20). The filtration treatment method also showed a high correlation with LDL subfractions and NMR spectra ApoB measurements (y = 2.4846x + 4.637, r = 0.89, n = 20). The presence of sd-LDL-ApoB in the effluent was also confirmed by ELISA assay. These results suggest that this filtration method is a simple and promising pretreatment for use with the SH-SAW biosensor as a rapid in vitro diagnostic (IVD) method for predicting sd-LDL concentrations. Overall, we propose a very sensitive and specific SH-SAW biosensor with the ApoB antibody in its sensitive region to monitor sd-LDL levels by employing a simple delay-time phase shifted SH-SAW device. In conclusion, based on the demonstration of our study, the SH-SAW biosensor could be a strong candidate for the future measurement of sd-LDL.

Frequency of ABO/Rh Blood Groups Among Patients with Diabetes Mellitus in Luanda, Angola

Background Diabetes is a chronic disease characterized by alterations in glucose, lipid, and protein metabolism, which can be identified by detecting high blood glucose levels. In this study we evaluated the frequency of ABO/Rh blood groups in patients with diabetes treated in Luanda, during the second half of 2020. Methods This was an observational, analytical, prospective study with a quantitative approach conducted with 100 patients with diabetes. Results The mean age of patients was 48,4±14 years old. Patients males (63%) with a mean age of 47.9±14.5 years old, secondary educational level (33%), and living in urbanized areas from Luanda (33%), which were the most prevalent in this studied population. About 57% did not exercise before the disease and did not have the disease in the family (51%). About 71% of the patients used insulin to treat diabetes. ORh+ and ARh+ blood groups were the most frequent. The majority of the patients were less than 4 years with diabetes. Conclusion We concluded that the patients most affected by diabetes were the elderly, males, from urbanized areas, and with blood groups ORh+ or ARh+. Further studies assessing the relationship between ABO/Rh blood groups and diabetes among the Angolan population are needed.

GULP1 deficiency reduces adipogenesis and glucose uptake via downregulation of PPAR signaling and disturbing of insulin/ERK signaling in 3T3-L1 cells.

Obesity and metabolic disorders caused by alterations in lipid metabolism are major health issues in developed, affluent societies. Adipose tissue is the only organ that stores lipids and prevents lipotoxicity in other organs. Mature adipocytes can affect themselves and distant metabolism-related tissues by producing various adipokines, including adiponectin and leptin. The engulfment adaptor phosphotyrosine-binding domain-containing 1 (GULP1) regulates intracellular trafficking of glycosphingolipids and cholesterol, suggesting its close association with lipid metabolism. However, the role of GULP1 in adipocytes remains unknown. Therefore, this study aimed to investigate the function of GULP1 in adipogenesis, glucose uptake, and the insulin signaling pathway in adipocytes. A 3T3-L1 cell line with Gulp1 knockdown (shGulp1) and a 3T3-L1 control group (U6) were established. Changes in shGulp1 cells due to GULP1 deficiency were examined and compared to those in U6 cells using microarray analysis. Glucose uptake was monitored via insulin stimulation in shGulp1 and U6 cells using a 2-NBDG glucose uptake assay, and the insulin signaling pathway was investigated by western blot analysis. Adipogenesis was significantly delayed, lipid metabolism was altered, and several adipogenesis-related genes were downregulated in shGulp1 cells compared to those in U6 cells. Microarray analysis revealed significant inhibition of peroxisome proliferator-activated receptor signaling in shGulp1 cells compared with U6 cells. The production and secretion of adiponectin as well as the expression of adiponectin receptor were decreased in shGulp1 cells. In particular, compared with U6 cells, glucose uptake via insulin stimulation was significantly decreased in shGulp1 cells through the disturbance of ERK1/2 phosphorylation. This is the first study to identify the role of GULP1 in adipogenesis and insulin-stimulated glucose uptake by adipocytes, thereby providing new insights into the differentiation and functions of adipocytes and the metabolism of lipids and glucose, which can help better understand metabolic diseases.

