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Background: Lipolysis-stimulated lipoprotein receptor (LSR), a lipid receptor, is associated with cancer progression. However, detailed effects on intracellular metabolism are unclear. We aimed to elucidate the mechanism of LSR-mediated lipid metabolism in gastric cancer. Methods: We investigated lipid metabolic changes induced by lipoprotein administration in gastric cancer cells and evaluated the significance of LSR expression and lipid droplets formation in gastric cancer patients. The efficacy of inhibiting β-oxidation in gastric cancer cells was also examined in vitro and vivo. Results: In gastric cancer cells, LSR promoted cellular uptake of lipoprotein and cell proliferation. Furthermore, the inhibition of LSR in gastric cancer cells expressing high levels of LSR counteracted both effects. Immunohistochemical analysis of human gastric cancer tissues showed that the increase in lipid droplets via LSR is a factor that influences prognosis. Lipidomics analysis of LSR-high-expressing gastric cancer cells revealed an increase in β-oxidation. Based on these results, we used etomoxir, a β-oxidation inhibitor, and found that it inhibited cell proliferation as well as the suppression of LSR. Similarly, in a mouse xenograft model of LSR-highly expressing gastric cancer cells, the tumor growth effect of high-fat diet feeding was counteracted by etomoxir, consistent with the Ki-67 labeling index. Conclusions: We demonstrated that lipids are taken up into gastric cancer cells via LSR and cause an increase in β-oxidation, resulting in the promotion of cancer progression. Controlling LSR-mediated lipid metabolism may be a novel therapeutic strategy for gastric cancer. [ABSTRACT FROM AUTHOR]

In our previous research, microporous packaging combined with chitosan active coating (MP-CH) treatment extended the shelf life of passion fruit at 25 °C to 12 days by regulating water loss and physiological metabolism. However, proteomic investigation and metabolic changes in passion fruit by MP-CH treatment are unclear. In this study, tandem mass tag (TMT) labeling combined with two-dimensional liquid chromatography tandem mass spectrometry (2D LC‒MS/MS) was used to monitor the metabolic changes in passion fruit treated with the MP-CH group and the control group. A total of 730 differentially expressed proteins (DEPs) were identified. Compared with the control group stored for 12 days, there were 359 DEPs in the MP-CH group, including 179 upregulated proteins and 180 downregulated proteins. The upregulated DEPs were mainly involved in the processes of L-ascorbic acid biosynthesis, anthocyanin-containing compound biosynthesis, aspartate family amino acid biosynthesis, and regulation of protein stability. The downregulated DEPs were mainly involved in oxaloacetate metabolism, carbohydrate metabolism, organic substance metabolism, cellular lipid metabolism, pectin catabolism, and galacturonan metabolism. Results showed that the expression of antioxidant enzymes in the MP-CH group was upregulated, which could enhance the antioxidant capacity and stress resistance of passion fruit. In addition, the expression of cell wall-degrading enzymes was downregulated, which could delay the degradation of cell wall components and maintain the relative stability of its cell wall structure, making for a further extended shelf life of passion fruit. [ABSTRACT FROM AUTHOR]

Lipid metabolism during curing of meat products is an essential biological process that affects their eating quality. Lipid droplets (LDs) are the main sites for storing neutral lipids and participating in lipid metabolism, and their surface lipid droplet-related proteins (LDRPs) directly regulate lipid degradation. In this study, we analyzed the expression changes of LDRPs in porcine biceps femoris muscle under curing conditions (1% and 3% salt concentration) by proteomics and discussed the role played by LDs in the regulation of lipid metabolism. A total of 1127 quantitative proteins were identified by mass spectrometry. Among them, the differential proteins between the control and cured groups were mainly involved in biological processes such as lipid metabolism and carbohydrate metabolism. Protein quantification results showed that RAB18 expression was downregulated after curing, suggesting that curing caused LDs to become small and dispersed. Besides, the expression trends of proteins responsible for macroautophagy (RAB7 and RAB10) and those responsible for CMA (HSPA8 and PLIN2) in LDs were opposite. The upregulation of CPT2, ACADL, FABP4, and FABP5, which were related to fatty acid transport and β-oxidation, intensified the degradation of fatty acid in cured samples. Consequently, we concluded that curing promoted LD degradation. Macroautophagy, CMA, and lipolysis were likely to occur alternately and synergistically during the degradation process. The results have significant implications for our understanding of the metabolic processes involved in lipid molecules during meat processing. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. This study was aimed to identify a lipid metabolism-related signature associated with the HCC microenvironment to improve the prognostic prediction of HCC patients. Clinical information and expression profile data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, including the GEO dataset GSE76427. The gene expression profile of lipid metabolism was downloaded from Molecular Signatures Database (MSigDB) database. The infiltrating immune cells were estimated by the Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE), MCP-counter, and TIMER algorithms. Functional analysis, including Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene set enrichment analysis (GSEA) were performed to elucidate the underlying mechanisms. The prognostic risk model was performed by Least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression analysis. Two distinct subgroups of survival were identified. Better prognosis was associated with high immune score, high abundance of immune infiltrating cells, and high immune status. GO and KEGG analysis showed that differentially expressed genes (DEGs) between the two subgroups were mainly enriched in immune related pathways. GSEA analysis suggested that the expression of lipid metabolism related genes (LMRGs) was related to dysregulation of immune in the high-risk group. Risk models and clinical features based on LMRGs predicted HCC prognosis. This study indicated that the lipid metabolism-related signature was important for the prognosis of HCC. The expression of LMRGs was related to the immune microenvironment of HCC patients and could be used to predict the prognosis of HCC. [ABSTRACT FROM AUTHOR]

