Dysregulation Of Lipid Metabolism Research Articles

Single-Cell Data Analysis Reveals Critical Hepatic Cells Subpopulations in the Progression of Non-alcoholic Fatty Liver Disease to Non-Alcoholic Steatohepatitis.

The aim of this study was to reveal the hepatic cell landscape and function in the progression of NAFLD to NASH. Non-alcoholic steatohepatitis (NASH) is the progressive form and turning point of nonalcoholic fatty liver disease (NAFLD), which severely causes irreversible cirrhosis as well as hepatocellular carcinoma. The mechanism underlying the progression of NAFLD to NASH has not been revealed. Unraveling the mechanism of action of NAFLD-NASH is an important goal in improving the survival of patients with liver disease. The aim of this study is to discover heterogeneous hepatic cells during the progression of NAFLD to NASH. Single-nucleus RNA-seq (snRNA-seq) data containing NASH in NAFLD samples were obtained from the Gene Expression Omnibus (GEO) database. Cell types in liver tissues from NASH and NAFLD were identified after dimensionality reduction analysis, cluster analysis, and cell annotation. The cell pathways in which differences existed were identified by analyzing metabolic pathways in Hepatic cells. We also identified cell subpopulations in Hepatic cells. The developmental trajectories of Hepatic cells were characterized by pseudotime trajectory analysis. Single-cell regulatory network inference and clustering analysis identified key transcription factors and gene regulatory networks in Hepatic cells. Moreover, cell communication analysis determined the potential interactions between Hepatic cells and immune cells, and heapatic stellate cells. Seven cell types were identified in NAFLD and NASH. The proportion of Hepatic cells was lower in NASH and showed greater energy metabolism and glucose metabolism activity. Hepatic cells exhibited heterogeneity, showing two cell subpopulations, Hepatic cells 1 and Hepatic cells 2. Dysregulation of lipid metabolism in Hepatic Cell 2 resulted in lipid accumulation in the liver, which might be involved in the progression of NAFLD. Four key transcription factors, BHLHE40, NFEL2L, RUNX1, and INF4A, were primarily found in Hepatic cells 2. The transcription factors within the hepatic cells 2 subpopulation mainly regulated genes related to lipid metabolism, energy metabolism, and inflammatory response. The cell communication analysis showed that hepatocyte interactions with immune cells were associated with inflammatory responses, while interactions with hepatic astrocytes were associated with liver injury and hepatocyte fibrosis. The hepatic cells 2 might promote the progression of NAFLD to NASH by regulating metabolic activity, which might contribute to liver injury through inflammation.

#2743 Impact of fatty acid-binding protein 4 on SUMOylation balance and renal tubular epithelial cell senescence in acute kidney injury

Abstract Background and Aims Dysregulated lipid metabolism and cellular senescence intricately interact in the context of acute kidney injury (AKI). Fatty acid-binding protein 4 (FABP4), a critical enzyme regulating lipid metabolism, potentially induces cell senescence through lipotoxicity in AKI. However, the specific mechanisms remain unclear. Method We established an ischemia-reperfusion-induced AKI (IRI-AKI) model in C57 mice and quantified and localized FABP4 expression in renal tissues using Western blotting (WB), qPCR, and immunofluorescence (IF). Oil Red O staining and beta-galactosidase staining were employed to assess lipid deposition and cellular senescence in tubular cells. The same measurements were repeated in IRI-AKI by knocking out Fabp4. Additionally, bulk mRNA sequencing and single-cell sequencing were conducted on renal tissues to analyze key molecules and related mechanisms. Results In vivo, we observed a significant decline in renal function, severe tubular epithelial damage, and abundant inflammation in the IRI-AKI group, which was noticeably alleviated in the Fabp4 knockout group (Fig. 1). Furthermore, we detected upregulation of FABP4 expression in the kidneys of IRI-AKI, primarily localized in the tubular epithelial cells. Fabp4 knockout effectively reduced tubular lipid accumulation and cellular senescence (Fig. 3). Through integrating mRNA and single-cell sequencing data, UBC9, an E2 enzyme involved in protein SUMOylation, emerged as a potential key regulator of cell senescence and AKI. WB and qPCR both confirmed the upregulation of UBC9 expression in IRI-AKI and its downregulation after Fabp4 knockout. Conversely, we observed that downregulated SUMOylation in IRI-AKI was upregulated in the Fabp4 knockout group (Fig. 4). Conclusion In conclusion, FABP4 modulates the expression of UBC9 and SUMOylation, thereby mediating cellular senescence and causing renal tubular cell damage in IRI-AKI. The mechanisms underlying FABP4’s regulation of UBC9 and the opposing trend between UBC9 and SUMOylation require further elucidation.