Investigation of the effects of T-2 toxin in chicken-derived three-dimensional hepatic cell cultures

Despite being one of the most common contaminants of poultry feed, the molecular effects of T-2 toxin on the liver of the exposed animals are still not fully elucidated. To gain more accurate understanding, the effects of T-2 toxin were investigated in the present study in chicken-derived three-dimensional (3D) primary hepatic cell cultures. 3D spheroids were treated with three concentrations (100, 500, 1000 nM) of T-2 toxin for 24 h. Cellular metabolic activity declined in all treated groups as reflected by the Cell Counting Kit-8 assay, while extracellular lactate dehydrogenase activity was increased after 500 nM T-2 toxin exposure. The levels of oxidative stress markers malondialdehyde and protein carbonyl were reduced by the toxin, suggesting effective antioxidant compensatory mechanisms of the liver. Concerning the pro-inflammatory cytokines, IL-6 concentration was decreased, while IL-8 concentration was increased by 100 nM T-2 toxin exposure, indicating the multifaceted immunomodulatory action of the toxin. Further, the metabolic profile of hepatic spheroids was also modulated, confirming the altered lipid and amino acid metabolism of toxin-exposed liver cells. Based on these results, T-2 toxin affected cell viability, hepatocellular metabolism and inflammatory response, likely carried out its toxic effects by affecting the oxidative homeostasis of the cells.

Effects of Dietary Plant Protein Replacement with Insect and Poultry By-Product Meals on the Liver Health and Serum Metabolites of Sea Bream (Sparus aurata) and Sea Bass (Dicentrarchus labrax).

The liver health of Gilthead sea bream and European sea bass, fed with fish meal-free diets, including various proportions of plant proteins, as well as insect and poultry by-product meals, was investigated through biochemical and histological analyses using a new liver index (LI) formula. Four isoproteic (45% Dry Matter, DM) and isolipidic (20% DM) diets were compared, including a plant-based control diet (CV) and three other test diets, in which 40% of a plant protein-rich ingredient mixture was replaced with meals from Hermetia illucens (H40) or poultry by-product (P40) alone, or in combination (H10P30). The trials lasted 12 and 18 weeks for sea bream and sea bass, respectively. The results obtained thus far highlighted species-specific differences in the physiological response to dietary changes. In sea bream, the biochemical and histological responses suggest favorable physiological and liver health statuses, with higher serum cholesterol (CHO) and triglyceride (TAG) levels, as well as moderate hepatocyte lipid accumulation, with the H10P30 diet compared to the CV (p < 0.05). In sea bass, all diets resulted in elevated serum TAG levels and lipid accumulation in the liver, particularly in fish fed the P40 one (p < 0.05), which resulted in the highest LI, coupled with a higher frequency of severe lipid accumulation, hypertrophy, cord loss, peripheral nuclei displacement, and pyknosis. In conclusion, sea bream adapted well to the test diets, whereas sea bass exhibited altered hepatic lipid metabolism leading to incipient liver steatosis, likely due to the high lipid contents of the diets, including the insect and poultry meals. The LI formula developed in this study proved to be a reliable tool for assessing the effects of dietary changes on the liver health of sea bream and sea bass, consistent with biochemical and histological findings.

Mitochondrial oxidative damage reprograms lipid metabolism of renal tubular epithelial cells in the diabetic kidney

The functional and structural changes in the proximal tubule play an important role in the occurrence and development of diabetic kidney disease (DKD). Diabetes-induced metabolic changes, including lipid metabolism reprogramming, are reported to lead to changes in the state of tubular epithelial cells (TECs), and among all the disturbances in metabolism, mitochondria serve as central regulators. Mitochondrial dysfunction, accompanied by increased production of mitochondrial reactive oxygen species (mtROS), is considered one of the primary factors causing diabetic tubular injury. Most studies have discussed how altered metabolic flux drives mitochondrial oxidative stress during DKD. In the present study, we focused on targeting mitochondrial damage as an upstream factor in metabolic abnormalities under diabetic conditions in TECs. Using SS31, a tetrapeptide that protects the mitochondrial cristae structure, we demonstrated that mitochondrial oxidative damage contributes to TEC injury and lipid peroxidation caused by lipid accumulation. Mitochondria protected using SS31 significantly reversed the decreased expression of key enzymes and regulators of fatty acid oxidation (FAO), but had no obvious effect on major glucose metabolic rate-limiting enzymes. Mitochondrial oxidative stress facilitated renal Sphingosine-1-phosphate (S1P) deposition and SS31 limited the elevated Acer1, S1pr1 and SPHK1 activity, and the decreased Spns2 expression. These data suggest a role of mitochondrial oxidative damage in unbalanced lipid metabolism, including lipid droplet (LD) formulation, lipid peroxidation, and impaired FAO and sphingolipid homeostasis in DKD. An in vitro study demonstrated that high glucose drove elevated expression of cytosolic phospholipase A2 (cPLA2), which, in turn, was responsible for the altered lipid metabolism, including LD generation and S1P accumulation, in HK-2 cells. A mitochondria-targeted antioxidant inhibited the activation of cPLA2f isoforms. Taken together, these findings identify mechanistic links between mitochondrial oxidative metabolism and reprogrammed lipid metabolism in diabetic TECs, and provide further evidence for the nephroprotective effects of SS31 via influencing metabolic pathways.