Unravelling abrupt alterations in the gut microbiota of wild species associated with nutritional stress is imperative but challenging for wildlife conservation. This study assessed the nutritional status of wild red deer during winter on the basis of changes in faecal nitrogen (FN) and urea nitrogen/creatinine (UN: C) levels and identified gut microbes associated with nutritional status via nutritional control experiments and metagenomic sequencing. The FN of wild red deer in winter 2022 was significantly lower than that in winter 2021 (p < 0.05, winter 2021: 1.37 ± 0.16% and winter 2022: 1.26 ± 0.22%), and the UN: C ratio increased (winter 2021: 2.19 ± 1.65 and winter 2022: 3.05 ± 3.50). Similar trends were found in late winter, which indicated greater nutritional pressure in winter (2022) and late winter. Compared with winter 2021, abundances of Ructibacterium and Butyrivibrio significantly increased, and Acetatifactor and Cuneatibacter significantly decreased during winter 2022 (p < 0.05). Compared with early winter, the cell growth and death pathways increased and lipid metabolism and its subpathway of secondary bile acid synthesis (ko00121) significantly decreased during late winter (p < 0.05), which was similar to the changes in malnourished experimental red deer. Abrupt alterations in the gut microbiota should receive increased attention when monitoring the nutritional health of wild ungulates. This study provides new insights and critical implications for the conservation of wild ungulate populations. [ABSTRACT FROM AUTHOR]

Introduction: A potential link between venous thromboembolism and the risk of ovarian cancer has been identified in clinical practice. However, it is unclear whether there is a causal relationship between the two. In this study, we applied a univariate two-sample Mendelian randomization method to explain the possible link between venous thromboembolism and ovarian cancer pathogenesis at the genetic level, and pointed out that lipid metabolism and ovarian cancer pathogenesis have innovative basic experimental directions. Objective: This study explored the causal effect between a history of venous thromboembolism and the risk of ovarian cancer. Methods: Genome-Wide Association Study (GWAS) data of venous thromboembolism patients (n = 9176) of the same ethnicity were selected as study exposures, and GWAS data of ovarian cancer patients (n = 1218) of the same ethnicity were selected as study exposures. In this study, univariate two-sample Mendelian randomization analysis (UVMR) was performed separately using inverse variance weighted (IVW), MR-Egger regression, and weighted median (WM) to assess causal effects. In this study, Cochran's Q test, MR-Egger regression intercept term, MR-PRESSO, and leave-one-out method were used for sensitivity analysis to assess the stability and reliability of the results. Results: The GWAS data screened in this study were all European ethnicity data. In this study, we found that genetically predicted history of venous thromboembolism was associated with an upward trend in ovarian cancer incidence, and the results of Weighted median, Simple mode, Weighted mode, and MR Egger showed a similar trend (OR = 1.0006, 95% CI: 1.00007–1.0013, p < 0.05). There was no heterogeneity of results (p = 0.18) and no horizontal pleiotropy (p = 0.77). The instrumental variables selected for venous thromboembolism in this study were all strong instrumental variables (F = 669.7). The results of the sensitivity analysis remained consistent. Conclusion: The results of this study indicate that patients with a history of venous thromboembolism are at increased risk of developing ovarian cancer and point to possible associations between lipid metabolism genes, such as CYP4V2, and the development of ovarian cancer, which provide interesting directions for further basic research. [ABSTRACT FROM AUTHOR]

Gliomas are malignant tumors originating from both neuroglial cells and neural stem cells. The involvement of neural stem cells contributes to the tumor's heterogeneity, affecting its metabolic features, development, and response to therapy. This review provides a brief introduction to the importance of metabolism in gliomas before systematically categorizing them into specific groups based on their histological and molecular genetic markers. Metabolism plays a critical role in glioma biology, as tumor cells rely heavily on altered metabolic pathways to support their rapid growth, survival, and progression. Dysregulated metabolic processes, involving carbohydrates, lipids, and amino acids not only fuel tumor development but also contribute to therapy resistance and metastatic potential. By understanding these metabolic changes, key intervention points, such as mutations in genes like RTK, EGFR, RAS, and IDH can be identified, paving the way for novel therapeutic strategies. This review emphasizes the connection between metabolic pathways and clinical challenges, offering actionable insights for future research and therapeutic development in gliomas. [ABSTRACT FROM AUTHOR]

There is cumulative evidence that lipid metabolism plays a key role in the pathogenesis of various neurodegenerative disorders including Alzheimer's disease (AD). Visualising lipid content in a non-destructive label-free manner can aid in elucidating the AD phenotypes towards a better understanding of the disease. In this study, we combined multiple optical molecular-specific methods, Fourier transform infrared (FTIR) spectroscopic imaging, synchrotron radiation-infrared (SR-IR) microscopy, Raman and stimulated Raman scattering (SRS) microscopy, and optical-photothermal infrared (O-PTIR) microscopy with multivariate data analysis, to investigate the biochemistry of brain hippocampus in situ using a mouse model of tauopathy (rTg4510). We observed a significant difference in the morphology and lipid content between transgenic (TG) and wild type (WT) samples. Immunohistochemical staining revealed some degree of microglia co-localisation with elevated lipids in the brain. These results provide new evidence of tauopathy-related dysfunction in a preclinical study at a subcellular level. Label-free chemical imaging of ex vivo transgenic mouse brain affected by dementia-inducing tauopathy reveals distinct morphological and biochemical features in a preclinical study. [ABSTRACT FROM AUTHOR]

Infection is a devastating post-surgical complication, often requiring additional procedures and prolonged antibiotic therapy. This is especially relevant for craniotomy and prosthetic joint infections (PJI), both of which are characterized by biofilm formation on the bone or implant surface, respectively, with S. aureus representing a primary cause. The local tissue microenvironment likely has profound effects on immune attributes that can influence treatment efficacy, which becomes critical to consider when developing therapeutics for biofilm infections. However, the extent to which distinct tissue niches influence immune function during biofilm development remains relatively unknown. To address this, we compare the metabolomic, transcriptomic, and functional attributes of leukocytes in mouse models of S. aureus craniotomy and PJI complemented with patient samples from both infection modalities, which reveals profound tissue niche-dependent differences in nucleic acid, amino acid, and lipid metabolism with links to immune modulation. These signatures are both spatially and temporally distinct, differing not only between infection sites but evolving over time within a single model. Collectively, this demonstrates that biofilms elicit unique immune and metabolic responses that are heavily influenced by the local tissue microenvironment, which will likely have important implications when designing therapeutic approaches targeting these infections. Here, Van Roy et al. show that Staphylococcus aureus biofilm elicits unique metabolic and immune signatures in different tissue niches that evolve over time. [ABSTRACT FROM AUTHOR]