Association of lipid-lowering drug targets with risk of cutaneous melanoma: a mendelian randomization study

BackgroundMelanoma proliferation is partly attributed to dysregulated lipid metabolism. The effectiveness of lipid-lowering drugs in combating cutaneous melanoma (CM) is a subject of ongoing debate in both in vitro and clinical studies.MethodThis study aims to evaluate the causal relationship between various lipid-lowering drug targets, namely 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR, targeted by statins), Proprotein convertase subtilisin/kexin type 9 (PCSK9, targeted by alirocumab and evolocumab), and Niemann-Pick C1-like 1 (NPC1L1, targeted by ezetimibe), and the outcomes of cutaneous melanoma. To mimic the effects of lipid-lowering drugs, we utilized two genetic tools: analysis of polymorphisms affecting the expression levels of drug target genes, and genetic variations linked to low-density lipoprotein cholesterol levels and drug target genes. These variations were sourced from genome-wide association studies (GWAS). We applied Summary-data-based Mendelian Randomization (SMR) and Inverse Variance Weighted Mendelian Randomization (IVW-MR) to gauge the effectiveness of these drugs.ResultsOur findings, with SMR results showing an odds ratio (OR) of 1.44 (95% CI: 1.08–1.92; P = 0.011) and IVW-MR results indicating an OR of 1.56 (95% CI: 1.10–2.23; P = 0.013), demonstrate a positive correlation between PCSK9 expression and increased risk of CM. However, no such correlations were observed in other analyses.ConclusionThe study concludes that PCSK9 plays a significant role in the development of CM, and its inhibition is linked to a reduced risk of the disease.

Deciphering fatty acid biosynthesis-driven molecular subtypes in pancreatic ductal adenocarcinoma with prognostic insights.

Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to its high heterogeneity and aggressiveness. Recognizing the urgency to delineate molecular subtypes, our study focused on the emerging field of lipid metabolism remodeling in PDAC, particularly exploring the prognostic potential and molecular classification associated with fatty acid biosynthesis. Gene set variation analysis (GSVA) and single-sample gene set enrichment analysis (ssGSEA) were performed to evaluate the dysregulation of lipid metabolism in PDAC. Univariate cox analysis and the LASSO module were used to build a prognostic risk score signature. The distinction of gene expression in different risk groups was explored by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Weighted Gene Co-expression Network Analysis (WGCNA). The biological function of Acyl-CoA Synthetase Long Chain Family Member 5 (ACSL5), a pivotal gene within 7-hub gene signature panel, was validated through in vitro assays. Our study identified a 7-hub gene signature associated with fatty acid biosynthesis-related genes (FRGs), providing a robust tool for prognosis prediction. The high-FRGs score group displayed a poorer prognosis, decreased immune cell infiltration, and a higher tumor mutation burden. Interestingly, this group exhibited enhanced responsiveness to various compounds according to the Genomics of Drug Sensitivity in Cancer (GDSC) database. Notably, ACSL5 was upregulated in PDAC and essential for tumor progression. In conclusion, our research defined two novel fatty acid biosynthesis-based subtypes in PDAC, characterized by distinct transcriptional profiles. These subtypes not only served as prognostic indicator, but also offered valuable insights into their metastatic propensity and therapeutic potential.