Kiwifruit Peel Extract Improves the Alterations in Lipid Metabolism in High-fat Diet-fed Model Rats.

Previous studies have demonstrated that the kiwifruit peel, which is usually discarded by consumers and factories, has the highest polyphenol content among all parts of the kiwifruit. To maximize the utilization of these waste resources, the aim of this study was to examine the regulatory effects of polyphenols extracted from kiwifruit peel (KPE) on lipid metabolism and investigate their underlying mechanisms. Thirty-two male Sprague‒Dawley rats were divided into four groups: those fed a normal diet, those fed a high-fat (HF) diet, and those fed a HF diet with a low dose of KPE solution (50 mg/kg) or a high dose of KPE (100 mg/kg) by gavage. The findings of the study revealed that KPE effectively reduced body weight gain and the increases in triglycerides and total cholesterol in serum induced by the HF diet (HFD). Additionally, KPE supplementation led to a significant decrease in hepatic fat accumulation, potentially by increasing hepatic oxidation abilities. Hepatic lipidomics demonstrated that KPE influenced various metabolic pathways, including linoleic acid metabolism, steroid biosynthesis, and the biosynthesis of unsaturated fatty acids in HFD-induced rats, which were associated with the downregulation of FATP2, ACC, FAS, GPAT, DGTA1, DGTA2, and PPARγ expression as well as the upregulation of AMPK, PGC-1α, CPT-1, and PPARα expression. These findings suggest that KPE has considerable regulatory effects in rats with dyslipidaemia, which may provide supporting information for the reuse of kiwifruit peel.

Mechanisms of thyrotropin receptor-mediated phenotype variability deciphered by gene mutations and M453T-knockin model.

The clinical spectrum of thyrotropin receptor-mediated (TSHR-mediated) diseases varies from loss-of-function mutations causing congenital hypothyroidism to constitutively active mutations (CAMs) leading to nonautoimmune hyperthyroidism (NAH). Variation at the TSHR locus has also been associated with altered lipid and bone metabolism and autoimmune thyroid diseases. However, the extrathyroidal roles of TSHR and the mechanisms underlying phenotypic variability among TSHR-mediated diseases remain unclear. Here we identified and characterized TSHR variants and factors involved in phenotypic variability in different patient cohorts, the FinnGen database, and a mouse model. TSHR CAMs were found in all 16 patients with NAH, with 1 CAM in an unexpected location in the extracellular leucine-rich repeat domain (p.S237N) and another in the transmembrane domain (p.I640V) in 2 families with distinct hyperthyroid phenotypes. In addition, screening of the FinnGen database revealed rare functional variants as well as distinct common noncoding TSHR SNPs significantly associated with thyroid phenotypes, but there was no other significant association between TSHR variants and more than 2,000 nonthyroid disease endpoints. Finally, our TSHR M453T-knockin model revealed that the phenotype was dependent on the mutation's signaling properties and was ameliorated by increased iodine intake. In summary, our data show that TSHR-mediated disease risk can be modified by variants at the TSHR locus both inside and outside the coding region as well as by altered TSHR-signaling and dietary iodine, supporting the need for personalized treatment strategies.

Altered lipid metabolism in patients with acute graft-versus-host disease after allogeneic hematopoietic cell transplantation

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the sole curative option for many hematological malignancies and other diseases. Nevertheless, its application is limited due to the risk of life-threatening complications, mainly graft-versus-host disease (GVHD). Currently, in clinical practice, the risk of developing GVHD is estimated for every patient based on factors related to the donor and the host. In our prospective, observational study, we analyzed serum from 38 patients undergoing allo-HCT at our institution. We compared the metabolic profiles of patients who developed acute GVHD (aGVHD) with those without such complication by identification and comparison of metabolites masses on the XCMS platform. We observed that patients diagnosed with aGVHD had different metabolic profiles compared to the remaining patients and this alteration was noticeable already 7 days before the procedure. We identified dysregulated metabolites involved in bile acid transformation and cholesterol synthesis. Our study of the untargeted metabolome in allo-HCT recipients has revealed a potential link between lipid metabolism, specifically involving bile acid transformation and cholesterol synthesis, and the development of aGVHD. This finding might be an important indication for future research focused on understanding GVHD development, discovering prediction models, and investigating possible prophylactic interventions.