Chronic liver disease is closely linked to dietary intake factors, such as high consumption of simple carbohydrates including sucrose. In this study, the influence of sucrose on the development of hepatocellular carcinoma (HCC), the most common primary liver malignancy, was explored. Using the hepatocarcinogen diethylnitrosamine (DEN) to induce HCC in the rat, we co-administered sucrose with DEN. The co-administration significantly modified body, liver and pancreas weight, as well as, serum fatty acids and triglycerides. DEN caused liver structural alteration, fibrosis, and tumor formation; surprisingly, co-administration with sucrose restored hepatic lipids, improved liver architecture, and reduced fibrosis and tumor development. Sucrose intake negatively regulated tumor markers and cell proliferation, and reduced the expression of genes associated with lipid metabolism and oxidative stress response. These findings highlight a hepatoprotective effect of sucrose during DEN-induced hepatocarcinogenesis, underlining an intriguing role of high sucrose consumption during HCC development and providing new insights as well as possible pathways of cellular protection under sucrose intake on hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

Previous studies suggest that a high body mass index (BMI) may be a risk factor for keratoconus (KC), but the causal relationship remains unclear. This study used Mendelian randomization (MR) to investigate this connection and explore the mediating role of circulating serum metabolites and inflammatory factors in this association. Two-sample MR analysis was conducted to assess the relationship between BMI and KC. The study employed a two-step MR approach to evaluate the mediating roles of 91 inflammatory markers and 249 serum metabolites in the BMI-KC relationship. Inverse variance weighting (IVW) was the primary method, and multiple sensitivity analyses were performed to ensure robustness. IVW analysis revealed a positive causal relationship between BMI and KC (OR IVW = 1.811, 95% CI 1.005–3.262, P = 0.048). Although IL-12β and IL-4 were causally associated with KC, they did not mediate the BMI-KC relationship. Five serum metabolites were identified as potential mediators, with HDL cholesterol and triglyceride ratios showing significance. This study clarified the causal relationship between high BMI and KC, suggesting that high BMI may induce KC through lipid metabolism abnormalities. These findings underscore the importance of managing BMI for KC prevention. [ABSTRACT FROM AUTHOR]

To investigate the effects of temperature on Brassica napus (canola) resistance to Leptosphaeria maculans (LM), the causal agent of blackleg disease, metabolic profiles of LM infected resistant (R) and susceptible (S) canola cultivars at 21 °C and 28 °C were analyzed. Metabolites were detected in cotyledons of R and S plants at 48- and 120-h post-inoculation with LM using UPLC-QTOF/MS. The mock-inoculated plants were used as controls. Some of the resistance-related specific pathways, including lipid metabolism, amino acid metabolism, carbohydrate metabolism, and aminoacyl-tRNA biosynthesis, were down-regulated in S plants but up-regulated in R plants at 21 °C. However, some of these pathways were down-regulated in R plants at 28 °C. Amino acid metabolism, lipid metabolism, alkaloid biosynthesis, phenylpropanoid biosynthesis, and flavonoid biosynthesis were the pathways linked to combined heat and pathogen stresses. By using network analysis and enrichment analysis, these pathways were identified as important. The pathways of carotenoid biosynthesis, pyrimidine metabolism, and lysine biosynthesis were identified as unique mechanisms related to heat stress and may be associated with the breakdown of resistance against the pathogen. The increased susceptibility of R plants at 28 °C resulted in the down-regulation of signal transduction pathway components and compromised signaling, particularly during the later stages of infection. Deactivating LM-specific signaling networks in R plants under heat stress may result in compatible responses and deduction in signaling metabolites, highlighting global warming challenges in crop disease control. [ABSTRACT FROM AUTHOR]

Flavivirus infection is tightly connected to host lipid metabolism. Here, we performed shotgun lipidomics of cells infected with neurotropic Zika, West Nile, and tick-borne encephalitis virus, as well as dengue and yellow fever virus. Early in infection specific lipids accumulate, e.g., neutral lipids in Zika and some lysophospholipids in all infections. Ceramide levels increase following infection with viruses that cause a cytopathic effect. In addition, fatty acid desaturation as well as glycerophospholipid metabolism are significantly altered. Importantly, depletion of enzymes involved in phosphatidylserine metabolism as well as phosphatidylinositol biosynthesis reduce orthoflavivirus titers and cytopathic effects while inhibition of fatty acid monounsaturation only rescues from virus-induced cell death. Interestingly, interfering with ceramide synthesis has opposing effects on virus replication and cytotoxicity depending on the targeted enzyme. Thus, lipid remodeling by orthoflaviviruses includes distinct changes but also common patterns shared by several viruses that are needed for efficient infection and replication. Viruses need host cell lipids for multiplication. Here, the authors use lipidomics to show that lipid remodeling by orthoflaviviruses includes distinct changes but also shared patterns, some of which are needed for efficient viral replication. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a cluster of clinical syndromes with diverse etiologies that ultimately result in a swift decline in kidney function. Regrettably, AKI lacks effective therapeutic agents at present. Neferine, a bioactive alkaloid derived from Lotus Plumule, has been reported to alleviate AKI triggered by cisplatin, ischemia/reperfusion (I/R), and sepsis by inhibiting inflammatory pathways. However, the precise molecular mechanisms underpinning its renoprotective effects remain elusive. Peroxisome proliferator-activated receptor alpha (PPAR-α), a regulator of lipid metabolism with anti-inflammatory properties, was investigated in this study to examine its role in neferine's renoprotective effects in cellular and mouse models of AKI. We found that neferine pretreatment in both I/R- or lipopolysaccharide (LPS)-induced AKI models inhibited the activation of the NF-κB inflammatory pathway and reversed PPAR-α deficiency. In NRK-52E cells exposed to hypoxia/reoxygenation (H/R) or LPS, overexpression of PPAR-α resulted in inhibition of the NF-κB pathway and TNF-α production, while PPAR-α silencing via siRNA transfection negated neferine's anti-inflammatory effects. Furthermore, pretreatment with neferine not only reduced lipid accumulation but also reversed the downregulation of FAO-related enzymes induced by LPS. Our findings suggest that neferine's renoprotective effects against AKI are partially mediated through the reversal of renal PPAR-α deficiency and subsequent inhibition of the inflammatory NF-κB pathway. Therefore, regulating renal PPAR-α expression by neferine could represent a promising therapeutic strategy for AKI. [ABSTRACT FROM AUTHOR]