Evaluation of Hepatic Glucose and Palmitic Acid Metabolism in Rodents on High‐Fat Diet Using Deuterium Metabolic Imaging

BackgroundOne of the main features of several metabolic disorders is dysregulation of hepatic glucose and lipid metabolism. Deuterium metabolic imaging (DMI) allows for assessing the uptake and breakdown of 2H‐labeled substrates, giving specific insight into nutrient processing in healthy and diseased organs. Thus, DMI could be a useful approach for analyzing the differences in liver metabolism of healthy and diseased subjects to gain a deeper understanding of the alterations related to metabolic disorders.PurposeEvaluating the feasibility of DMI as a tool for the assessment of metabolic differences in rodents with healthy and fatty livers (FLs).Study TypeAnimal Model.Population18 male Sprague Dawley rats on standard (SD, n = 9, healthy) and high‐fat diet (HFD, n = 9, FL disease).Field Strength/SequencePhase‐encoded 1D pulse‐acquire sequence and anatomy co‐registered phase‐encoded 3D pulse‐acquire chemical shift imaging for 2H at 9.4T.AssessmentLocalized and nonlocalized liver spectroscopy was applied at eight time points over 104 minutes post injection. The obtained spectra were preprocessed and quantified using jMRUI (v7.0) and the resulting amplitudes translated to absolute concentration (mM) according to the 2H natural abundance water peak.Statistical TestsTwo‐way repeated measures ANOVA were employed to assess between‐group differences, with statistical significance at P < 0.05.ResultsDMI measurements demonstrated no significant difference (P = 0.98) in the uptake of [6,6′‐2H2]glucose between healthy and impaired animals (AUCSD = 1966.0 ± 151.5 mM ‐ minutes vs. AUCHFD = 2027.0 ± 167.6 mM·minutes). In the diseased group, the intrahepatic uptake of palmitic acid d‐31 was higher (AUCHFD = 57.4 ± 17.0 mM·minutes, AUCSD = 33.3 ± 10.5 mM·minutes), but without statistical significance owing to substantial in‐group variation (P = 0.73).Data ConclusionDMI revealed higher concentrations of palmitic acid in rats with FL disease and no difference in hepatic glucose concentration between healthy and impaired animals. Thus, DMI appears to be a useful tool for evaluating metabolism in rodents with FL disease.Level of Evidence2Technical EfficacyStage 3.

Lipidomic signatures in Colombian adults with metabolic syndrome

Abstract Background and Aims Metabolic syndrome (MetS) comprises a set of risk factors that contribute to the development of chronic and cardiovascular diseases, increasing the mortality rate. Altered lipid metabolism is associated with the development of metabolic disorders such as insulin resistance, obesity, atherosclerosis, and metabolic syndrome; however, there is a lack of knowledge about lipids compounds and the lipidic pathways associated with this condition, particularly in the Latin-American population. Innovative approaches, such as lipidomic analysis, facilitate the identification of lipid species related to these risk factors. This study aimed to assess the plasma lipidome in subjects with MetS. Methods This correlation study included healthy adults and adults with MetS. Blood samples were analyzed. The lipidomic profile was determined using an Agilent Technologies 1260 liquid chromatography system coupled to a Q-TOF 6545 quadrupole mass analyzer with electrospray ionization. The main differences were determined between the groups. Results The analyses reveal a distinct lipidomic profile between healthy adults and those with MetS, including increased concentrations of most identified glycerolipids -both triglycerides and diglycerides- and decreased levels of ether lipids and sphingolipids, especially sphingomyelins, in MetS subjects. Association between high triglycerides, waist circumference, and most differentially expressed lipids were found. Conclusion Our results demonstrate dysregulation of lipid metabolism in subjects with Mets, supporting the potential utility of plasma lipidome analysis for a deeper understanding of MetS pathophysiology.