Localization, traffic and function of Rab34 in adipocyte lipid and endocrine functions

BackgroundExcessive lipid accumulation in the adipose tissue in obesity alters the endocrine and energy storage functions of adipocytes. Adipocyte lipid droplets represent key organelles coordinating lipid storage and mobilization in these cells. Recently, we identified the small GTPase, Rab34, in the lipid droplet proteome of adipocytes. Herein, we have characterized the distribution, intracellular transport, and potential contribution of this GTPase to adipocyte physiology and its regulation in obesity.Methods3T3-L1 and human primary preadipocytes were differentiated in vitro and Rab34 distribution and trafficking were analyzed using markers of cellular compartments. 3T3-L1 adipocytes were transfected with expression vectors and/or Rab34 siRNA and assessed for secretory activity, lipid accumulation and expression of proteins regulating lipid metabolism. Proteomic and protein interaction analyses were employed for the identification of the Rab34 interactome. These studies were combined with functional analysis to unveil the role played by the GTPase in adipocytes, with a focus on the actions conveyed by Rab34 interacting proteins. Finally, Rab34 regulation in response to obesity was also evaluated.ResultsOur results show that Rab34 localizes at the Golgi apparatus in preadipocytes. During lipid droplet biogenesis, Rab34 translocates from the Golgi to endoplasmic reticulum-related compartments and then reaches the surface of adipocyte lipid droplets. Rab34 exerts distinct functions related to its intracellular location. Thus, at the Golgi, Rab34 regulates cisternae integrity as well as adiponectin trafficking and oligomerization. At the lipid droplets, this GTPase controls lipid accumulation and lipolysis through its interaction with the E1-ubiquitin ligase, UBA1, which induces the ubiquitination and proteasomal degradation of the fatty acid transporter and member of Rab34 interactome, FABP5. Finally, Rab34 levels in the adipose tissue and adipocytes are regulated in response to obesity and related pathogenic insults (i.e., fibrosis).ConclusionsRab34 plays relevant roles during adipocyte differentiation, including from the regulation of the oligomerization (i.e., biological activity) and secretion of a major adipokine with insulin-sensitizing actions, adiponectin, to lipid storage and mobilization from lipid droplets. Rab34 dysregulation in obesity may contribute to the altered adipokine secretion and lipid metabolism that characterize adipocyte dysfunction in conditions of excess adiposity.

Effects of simulated winter short photoperiods on the microbiome and intestinal metabolism in Huanghe carp (Cyprinus carpio haematopterus).

As one of the most important environmental signals, photoperiod plays a crucial role in regulating the growth, metabolism, and survival of organisms. The photoperiod shifts with the transition of the seasons. The difference in photoperiod between summer and winter is the greatest under natural conditions. However, the effect of photoperiod on Huanghe carp (Cyprinus carpio haematopterus) was paid little attention. We investigated the impact of artificial manipulation of seasonal photoperiod on Huanghe carp by integrating growth performance, intestinal flora, and intestinal metabolome. We conducted an 8-week culture experiment with summer photoperiod (14 h light:10 h dark, n = 60) as the control group and winter photoperiod (10 h light:14 h dark, n = 60) based on the natural laws. Winter photoperiod provokes significant weight increases in Huanghe carp. The altered photoperiod contributed to a significant increase in triglyceride and low-density lipoprotein cholesterol levels and the gene expressions of lipid metabolism in the intestine of Huanghe carp. 16s rDNA sequencing revealed that winter photoperiod diminished intestinal flora diversity and altered the abundance. Specifically, the relative abundances of Fusobacteria and Acidobacteriota phyla were higher but Proteobacteria, Firmicutes, and Bacteroidetes phyla were reduced. Analogously, photoperiodic changes induced a significant reduction in the Pseudomonas, Vibrio, Ralstonia, Acinetobacter, and Pseudoalteromonas at the genus level. Additionally, metabolomics analysis showed more than 50% of differential metabolites were associated with phospholipids and inflammation. Microbiome and metabolome correlation analyses revealed that intestinal microbe mediated lipid metabolism alteration. The winter photoperiod induced intestinal flora imbalance and lipid metabolism modification, ultimately affecting the growth of Huanghe carp. This study provides new insights into the effects of seasonal photoperiodic alteration on the well-being of fish.