Purpose: Nut-enriched diets are related to improve lipid and inflammatory biomarkers in meta-analyses in the context of primary cardiovascular prevention. However, primary studies on secondary cardiovascular prevention are scarce and controversial. This systematic review and meta-analysis aimed to evaluate the effect of nut supplementation on lipid and inflammatory profiles in individuals with atherosclerotic cardiovascular disease, and the frequency of adverse events. Methods: Six databases were used for research: PubMed, EMBASE, BVS, Cochrane Library, Web of Science, and ClinicalTrials.gov, until February 2023, with no language restrictions. We performed random-effects meta-analyses to compare nut-enriched diets vs. control diets for pre-post intervention changes. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system assessed the evidence's certainty. Results: From the 5187 records identified, eight publications containing data referring to five randomized clinical trials involving 439 participants were included in the final analyses. The nuts evaluated were almonds, pecans, Brazil nuts, and mixed nuts, with doses ranging between 5 g and 85 g (median: 30 g/day). The intervention time varied between 6 and 12 weeks. Compared to nut-free diets, nut intake did not have a statistically significant effect on lipid profile biomarkers, except on the atherogenic index (MD: -0.32 [95% CI -0.58 to -0.06], I2 = 0% - moderate certainty of the evidence). Similarly, there was no effect of nuts on inflammatory profile biomarkers. It was not possible to aggregate data on adverse events. Conclusions: Nut supplementation did not change lipid and inflammatory profiles in the secondary cardiovascular prevention setting. [ABSTRACT FROM AUTHOR]

Purpose: Our study aimed to explore the efficacy of Bifidobacterium breve 207-1 on specific neurotransmitters and hormones and the ability to regulate lifestyle behaviors in healthy adults. Methods: In total, 120 healthy adults with high mental stress, overweight, insomnia, and constipation were randomly assigned to receive low-dose B. breve 207-1 (LD, n = 40), high-dose B. breve 207-1 (HD, n = 40), or placebo (n = 40) for 28 days. Fecal and blood samples were collected and questionnaires were answered before and after the trial. Neurotransmitters and serum hormones were detected using enzyme-linked immunosorbent assay. The gut microbiota composition was assessed using 16 S rRNA sequencing. Short–chain fatty acids (SCFAs) concentrations were determined via gas chromatography–mass spectrometry (GC–MS). Results: The primary outcome of our study was changes in mental wellness, including neurotransmitters, the hypothalamic–pituitary–adrena (HPA) axis hormones, and the psychological scales. The results showed that γ-aminobutyric acid (GABA) increased significantly and the HPA axis hormones were suppressed overall in the probiotic groups while 5-hydroxytryptamine (5-HT) did not change significantly. However, there was no significant change in mood scale scores. The secondary outcome focused on the ability of 207-1 to regulate the body and lifestyle of healthy adults (e.g., sleep, diet, exercise, etc.). The PSQI scores in the probiotics groups significantly decreased, indicating improved sleep quality. Meanwhile, the probiotic groups had a slight increase in exercise consumption while dietary intake stabilized. By physical examination, the participants showed weight loss although no statistically significant difference was observed between the groups. Then, validated by gut microbiota, changes in the gut microbiota were observed under the effective intervention of 207-1 while short-chain fatty acids (SCFAs) increased in the LD group, particularly acetic and propionic acids. There was a slight decrease in alpha–diversity in the HD group. Conclusion: Bifidobacterium breve 207-1 entered the organism and affected neurotransmitter and the HPA axis hormone levels via the microbiome-gut-brain axis. Meanwhile, 207-1 supplementation improved daily lifestyle behaviors in healthy adults, which may in turn lead to changes in their bodies (e.g. weight and lipid metabolism). However, this study did not find significant mood-modulating efficacy. The mechanism of the overall study is unclear, but we hypothesize that SCFAs may be the key pathway, and more experiments are needed for validation in the future. Trial registration: This trial was retrospectively registered in the Chinese Clinical Trial Registry under the accession number ChiCTR2300069453 on March 16, 2023. [ABSTRACT FROM AUTHOR]

Bioactive metabolites play a crucial role in shaping interactions among diverse organisms. In this study, we identified cyclo(Pro-Tyr), a metabolite produced by Bacillus velezensis, as a potent inhibitor of Botrytis cinerea and Caenorhabditis elegans, two potential cohabitant eukaryotic organisms. Based on our investigation, cyclo(Pro-Tyr) disrupts plasma membrane polarization, induces oxidative stress and increases membrane fluidity, which compromises fungal membrane integrity. These cytological and physiological changes induced by cyclo(Pro-Tyr) may be triggered by the destabilization of membrane microdomains containing the [H+]ATPase Pma1. In response to cyclo(Pro-Tyr) stress, fungal cells activate a transcriptomic and metabolomic response, which primarily involves lipid metabolism and Reactive Oxygen Species (ROS) detoxification, to mitigate membrane damage. This similar response occurs in the nematode C. elegans, indicating that cyclo(Pro-Tyr) targets eukaryotic cellular membranes. Cyclo(Pro-Tyr), a metabolite from Bacillus velezensis, inhibits Botrytis cinerea and Caenorhabditis elegans by disrupting membrane polarization, inducing oxidative stress, and increasing membrane fluidity. These effects trigger lipid metabolism and ROS detoxification, targeting eukaryotic membranes. [ABSTRACT FROM AUTHOR]

Akebia trifoliata is a medicinal plant with high oil content and broad pharmacological effects. To investigate the regulatory mechanisms of key metabolic pathways during seed development, we conducted an integrated multi-omics analysis, including transcriptomics, proteomics, and metabolomics, exploring the dynamic changes in carbon and lipid metabolism. Metabolomics analysis revealded that glucose and sucrose levels decreased, while glycolytic intermediate phosphoenolpyruvate and fatty acids increased with seed development, indicating a shift in carbon flux towards fatty acid synthesis. Integrated transcriptomic and proteomic analyses showed that 70 days after flowering, the expression levels of genes and proteins associated with carbon and fatty acid metabolism were upregulated, suggesting an increased energy demand. Additionally, LEC2, LEC1, WRI1, FUS3, and ABI3 were identified as vital regulators of lipid synthesis. By constructing a multi-omics co-expression network, we identified hub genes such as aroE, GAPDH, KCS, TPS, and hub proteins like PGM, PDH, ENO, PFK, PK, ACCase, SAD, PLC, and OGDH that play critical regulatory roles in seed lipid synthesis. This study provides new ideas for the molecular basis of lipid synthesis in Akebia trifoliata seeds and can facilitate future research on the genetic improvement through molecular-assisted breeding. [ABSTRACT FROM AUTHOR]