Probabilistic Scatter Plots for visualizing carbohydrate and lipid metabolism states in Non-Alcoholic Fatty Liver Disease

BackgroundNon-alcoholic fatty liver disease (NAFLD) is characterized by dysregulated carbohydrate and lipid metabolism, which are its primary features. However, traditional biochemical markers pose challenges for accurate quantification and visualization of metabolic states. This study introduces a novel states-based approach for accurate NAFLD assessment. MethodsJoint probabilistic distributions of triglycerides and glycemia were constructed using dual-indicator Probabilistic Scatter Plots based on clinical data (healthy controls: n = 1978; NAFLD patients: n = 471). Patterns of metabolic dysregulation were revealed through comparison against healthy profiles. Self-organizing feature mapping (SOFM) clustered the distributions into four dominant states. ResultsHealthy scatter plots demonstrated a distinct progression of sub-states ranging from very healthy to sub-healthy. In contrast, NAFLD plots exhibited shifted probability centers and outward divergence. SOFM clustering classified the states into: mild; moderate and severe lipid metabolism disorders; and carbohydrate metabolism disorders. ConclusionsProbabilistic Scatter Plots, when combined with SOFM clustering, facilitate a states-based quantification of NAFLD metabolic dysregulation. This method integrates multi-dimensional biochemical indicators and their distributions into a cohesive framework, enabling precise and intuitive visualization for personalized diagnosis and monitoring of prognostic developments.

Metabolic Rewiring in Cancer: Small Molecule Inhibitors in Colorectal Cancer Therapy.

Alterations in cellular metabolism, such as dysregulation in glycolysis, lipid metabolism, and glutaminolysis in response to hypoxic and low-nutrient conditions within the tumor microenvironment, are well-recognized hallmarks of cancer. Therefore, understanding the interplay between aerobic glycolysis, lipid metabolism, and glutaminolysis is crucial for developing effective metabolism-based therapies for cancer, particularly in the context of colorectal cancer (CRC). In this regard, the present review explores the complex field of metabolic reprogramming in tumorigenesis and progression, providing insights into the current landscape of small molecule inhibitors targeting tumorigenic metabolic pathways and their implications for CRC treatment.

MED15 is upregulated by HIF-2α and promotes proliferation and metastasis in clear cell renal cell carcinoma via activation of SREBP-dependent fatty acid synthesis

Emerging evidence has highlighted that dysregulation of lipid metabolism in clear cell renal cell carcinoma (ccRCC) is associated with tumor development and progression. HIF-2α plays an oncogenic role in ccRCC and is involved in abnormal lipid accumulation. However, the underlying mechanisms between these two phenomena remain unknown. Here, MED15 was demonstrated to be a dominant factor for HIF-2α-dependent lipid accumulation and tumor progression. HIF-2α promoted MED15 transcriptional activation by directly binding the MED15 promoter region, and MED15 overexpression significantly alleviated the lipid deposition inhibition and malignant tumor behavior phenotypes induced by HIF-2α knockdown. MED15 was upregulated in ccRCC and predicted poor prognosis. MED15 promoted lipid deposition and tumor progression in ccRCC. Mechanistic investigations demonstrated that MED15 acts as SREBP coactivator directly interacting with SREBPs to promote SREBP-dependent lipid biosynthesis enzyme expression, and promotes SREBP1 and SREBP2 activation through the PLK1/AKT axis. Overall, we describe a molecular regulatory network that links MED15 to lipid metabolism induced by the SREBP pathway and the classic HIF-2α pathway in ccRCC. Efforts to target MED15 or inhibit MED15 binding to SREBPs as a novel therapeutic strategy for ccRCC may be warranted.

Traditional and non-traditional lipid parameters as risk factors for sudden sensorineural hearing loss

ObjectiveThe purpose was to explore the effects of traditional and non-traditional lipid parameters on Sudden Sensorineural Hearing Loss (SSNHL). MethodsThe study included 452 patients diagnosed with SSNHL, among whom 206 patients had a level of hearing improvement ≥10 dB after one month of follow-up. A propensity score-matched (2:1) control group was used. Conditional and unconditional logistic regression were used to analyze the risk factors for SSNHL. ResultsPatients with SSNHL had a higher risk of concomitant hypertension and elevated atherosclerogenic lipid levels, with apolipoprotein B and apolipoprotein E identified as independent risk factors for the onset of SSNHL. Additionally, the Lipid Comprehensive Index (LCI) was an independent risk factor for the degree of hearing loss. A positive linear correlation was revealed between triglyceride, non-high-density lipoprotein cholesterol, atherogenic index, Castelli risk index, atherogenic index of plasma, LCI and hearing loss. However, no linear relationship was observed between hearing gain and any lipid parameters. When Total Cholesterol (TC) was in the range of borderline high, the treatment effect was the best. However, the statistical significance disappeared upon adjusting for confounding factors. ConclusionPatients with SSNHL exhibited markedly dysregulated lipid metabolism. Elevated serum lipid levels may be a causative factor in auditory impairment and can influence the extent of hearing loss. Promptly improving cochlear microcirculation may benefit patients with borderline elevated TC. Level of evidence4.