Mulberry leaves supplementation alters lipid metabolism and promotes fatty acid β oxidation in growing mutton sheep.

Mulberry leaves (MLs) are an unconventional feed with fiber and various active ingredients, and are acknowledged as likely to regulate lipid metabolism, while the molecular mechanism remains undefined. Therefore, our objective was to define the role of MLs on the overall lipid metabolism. We conducted a feeding experiment of three groups on growing mutton sheep fed with dried mulberry leaves (DMLs), with fermented mulberry leaves (FMLs), or without MLs (as control). Analyses of transcriptome and widely target lipids demonstrated the addition of MLs triggered big perturbations in genes and metabolites related to glycerolipid, phospholipid, ether lipid, and sphingolipid metabolism. Additionally, the variations of the above lipids in the treatment of MLs possibly facilitate immunity enhancement of growing mutton sheep via the activation of complement and coagulation cascades. Furthermore, treatments with MLs could expedite proceedings of lipid degradation and fatty acid β oxidation in mitochondria, thereby to achieve the effect of lipid reduction. Besides, added DMLs also fuel fatty acid β-oxidation in peroxisomes and own much stronger lipolysis than added FMLs, possibly attributed to high fiber content in DMLs. These findings establish the novel lipid-lowering role and immune protection of MLs, which lays the foundation for the medicinal application of MLs.

New insights in lipid metabolism: potential therapeutic targets for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is increasingly recognized as being intertwined with the dysregulation of lipid metabolism. Lipids are a significant class of nutrients vital to all organisms, playing crucial roles in cellular structure, energy storage, and signaling. Alterations in the levels of various lipids in AD brains and dysregulation of lipid pathways and transportation have been implicated in AD pathogenesis. Clinically, evidence for a high-fat diet firmly links disrupted lipid metabolism to the pathogenesis and progression of AD, although contradictory findings warrant further exploration. In view of the significance of various lipids in brain physiology, the discovery of complex and diverse mechanisms that connect lipid metabolism with AD-related pathophysiology will bring new hope for patients with AD, underscoring the importance of lipid metabolism in AD pathophysiology, and promising targets for therapeutic intervention. Specifically, cholesterol, sphingolipids, and fatty acids have been shown to influence amyloid-beta (Aβ) accumulation and tau hyperphosphorylation, which are hallmarks of AD pathology. Recent studies have highlighted the potential therapeutic targets within lipid metabolism, such as enhancing apolipoprotein E lipidation, activating liver X receptors and retinoid X receptors, and modulating peroxisome proliferator-activated receptors. Ongoing clinical trials are investigating the efficacy of these strategies, including the use of ketogenic diets, statin therapy, and novel compounds like NE3107. The implications of these findings suggest that targeting lipid metabolism could offer new avenues for the treatment and management of AD. By concentrating on alterations in lipid metabolism within the central nervous system and their contribution to AD development, this review aims to shed light on novel research directions and treatment approaches for combating AD, offering hope for the development of more effective management strategies.

Comprehensive assessment of per and polyfluoroalkyl substances (PFAS) contamination in groundwater of Kamrup, Assam, India: occurrence, health risks, and metabolomic insights.