Background: Neutrophils are key players in the innate immune system, actively migrating to sites of inflammation in the highly energetic process of chemotaxis. In this study, we focus on the role of acyl-CoA: diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the synthesis of triglycerides, the major form of stored energy, in neutrophil chemotaxis. Methods and results: Using a mouse model of psoriasis, we show that DGAT1-deficiency reduces energy-demanding neutrophil infiltration to the site of inflammation, but this inhibition is not caused by decreased glycolysis and reduced ATP production by neutrophils lacking DGAT1. Flow cytometry and immunohistochemistry analysis demonstrate that DGAT1 also does not influence lipid accumulation in lipid droplets during inflammation. Interestingly, as has been shown previously, a lack of DGAT1 leads to an increase in the concentration of retinoic acid, and here, using real-time PCR and publicly-available next-generation RNA sequencing datasets, we show the upregulation of retinoic acid-responsive genes in Dgat1KO neutrophils. Furthermore, supplementation of WT neutrophils with exogenous retinoic acid mimics DGAT1-deficiency in the inhibition of neutrophil chemotaxis in in vitro transwell assay. Conclusions: These results suggest that impaired skin infiltration by neutrophils in Dgat1KO mice is a result of the inhibitory action of an increased concentration of retinoic acid, rather than impaired lipid metabolism in DGAT1-deficient mice. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is caused by a variety of intrapulmonary and extrapulmonary factors and is associated with high morbidity and mortality. Oxidative stress is an important part of the pathological mechanism of ALI. Ferroptosis is a mode of programmed cell death distinguished from others and characterized by iron-dependent lipid peroxidation. This article reviews the metabolic regulation of ferroptosis, its role in the pathogenesis of ALI, and the use of ferroptosis as a therapeutic target regarding the pharmacological treatment of ALI. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress is a major cause of hepatic steatosis through increasing de novo lipogenesis. Forkhead box O6 (FoxO6) is a transcription factor mediating insulin signaling to glucose and lipid metabolism. Therefore, dysregulated FoxO6 is involved in hepatic lipogenesis. This study elucidated the role of FoxO6 in ER stress–induced hepatic steatosis in vivo and in vitro. Hepatic ER stress responses and β-oxidation were monitored in mice overexpressed with constitutively active FoxO6 allele and FoxO6-null mice. For the in vitro study, liver cells overexpressing constitutively active FoxO6 and FoxO6-siRNA were treated with high glucose, and lipid metabolism alterations were measured. ER stress–induced FoxO6 activation suppressed hepatic β-oxidation in vivo. The expression and transcriptional activity of peroxisome proliferator-activated receptor α (PPARα) were significantly decreased in the constitutively active FoxO6 allele. Otherwise, inhibiting β-oxidation genes were reduced in the FoxO6-siRNA and FoxO6-KO mice. Our data showed that the FoxO6-induced hepatic lipid accumulation was negatively regulated by insulin signaling. High glucose treatment as a hyperglycemia condition caused the expression of ER stress–inducible genes, which was deteriorated by FoxO6 activation in liver cells. However, high glucose-mediated ER stress suppressed β-oxidation gene expression through interactions between PPARα and FoxO6 corresponding to findings in the in vivo study—lipid catabolism is also regulated by FoxO6. Furthermore, insulin resistance suppressed b-oxidation through the interaction between FoxO6 and PPARα promotes hepatic steatosis, which, due to hyperglycemia-induced ER stress, impairs insulin signaling. Key messages: Our original aims were to delineate the interrelation between the regulation of PPARα and the transcription factor FoxO6 pathway in relation to lipid metabolism at molecular levels. Evidence on high glucose promoted FoxO6 activation induced lipid accumulation in liver cells. The effect of PPARα activation of the insulin signaling. FoxO6 plays a pivotal role in hepatic lipid accumulation through inactivation of PPARα in FoxO6-overexpression mice. [ABSTRACT FROM AUTHOR]

Vitamin E is associated with the regulation of lipid metabolism. Our previous study revealed an inverse relationship between birth weight and cord blood vitamin E levels, suggesting a potential link between vitamin E and fetal growth. The aim of this study was to determine the association between vitamin E with fetal growth and lipids. In this investigation, a study involving 146 mother-infant pairs was performed. Cord plasma concentrations of vitamin E and lipids were measured. Our findings showed that cord plasma vitamin E levels were elevated in small for gestational age (SGA) infants, and higher vitamin E levels were associated with an increased risk of SGA (OR = 2.239, 95% CI 1.208, 4.742). Additionally, among lipid levels, higher cord plasma triglyceride (TG) levels were associated with increased risks of SGA (OR = 97.020, 95% CI 5.137, 1832.305), whereas after adjusting for confounding factors, the risk became no longer statistically significant. We also found a positive correlation between cord blood vitamin E concentrations and lipid levels. Conclusion: elevated cord blood vitamin E concentrations may be associated with a higher risk of SGA and are positively correlated with lipid levels, suggesting a potential role for vitamin E in fetal lipid metabolism. What is Known: • Vitamin E is associated with the regulation of lipid metabolism. • Vitamin E is inversely related to birth weight. What is New: • Elevated cord blood vitamin E concentrations may be associated with a higher risk of SGA and positively correlated with lipid levels. [ABSTRACT FROM AUTHOR]