Comparative impact of pristine and aged microplastics with triclosan on lipid metabolism in larval zebrafish: Unveiling the regulatory role of miR-217

The prevalence of microplastics (MPs), especially aged particles, interacting with contaminants like triclosan (TCS), raises concerns about their toxicological effects on aquatic life. This study focused on the impact of aged polyamide (APA) MPs and TCS on zebrafish lipid metabolism. APA MPs, with rougher surfaces and lower hydrophobicity, exhibited reduced TCS adsorption than unaged polyamide (PA) MPs. Co-exposure to PA/APA MPs and TCS resulted in higher TCS accumulation in zebrafish larvae, notably more with PA than APA. Larvae exposed to PA + TCS exhibited greater oxidative stress, disrupted lipid metabolism, and altered insulin pathway genes than those exposed to TCS. However, these negative effects were lessened in the APA + TCS group. Through miRNA-seq and miR-217 microinjection, it was revealed that PA + TCS co-exposure upregulated miR-217, linked to lipid metabolic disorders in zebrafish. Moreover, molecular docking showed stable interactions formed between PA, TCS, and the insulin signaling protein Pik3r2. This study demonstrated that PA and TCS co-exposure significantly inhibited the insulin signaling in zebrafish, triggering lipid metabolism dysregulation mediated by miR-217 upregulation, while APA and TCS co-exposure alleviated these disruptions. This research underscored the ecological and toxicological risks of aged MPs and pollutants in aquatic environments, providing crucial insights into the wider implications of MPs pollution.

Identification of two distinct head and neck squamous cell carcinoma subtypes based on fatty acid metabolism-related signatures: Implications for immunotherapy and chemotherapy.

The dysregulation of lipid metabolism is a critical factor in the initiation and progression of tumors. In this investigation, we aim to characterize the molecular subtypes of head and neck squamous cell carcinoma (HNSCC) based on their association with fatty acid metabolism and develop a prognostic risk model. The transcriptomic and clinical data about HNSCC were obtained from public databases. Clustering analysis was conducted on fatty acid metabolism genes (FAMG) associated with prognosis, utilizing the non-negative matrix factorization algorithm. The immune infiltration, response to immune therapy, and drug sensitivity between molecular subtypes were evaluated. Differential expression genes were identified between subtypes, and a prognostic model was constructed using Cox regression analyses. A nomogram for HNSCC was constructed and evaluated. Thirty FAMGs have been found to exhibit differential expression in HNSCC, out of which three are associated with HNSCC prognosis. By performing clustering analysis on these 3 genes, 2 distinct molecular subtypes of HNSCC were identified that exhibit significant heterogeneity in prognosis, immune landscape, and treatment response. Using a set of 7778 genes that displayed differential expression between the 2 molecular subtypes, a prognostic risk model for HNSCC was constructed comprising 11 genes. This model has the ability to stratify HNSCC patients into high-risk and low-risk groups, which exhibit significant differences in prognosis, immune infiltration, and immune therapy response. Moreover, our data suggest that this risk model is negatively correlated with B cells and most T cells, but positively correlated with macrophages, mast cells, and dendritic cells. Ultimately, we constructed a nomogram incorporating both the risk signature and radiotherapy, which has demonstrated exceptional performance in predicting prognosis for HNSCC patients. A molecular classification system and prognostic risk models were developed for HNSCC based on FAMGs. This study revealed the potential involvement of FAMGs in modulating tumor immune microenvironment and response to treatment.