Per-and polyfluoroalkyl substances (PFAS) are synthetic chemicals that are known for their environmental persistence and adverse health effects. This study comprehensively assessed PFAS contamination in the Kamrup region of Assam, India, focusing on its presence in groundwater and associated health risks. The analysis detected 12 PFAS in groundwater samples from both the Kamrup Metro and Rural regions. In Kamrup Rural, Perfluorohexanoic acid (PFHxA), perfluorononanoic acid (PFNA), and perfluorooctanesulfonic acid (PFOS) were prevalent, whereas in Kamrup Metro, PFNA and PFOS were dominant, based on detection frequencies. These findings are noteworthy, as they demonstrate the widespread presence of PFAS in groundwater, a vital source of drinking water in the region. The assessment of PFAS health risks in India involved hazard quotient calculations for different age groups. Perfluorobutanesulfonic acid (PFBS) posed the highest risk, ranking children > boys > men > girls > women. Overall, ∑PFAS had low hazard (HQ: 0.27-0.41). Further, this study assessed PFBS and PFOS toxicity in human kidney epithelial cell lines (HEK293T) cells, revealing that PFBS was more cytotoxic than PFOS. The study examined the metabolomics of HEK293T cells after PFBS exposure, revealing significant alterations in lipid metabolism, particularly glycerophospholipids, potentially affecting cellular function and health. These findings underscore the importance of monitoring PFAS contamination in drinking water sources, especially in regions such as Kamrup, where groundwater is a primary source. Our metabolomics results show significant health effects at the cellular level, raising concerns about the impact of PFAS exposure on human health. This study highlights PFAS contamination in Kamrup, Assam's groundwater and its health risks, providing valuable insights for policymakers and public health management.

Empagliflozin alters lipid metabolism in the myocardium and liver in a prediabetes model with severe dyslipidemia.

Recent studies suggest that empagliflozin reduces total and cardiovascular mortality in both diabetic and nondiabetic subjects. Although the exact mechanism is unclear, it is understood to positively affect myocardial energetics, including the metabolism of ketone bodies, lipids, and fatty acids. In this study, we compared empagliflozin effects on lipid metabolism in the heart and liver in a prediabetic rat model with severe dyslipidemia. Wistar rats served as the control group, while hereditary hypertriglyceridemic (HHTg) rats were used as a nonobese, prediabetic model. Rats were treated with or without empagliflozin at a dose of 10mg/kg body weight (BW) for 8weeks. In HHTg rats, empagliflozin decreased body weight and adiposity, improved glucose tolerance, and decreased serum triacylglycerols (TAGs) (p < 0.001). Empagliflozin decreased the activity and gene expression of the lipogenic enzyme SCD-1 (p < 0.001) in the myocardium, which may have led to a decrease in the ectopic accumulation of TAGs and lipotoxic diacylglycerols and lysophosphatidylcholines (p < 0.001). Changes in the myocardial phosphatidylcholine/phosphatidylethanolamine ratio (p < 0.01) and in the fatty acid profile of myocardial phospholipids may have contributed to the antifibrotic effects of empagliflozin. The anti-inflammatory effects of empagliflozin were evidenced by an increased IL-10/TNFα ratio (p < 0.001), a marked decrease in arachidonic acid metabolites (20-HETE, p < 0.001), and an increase in PUFA metabolites (14,15-EETs, p < 0.001) in the myocardium. However, empagliflozin did not significantly affect either the concentration or utilization of ketone bodies. In the liver, empagliflozin decreased lipogenesis and the accumulation of TAGs and lipotoxic intermediates. Its effect on arachidonic acid metabolites and alterations in n-3 PUFA metabolism was less pronounced than in the myocardium. Our findings suggest that empagliflozin treatment in the heart and liver reduced the accumulation of neutral lipids and lipotoxic intermediates and altered the metabolism of n-3 PUFA. In the heart, empagliflozin altered arachidonic acid metabolism, which is likely associated with the anti-inflammatory and antifibrotic effects of the drug. We assume that these alterations in lipid metabolism contribute to the cardioprotective effects of empagliflozin in prediabetic states with severe dyslipidemia.

Characterizing defective lipid metabolism in the lateral septum of mice treated with olanzapine: implications for its side effects.

Schizophrenia significantly impacts cognitive and behavioral functions and is primarily treated with second-generation antipsychotics (SGAs) such as olanzapine. Despite their efficacy, these drugs are linked to serious metabolic side effects which can diminish patient compliance, worsen psychiatric symptoms and increase cardiovascular disease risk. This study explores the hypothesis that SGAs affect the molecular determinants of synaptic plasticity and brain activity, particularly focusing on the lateral septum (LS) and its interactions within hypothalamic circuits that regulate feeding and energy expenditure. Utilizing functional ultrasound imaging, RNA sequencing, and weighted gene co-expression network analysis, we identified significant alterations in the functional connection between the hypothalamus and LS, along with changes in gene expression in the LS of mice following prolonged olanzapine exposure. Our analysis revealed a module closely linked to increases in body weight and adiposity, featuring genes primarily involved in lipid metabolism pathways, notably Apoa1, Apoc3, and Apoh. These findings suggest that olanzapine may influence body weight and adiposity through its impact on lipid metabolism-related genes in the LS. Therefore, the neural circuits connecting the LS and LH, along with the accompanying alterations in lipid metabolism, are likely crucial factors contributing to the weight gain and metabolic side effects associated with olanzapine treatment.