Per- and polyfluoroalkyl substances (PFAS) are man-made chemicals used in many industrial applications. Exposure to PFAS is associated with several health risks, including a decrease in infant birth weight, hepatoxicity, disruption of lipid metabolism, and decreased immune response. We used the in vitro cell models to screen six less studied PFAS [perfluorooctane sulfonamide (PFOSA), perfluoropentanoic acid (PFPeA), perfluoropropionic acid (PFPrA), 6:2 fluorotelomer alcohol (6:2 FTOH), 6:2 fluorotelomer sulfonic acid (6:2 FTSA), and 8:2 fluorotelomer sulfonic acid (8:2 FTSA)] for their capacity to activate nuclear receptors and to cause differential expression of genes involved in lipid metabolism. Cytotoxicity assays were run in parallel to exclude that observed differential gene expression was due to cytotoxicity. Based on the cytotoxicity assays and gene expression studies, PFOSA was shown to be more potent than other tested PFAS. PFOSA decreased the gene expression of crucial genes involved in bile acid synthesis and detoxification, cholesterol synthesis, bile acid and cholesterol transport, and lipid metabolism regulation. Except for 6:2 FTOH and 8:2 FTSA, all tested PFAS downregulated PPARA gene expression. The reporter gene assay also showed that 8:2 FTSA transactivated the farnesoid X receptor (FXR). Based on this study, PFOSA, 6:2 FTSA, and 8:2 FTSA were prioritized for further studies to confirm and understand their possible effects on hepatic lipid metabolism. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is a heterogenous endocrine condition and combined oral contraceptives (COCs) have been demonstrated to be the first-line treatment to women who do not intend to become pregnant. The combination of COCs and PCOS may or may not amplify the risks of cardiovascular events. Objective: To investigate whether surrogates for obesity may be influenced by the use of COCs containing different formulations in women with PCOS. Method: From January 2024 a literature search was conducted in Google Scholar and Pubmed databases using PCOS, COC, and obesity terms. Hand search of randomized clinical trials in the references of obtained manuscripts was also performed. After the exclusion of reviews and articles that did not fulfill eligibility criteria, compared the results obtained before and after the use of COCs in 13 randomized clinical trials (RCTs). Random-effects model was used to estimate the standardized mean differences (SMD) and standard errors (SE). Risk of bias was examined using the Rob2 tool. Result: Thirteen heterogeneous RCTs reported no difference in waist circumference with the use of different COC formulations (p = 0.714). On the contrary, body fat mass increased with the use of pill (p = 0.013). Waist triglyceride index and lipid accumulation product tended to be higher after the use of COCs (p = 0.073 and p = 0.064, respectively). Conclusion: Combined oral contraceptives with different formulations might increase fat mass accumulation in women with PCOS. Lipids may also be increased in PCOS users. Because some concerns about the quality and heterogeneity identified in various RCTs, caution should be taken before a definitive conclusion regarding the use of COCs and obesity. [ABSTRACT FROM AUTHOR]

Crayfish species like Cherax quadricarinatus are crucial nutrients that contribute to the world economy but face challenges in production due to dietary supplements. Octacosanol offers diverse health benefits, from immunity boosts to anti-inflammatory and anti-tumor effects. The current investigation assessed the ovarian changes, immune reaction, availability of antioxidants, gene response pattern, and entire organ performance of the red claw crayfish after supplementation with different levels of octacosanol. Two hundred twenty-five C. quadricarinatus with an initial weight of 53 ± 1.11 (g/crayfish) were randomly stocked into fiberglass tanks (15 crayfish/tank) and fed each day with three diverse dietary octacosanols. Different levels of octacosanol (4, 8, 12, and 16 mg/kg) were tested in triplicates over 60 days, denoted as D1, D2, D3, and D4, respectively, excluding the control group. The study revealed that 8 mg/kg octacosanol effectively enhances growth and feed utilization in C. quadricarinatus, while also improving ovarian performance by increasing hepatosomatic index (HSI), gonadosomatic index (GSI), and condition factor (CF). Additionally, it decreased levels of MDA and NO in crayfish. Supplementation with 16 mg/kg octacosanol boosted antioxidant capacity by enhancing activities of T-AOC and SOD, as well as influencing nonspecific immune enzymes in the hepatopancreas at doses of D3 (12 mg/kg) and D4 (16 mg/kg). Furthermore, it positively impacted GLU and protein profiles while reducing levels of T-BIL, T-CHOL, TG, LDL-c, and VLDL-c in crayfish. These dietary interventions also regulated gene expression associated with reproduction, lipid metabolism, antioxidants, and immune response in various organs of C. quadricarinatus. Octacosanol demonstrated potential as a safe and effective feed additive. According to quadratic regression analysis, nutritional supplementation of octacosanol at 9 mg/kg diet is considered the recommended dosage in the red claw crayfish diet. [ABSTRACT FROM AUTHOR]

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This study investigates the intricate mechanisms underlying the correlation between elevated consumption of harmful fats and the onset of kidney malignancies. The rise in global obesity rates has been accompanied by an increased prevalence of renal cancers, prompting an exploration into the molecular pathways and biological processes linking these phenomena. Through an extensive review of current literature and clinical studies, we identify potential key factors contributing to the carcinogenic influence of harmful fats on renal tissues. Our analysis highlights the role of adipose tissue-derived factors, inflammatory mediators, and lipid metabolism dysregulation in fostering a microenvironment conducive to renal tumorigenesis. Furthermore, we delve into the impact of harmful fats on signaling pathways associated with cell proliferation, apoptosis evasion, and angiogenesis within the renal parenchyma. This review underscores the importance of elucidating the molecular intricacies linking lipid metabolism and kidney malignancies, offering a foundation for future research and the development of targeted preventive and therapeutic interventions. The findings discussed herein contribute to our understanding of the complex relationship between lipid mediators and renal cancer, providing a basis for public health strategies aimed at mitigating the impact of harmful fats on kidney health. [ABSTRACT FROM AUTHOR]