Dysregulated Lipid Metabolism Networks Modulate T-cell Function in People with Relapsing Remitting Multiple Sclerosis.

Altered cholesterol, oxysterol, sphingolipid, and fatty acid concentrations are reported in blood, cerebrospinal fluid, and brain tissue of people with relapsing remitting multiple sclerosis (RRMS) and are linked to disease progression and treatment responses. CD4+ T cells are pathogenic in RRMS, and defective T cell function could be mediated in part by liver X receptors (LXRs) - nuclear receptors that regulate lipid homeostasis and immunity. RNA-sequencing and pathway analysis identified that genes within the 'lipid metabolism' and 'signalling of nuclear receptors' pathways were dysregulated in CD4+ T cells isolated from RRMS patients compared with healthy donors. While LXRB and genes associated with cholesterol metabolism were upregulated, other T cell LXR-target genes, including genes involved in cellular lipid uptake (inducible degrader of the LDL receptor, IDOL), and the rate-limiting enzyme for glycosphingolipid biosynthesis (UDP-glucosylceramide synthase, UGCG) were downregulated in T cells from patients with RRMS compared to healthy donors. Correspondingly, plasma membrane glycosphingolipids were reduced, and cholesterol levels increased in RRMS CD4+ T cells, an effect partially recapitulated in healthy T cells by in vitro culture with T cell receptor stimulation in the presence of serum from RRMS patients. Notably, stimulation with LXR-agonist GW3965 normalised membrane cholesterol levels, and reduced proliferation and IL17 cytokine production in RRMS CD4+ T-cells. Thus, LXR-mediated lipid metabolism pathways were dysregulated in T cells from patients with RRMS and could contribute to RRMS pathogenesis. Therapies that modify lipid metabolism could help restore immune cell function.

Theabrownin as a Potential Prebiotic Compound Regulates Lipid Metabolism via the Gut Microbiota, Microbiota-Derived Metabolites, and Hepatic FoxO/PPAR Signaling Pathways.

The dysregulation of lipid metabolism poses a significant health threat, necessitating immediate dietary intervention. Our previous research unveiled the prebiotic-like properties of theabrownin. This study aimed to further investigate the theabrownin-gut microbiota interactions and their downstream effects on lipid metabolism using integrated physiological, genomic, metabolomic, and transcriptomic approaches. The results demonstrated that theabrownin significantly ameliorated dyslipidemia, hepatic steatosis, and systemic inflammation induced by a high-fat/high-cholesterol diet (HFD). Moreover, theabrownin significantly improved HFD-induced gut microbiota dysbiosis and induced significant alterations in microbiota-derived metabolites. Additionally, the detailed interplay between theabrownin and gut microbiota was revealed. Analysis of hepatic transcriptome indicated that FoxO and PPAR signaling pathways played pivotal roles in response to theabrownin-gut microbiota interactions, primarily through upregulating hepatic Foxo1, Prkaa1, Pck1, Cdkn1a, Bcl6, Klf2, Ppara, and Pparg, while downregulating Ccnb1, Ccnb2, Fabp3, and Plin1. These findings underscored the critical role of gut-liver axis in theabrownin-mediated improvements in lipid metabolism disorders and supported the potential of theabrownin as an effective prebiotic compound for targeted regulation of metabolic diseases.

Hesperidin Attenuate Olanzapine-Induced Weight Gain, Dysregulation of Lipid and Glucose Metabolism in Rats

Hesperidin Attenuate Olanzapine-Induced Weight Gain, Dysregulation of Lipid and Glucose Metabolism in Rats

A Review: Cytochrome P450 in Alcoholic and Non-Alcoholic Fatty Liver Disease.

Alcoholic fatty liver disease (FALD) and non-alcoholic fatty liver disease (NAFLD) have similar pathological spectra, both of which are associated with a series of symptoms, including steatosis, inflammation, and fibrosis. These clinical manifestations are caused by hepatic lipid synthesis and metabolism dysregulation and affect human health. Despite having been studied extensively, targeted therapies remain elusive. The Cytochrome P450 (CYP450) family is the most important drug-metabolising enzyme in the body, primarily in the liver. It is responsible for the metabolism of endogenous and exogenous compounds, completing biological transformation. This process is relevant to the occurrence and development of AFLD and NAFLD. In this review, the correlation between CYP450 and liver lipid metabolic diseases is summarised, providing new insights for the treatment of AFLD and NAFLD.