Relationship between organophosphate and pyrethroid pesticides and metabolic syndrome in Korean farmers.

The global use of pesticides steadily increased until the early 2010s. Pesticides play a significant role in agriculture in Korea. Metabolic syndrome is more prevalent in rural areas than in urban areas. This study explored the potential association between organophosphate and pyrethroid pesticide exposure and metabolic syndrome. This study enrolled 1,317 individuals who participated in the Pesticide Exposure and Intoxication Study conducted by the Dankook University Hospital Center for Farmers' Safety and Health from 2014 to 2019. Urinary levels of dimethylphosphate, dimethylthiophosphat, diethylphosphate, and diethylthiophosphate were measured to assess organophosphate pesticide exposure and urinary levels cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid, trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid, cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane carboxylic acid, and 3-phenoxybenzoic acid were measured to assess pyrethroid pesticide exposure. The odds ratio for the 4th quartile group of organophosphate metabolites concentration was 1.48 (95% confidence interval: 1.06-2.09) compared to the 1st quartile group after adjustment for general factors. In addition, a positive trend was observed across the quartile groups of organophosphate metabolites concentration. A positive trend was noted across the quartile groups of organophosphate metabolites in males, while no significant association was observed in females. Furthermore, no significant associations were observed between metabolic syndrome and pyrethroid metabolites concentration. A positive correlation was observed between the prevalence of metabolic syndrome and the concentrations of urinary organophosphate metabolites, consistent with previous research finding. This association may be attributed to the action of organophosphates as acetylcholinesterase inhibitors, stimulating beta cells in the islets of Langerhans. This can lead to alterations in lipid metabolism and insulin resistance, ultimately leading to metabolic syndrome development. Metabolic syndrome is a major contributor to cardiovascular disease; therefore, it is necessary to identify the risk factors unique to rural areas, such as pesticide exposure.

ВПЛИВ АЛКОГОЛЮ НА ЛІПІДНИЙ СКЛАД КРОВІ ТА ЛІПОПЕРОКСИДНІ ПРОЦЕСИ У ТКАНИНАХ МОЗКУ ЩУРІВ З РІЗНОЮ АЛКОГОЛЬНОЮ МОТИВАЦІЄЮ І РІЗНОЮ ЗДАТНІСТЮ ДО НАВЧАННЯ

B a c k g r o u n d . Alcohol, as a factor of negative influence on the organism, induces metabolic changes and may affect cognitive task performance, asnervous tissue is particularly sensitive to ethanol exposure. This sensitivity is manifested through oxidative processes in the brain and alterations in lipid metabolism. The study investigated the sensitivity of oxidative processes in brain tissue and changes in the blood lipid spectrum under the influence of ethanol with different combinations of alcoholization and trainingin rats. M e t h o d s . Male rats aged three to five months were used in the study. Learning ability was assessed in the radialmaze. The impact of ethanol on metabolic processes wase valuated by determining the lipid levels in blood plasma usingthin-layer chromatography. The effect of ethanol and training on brain tissues was examined by determining the amount of malondialdehyde in rat brain tissues spectrophotometrically using the 2-thiobarbituric acidtest. R e s u l t s . Unequali poperoxidative reactivity of rat brain tissues with different alcohol motivations was demonstrated under various combinations of ethanol and training. Rats showing no preference for alcohol exhibited higher lipoperoxidative reactivity, especially those that performed poorly in learning and consumed ethanol after training. Animals that learned well had a lowerlevel of peroxide oxidation after alcohol consumption. Rats preferring alcohol demonstrated the lowest degree of peroxideoxidation in brain tissues. C o n c l u s i o n s . Chronic alcoholism led to alterations in the lipid concentration in the rats' blood, indicating a moderate destabilizing effect of ethanol on lipid metabolism under the conditions of our experiment. High levels of lipid peroxidation in rat brain tissues are characteristic of rats with low alcohol motivation, while training rat spriorto the onset of alcoholismmayreduce the level of lipidperoxidation.