The miRNAs regulate various biological processes in the mammalian body system. The role of miR-181a in the development, progression, and expansion of cancers is well-documented. However, the role of miR-181a in adipogenesis; lipid metabolism; obesity; and obesity-related issues such as diabetes mellitus needs to be explored. Therefore, in the present study, the literature was searched and bioinformatics tools were applied to explore the role of miR-181a in adipogenesis. The list of adipogenic and lipogenic target genes validated through different publications were extracted and compiled. The network and functional analysis of these target genes was performed through in-silico analysis. The mature sequence of miR-181a of different species were extracted from and were found highly conserved among the curated species. Additionally, we also used various bioinformatics tools such as target gene extraction from Targetscan, miRWalk, and miRDB, and the list of the target genes from these different databases was compared, and common target genes were predicted. These common target genes were further subjected to the enrichment score and KEGG pathways analysis. The enrichment score of the vital KEGG pathways of the target genes is the key regulator of adipogenesis, lipogenesis, obesity, and obesity-related syndromes in adipose tissues. Therefore, the information presented in the current review will explore the regulatory roles of miR-181a in fat tissues and its associated functions and manifestations. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction associated fatty liver disease (MAFLD) is an increasing public health problem, affecting one third of the global population. Contrary to conventional wisdom, MAFLD is not exclusive to obese or overweight individuals. Epidemiological studies have revealed a remarkable prevalence among healthy weight individuals, leading investigations into the genetic, lifestyle, and dietary factors that contribute to the development of MAFLD in this population. This shift in perspective requires reconsideration of preventive strategies, diagnostic criteria and therapeutic approaches tailored to address the unique characteristics of MAFLD healthy weight individuals. It also underscores the importance of widespread awareness and education, within the medical community and among the general population, to promote a more inclusive understanding of liver metabolic disorders. With this review, we aim to provide a comprehensive exploration of MAFLD in healthy weight individuals, encompassing epidemiological, pathophysiological, and clinical aspects. [ABSTRACT FROM AUTHOR]

A spontaneously occurring temperature increase in solid tumors has been reported sporadically, but is largely overlooked in terms of cancer biology. Here we show that temperature is increased in tumors of patients with pancreatic ductal adenocarcinoma (PDAC) and explore how this could affect therapy response. By mimicking this observation in PDAC cell lines, we demonstrate that through adaptive changes in lipid metabolism, the temperature increase found in human PDAC confers protection to lipid peroxidation and contributes to gemcitabine resistance. Consistent with the recently uncovered role of p38 MAPK in ferroptotic cell death, we find that the reduction in lipid peroxidation potential following adaptation to tumoral temperature allows for p38 MAPK inhibition, conferring chemoresistance. As an increase in tumoral temperature is observed in several other tumor types, our findings warrant taking tumoral temperature into account in subsequent studies related to ferroptosis and therapy resistance. More broadly, our findings indicate that tumoral temperature affects cancer biology. The development of cancer is typically accompanied by changes in the tumor microenvironment that support tumor growth and affect therapy response. Here, the authors show that increased intratumoral temperature is an inherent feature of human pancreatic cancer and contributes to therapy resistance by altering the lipid content of the tumor. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are a class of cells with self-renewal and multi-directional differentiation potential, which are present in most tumors, particularly in aggressive tumors, and perform a pivotal role in recurrence and metastasis and are expected to be one of the important targets for tumor therapy. Studies of tumor metabolism in recent years have found that the metabolic characteristics of CSCs are distinct from those of differentiated tumor cells, which are unique to CSCs and contribute to the maintenance of the stemness characteristics of CSCs. Moreover, these altered metabolic profiles can drive the transformation between CSCs and non-CSCs, implying that these metabolic alterations are important markers for CSCs to play their biological roles. The identification of metabolic changes in CSCs and their metabolic plasticity mechanisms may provide some new opportunities for tumor therapy. In this paper, we review the metabolism-related mechanisms of CSCs in order to provide a theoretical basis for their potential application in tumor therapy. [ABSTRACT FROM AUTHOR]

Background: Hepatic steatosis is characterized by lipid accumulation in hepatocytes. Cheong-sang-gyeon-tong-tang is a major prescription for all types of headaches in traditional East Asian medicine. Objective: This study aimed to investigate the pharmacological effects of Cheong-sang-gyeon-tong-tang extract (CG) on high-fat diet (HFD)-induced hepatic steatosis in mice and to explore the underlying mechanism. Results: Treatment with CG significantly reduced body weight, liver weight, and epididymal fat mass, as well as improved the serum and hepatic lipid profiles in the HFD-induced fatty liver mouse model. Further, CG alleviated lipid accumulation in HFD-fed mice by controlling lipid metabolism, including triglyceride and cholesterol synthesis, and fatty acid oxidation at the mRNA level. CG also regulated the expression of cholesterol regulatory proteins in HFD-induced fatty liver mice. Conclusions: These results indicate that CG alleviates hepatic steatosis by regulating cholesterol homeostasis in HFD-induced fatty liver mice, thus improving our understanding of the mechanisms by which CG improves hepatic steatosis. Therefore, we propose CG as a therapeutic candidate for lipid metabolic disorders such as fatty liver disease. [ABSTRACT FROM AUTHOR]

Physical inactivity as well as breakfast skipping is known as risk factor for various metabolic diseases, such as obesity and type 2 diabetes. We have previously reported that a breakfast skipping model, in which the timing of feeding is delayed, induces abnormal lipid metabolism by altering the circadian rhythm of lipid metabolism-related genes in rats. The purpose of this study was to elucidate the synergistic effect of physical inactivity and breakfast skipping on lipid metabolism. We adopted sciatic neurectomized rats as physically inactive models, because we confirmed that the rats mildly decreased their spontaneous locomotor activity compared to sham-operated rats. And then the physically inactive model rats were fed a mild high-fat diet during zeitgeber time (ZT) 12–0 in the control group and ZT16–0 in the breakfast skipping group for 11 days. Body weight gain and total food intake were similar in both groups. Breakfast skipping induced a significant visceral fat accumulation, which was not observed in our previous breakfast skipping or physically inactive studies. The mRNA levels of clock and lipogenesis-related genes were altered by breakfast skipping in the liver and epididymal adipose tissue, and serum insulin level was altered by breakfast skipping. These results suggest that physical inactivity and breakfast skipping synergistically induces drastic visceral fat accumulation due to the alteration of circadian clock and lipid metabolism in the liver and adipose tissue. Therefore, regular feeding timing plays an important role in the health of a sedentary modern society. [ABSTRACT FROM AUTHOR]