Allele-specific dysregulation of lipid and energy metabolism in early-stage hypertrophic cardiomyopathy

IntroductionHypertrophic cardiomyopathy (HCM) results from pathogenic variants in sarcomeric protein genes that increase myocyte energy demand and lead to cardiac hypertrophy. However, it is unknown whether a common metabolic trait underlies cardiac phenotype at the early disease stage. To address this question and define cardiac biochemical pathology in early-stage HCM, we studied two HCM mouse models that express pathogenic variants in cardiac troponin T (Tnt2) or myosin heavy chain (Myh6) genes, and have marked differences in cardiac imaging phenotype, mitochondrial function at early disease stage. MethodsWe used a combination of echocardiography, transcriptomics, mass spectrometry-based untargeted metabolomics (GC-TOF, HILIC, CSH-QTOF), and computational modeling (CardioNet) to examine cardiac structural and metabolic remodeling at early disease stage (5 weeks of age) in R92W-TnT+/− and R403Q-MyHC+/− mutant mice. Data from mutants was compared with respective littermate controls (WT). ResultsAllele-specific differences in cardiac phenotype, gene expression and metabolites were observed at early disease stage. LV diastolic dysfunction was prominent in TnT mutants. Differentially-expressed genes in TnT mutant hearts were predominantly enriched in the Krebs cycle, respiratory electron transport, and branched-chain amino acid metabolism, whereas MyHC mutants were enriched in mitochondrial biogenesis, calcium homeostasis, and liver-X-receptor signaling. Both mutant hearts demonstrated significant alterations in levels of purine nucleosides, trisaccharides, dicarboxylic acids, acylcarnitines, phosphatidylethanolamines, phosphatidylinositols, ceramides and triglycerides; 40.4 % of lipids and 24.7 % of metabolites were significantly different in TnT mutants, whereas 10.4 % of lipids and 5.8 % of metabolites were significantly different in MyHC mutants. Both mutant hearts had a lower abundance of unsaturated long-chain acyl-carnitines (18:1, 18:2, 20:1), but only TnT mutants showed enrichment of FA18:0 in ceramide and cardiolipin species. CardioNet predicted impaired energy substrate metabolism and greater phospholipid remodeling in TnT mutants than in MyHC mutants. ConclusionsOur systems biology approach revealed marked differences in metabolic remodeling in R92W-TnT and R403Q-MyHC mutant hearts, with TnT mutants showing greater derangements than MyHC mutants, at early disease stage. Changes in cardiolipin composition in TnT mutants could contribute to impairment of energy metabolism and diastolic dysfunction observed in this study, and predispose to energetic stress, ventricular arrhythmias under high workloads such as exercise.

Targeting Dysregulated Lipid Metabolism in Cancer with Pharmacological Inhibitors.

Metabolic plasticity is recognised as a hallmark of cancer cells, enabling adaptation to microenvironmental changes throughout tumour progression. A dysregulated lipid metabolism plays a pivotal role in promoting oncogenesis. Oncogenic signalling pathways, such as PI3K/AKT/mTOR, JAK/STAT, Hippo, and NF-kB, intersect with the lipid metabolism to drive tumour progression. Furthermore, altered lipid signalling in the tumour microenvironment contributes to immune dysfunction, exacerbating oncogenesis. This review examines the role of lipid metabolism in tumour initiation, invasion, metastasis, and cancer stem cell maintenance. We highlight cybernetic networks in lipid metabolism to uncover avenues for cancer diagnostics, prognostics, and therapeutics.

Abstract 4437: Dysregulated lipid metabolism and high-fat diet influences prostate cancer (PCa) progression

Abstract Dysregulation of lipid metabolism is observed during the development and progression of various types of cancer including prostate cancer (PCa). Systemic metabolic changes driven by genetic alterations in conjunction with obesity and a high-fat diet have been demonstrated to induce PCa progression. In this study, we aimed to investigate the impact of high- and low-fat diets on the progression and morbidity of prostate cancer, utilizing inducible genetically engineered mouse models (GEMMs) that mimic different grades of prostate cancer. The mice were initially placed on a standard diet until week 6, after which they were randomly assigned to either a low-fat or high-fat diet. At week 8, the Cre recombinase enzyme was activated to induce the desired phenotype in the GEMMs, effectively mimicking the initiation and progression of prostate cancer. The experimental design allowed us to gain insights into the interplay between dysregulated lipid metabolism, diet, and the pathogenesis of prostate cancer. Two groups of mice were taken for the study, with one group being fed a low-fat diet and the other group being fed a high-fat diet. The mice were maintained on their respective diets for a period of 1, 3, and 5 months. At each endpoint, tissue samples were collected. Samples were taken from the prostate, plasma, and liver tissues. These samples were then subjected to various analyses to investigate the changes occurring at the molecular and cellular level. Blood was collected to determine lipidomic content in response to high and low-fat diet and the relation of tumour progression. Finally, faecal samples were collected throughout the duration of the experiment to perform metagenomic studies. The consumption of a high-fat diet significantly increased the body weight of the mice which corresponded to increased liver weight. Furthermore, we identified that the consumption of a high-fat diet significantly correlated with an increase in prostate weight at 3 and 5 months after initiation. Preliminary metabolomic analysis of the plasma revealed a distinct clustering of samples based on the consumed diet. Metagenomic analyses conducted at 1 and 3 months indicated a visible shift in the composition and diversity of gut microbiota in mice fed either a high- or low-fat diet. In conclusion, our study will shed light on the influence of dietary factors on prostate cancer development, providing valuable information for the development of targeted therapeutic strategies to combat this disease. Citation Format: Saurav Subedi, Federico La Manna, Katja Ovchinnikova, Eugenio Zoni, Nicola Zamboni, Bahtiyar Yilmaz, George N. Thalmann, Marianna Kruithof-de Julio. Dysregulated lipid metabolism and high-fat diet influences prostate cancer (PCa) progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4437.

Senolytic drugs dasatinib and quercetin combined with Carboplatin or Olaparib reduced the peritoneal and adipose tissue metastasis of ovarian cancer

Chemotherapy and targeted drugs-induced senescent ovarian cancer cells that accumulate in peritoneal adipose tissue contribute significantly to chronic inflammation, disrupt homeostasis, and may fuel various aspects of cancer progression. However, the pro-senescence effects of chemotherapy and targeted drugs on adipose derived stem cells (ADSCs) within peritoneal adipose tissue remain poorly understood. In this study, we show that the first-line chemotherapy and targeted drugs can induce the cellular senescence of ADSCs in vitro and increase the aging of peritoneal adipose tissue in vivo. These treatments significantly promoted the dysregulation of glucose and lipid metabolism, including insulin resistance and liver lipid accumulation. Our study shows that dasatinib and quercetin, as senolytics, effectively restore glucose homeostasis in mice with ovarian cancer and significantly reduce adipose tissue aging. Importantly, combining these drugs with Carboplatin or Olaparib results in a marked decrease in both peritoneal and adipose tissue metastasis of ovarian cancer cells. Mechanistically, we revealed that there is crosstalk between ovarian cancer cells and senescent ADSCs. The crosstalk increases inflammatory cytokines and chemokines production in ADSCs and notably upregulates chemokine receptors on cancer cells. Collectively, these data indicate that senescent ADSCs induced by chemotherapy and targeted therapy drugs impair adipose tissue function. However, the senolytic drugs dasatinib and quercetin, can significantly ameliorate organ aging and damage induced by these treatments. Notably, dasatinib and quercetin combined with Carboplatin or Olaparib reduced the peritoneal and adipose tissue metastasis of ovarian cancer, ultimately benefiting the mice undergoing chemotherapy and targeted therapy.