Migration is one of the most extreme and energy demanding life history strategies to have evolved in the animal kingdom. In birds, champions of long-distance migrations, the seasonal emergence of the migratory phenotype is characterised by rapid physiological and metabolic remodelling, including substantial accumulation of fat stores and increases in nocturnality. The molecular underpinnings and brain adaptations to seasonal migrations remain poorly understood. Here, we exposed Common quails (Coturnix coturnix) to controlled changes in day length to simulate southward autumn migration, and then blocked the photoperiod until birds entered the non-migratory wintering phase. We first performed de novo RNA-Sequencing from selected brain samples (hypothalamus) collected from birds at a standardised time at night, either in a migratory state (when restlessness was highest and at their body mass peak), or in a non-migratory state and conducted differential gene expression and functional pathways analyses. We found that the migratory state was associated with up-regulation of a few, yet functionally well defined, gene expression networks implicated in fat trafficking, protein and carbohydrate metabolism. Further analyses that focused on candidate genes (apolipoprotein H or APOH, lysosomal associated membrane protein-2 or LAMP2) from samples collected during the day or night across the entire study population suggested differences in the expression of these genes depending on the time of the day with the largest expression levels being found in the migratory birds sampled at night. We also found that expression of APOH was positively associated with levels of nocturnal activity in the migratory birds; such an association was absent within the non-migratory birds. Our results provide novel experimental evidence revealing that hypothalamic changes in expression of apolipoprotein pathways, which regulate the circulatory transport of lipids, are likely key regulatory activators of nocturnal migratory movements. Our study paves the way for performing deeper functional investigations on seasonal molecular remodelling underlying the development of the migratory phenotype. [ABSTRACT FROM AUTHOR]

Osteonecrosis of the femoral head (ONFH) is a common orthopedic disease characterized by disability and deformity. To better understand ONFH at molecular level and to explore the possibility of early diagnosis, instead of diagnosis based on macroscopic spatial characteristics, a matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) method was developed for ONFH disease for the first time. The most challenging step for ONFH MSI is to deal with human bone tissues which are much harder than the other biological samples studied by the reported MSI studies. In this work, the MSI sectioning method of hard bone tissues was established using tender acids and a series of test criteria. Small-molecule metabolites, such as lipids and amino acids, were detected in bone sections, realizing the in situ detection of spatial distribution of biometabolites. By comparing the distribution of metabolites from different regions of normal femoral head, ONFH bone tissue (ONBT), and adjacent ONFH bone tissue (ANBT), the whole process of femoral head from normal stage to necrosis was monitored and visualized at molecular level. Moreover, this developed MSI method was used for metabolomics study of ONFH. 72 differential metabolites were identified, suggesting that disturbances in energy metabolism and lipid metabolism affected the normal life activities of osteoblasts and osteoclasts. This study provides new perspectives for future pathological studies of ONFH. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) is an inflammatory disease of the pancreas. Despite of a steadily increasing in morbidity and mortality, there is still no effective therapy. Gut microbial dysbiosis and its derived-metabolites disorder have been shown to play an important role in the development of AP, however, little is known regarding the crosstalk between gut microbiota and metabolites. In this study, we assessed the alterations in gut microbiota and metabolites by constructing three AP mouse models by means of metagenomic and metabolomic sequencing, and further clarified their relationship by correlation analysis. The results revealed that each model exhibited unique flora and metabolite profiles. KEGG analysis showed that the differential flora and metabolite-enriched pathway functions were correlated with lipid metabolism and amino acid metabolism. Moreover, two core differential bacterial species on Burkholderiales bacterium YL45 and Bifidobacterium pseudolongum along with eleven differential metabolites appeared to exert certain effects during the course of AP. In conclusion, further exploration of the crosstalk between microbiota and derived metabolites may provide novel insights and strategies into the diagnosis and treatment of AP. [ABSTRACT FROM AUTHOR]

Biofilms are considered a basal resource with high nutritional quality in stream food webs, as periphytic algae are abundant of polyunsaturated fatty acids (PUFAs). PUFAs are essential for growth and reproduction of consumers who cannot or have very limited capacity to biosynthesize. Yet, how the nutritional quality based on PUFA of basal food sources changes with light intensity remains unclear. We conducted a manipulative experiment in mesocosms to explore the response and mechanisms of nutritional quality to shading, simulating riparian restoration. We found a significant increase in PUFA% (including arachidonic acid, ARA) under shading conditions. The increased PUFA is caused by the algal community succession from Cyanobacteria and Chlorophyta to Bacillariophyta which is abundant of PUFA (especially eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA). On the other hand, shading increased PUFA via upregulating enzymes such as Δ12 desaturase (FAD2, EC:1.14.19.6) and 3-ketoacyl-CoA synthase (KCS, EC:2.3.1.199) in the biosynthesis of unsaturated fatty acid elongation pathways. Our findings imply that riparian reforestation by decreasing light intensity increases the nutritional quality of basal resources in streams, which may enhance transfer of good quality carbon to consumers in higher trophic levels through bottom-up effects. [ABSTRACT FROM AUTHOR]

Fatty acid-binding protein 4 (FABP4) plays an essential role in metabolism and inflammation. However, the role of FABP4 in alcoholic steatohepatitis (ASH) remains unclear. This study aimed to investigate the function and underlying mechanisms of FABP4 in the progression of ASH. We first obtained alcoholic hepatitis (AH) datasets from the National Center for Biotechnology Information–Gene Expression Omnibus database and conducted bioinformatics analysis to identify critical genes in the FABP family. We then established ASH models of the wild-type (WT) and Fabp4-deficient (Fabp4−/−) mice to investigate the role of FABP4 in ASH. Additionally, we performed transcriptional profiling of mouse liver tissue and analyzed the results using integrative bioinformatics. The FABP4-associated signaling pathway was further verified. FABP4 was upregulated in two AH datasets and was thus identified as a critical biomarker for AH. FABP4 expression was higher in the liver tissues of patients with alcoholic liver disease and ASH mice than in the corresponding control samples. Furthermore, the Fabp4−/− ASH mice showed reduced hepatic lipid deposition and inflammation compared with the WT ASH mice. Mechanistically, Fabp4 may be involved in regulating the p53 and sirtuin-1 signaling pathways, subsequently affecting lipid metabolism and macrophage polarization in the liver of ASH mice. Our results demonstrate that Fabp4 is involved in the progression of ASH and that Fabp4 deficiency may ameliorate ASH. Therefore, FABP4 may be a potential therapeutic target for ASH treatment. [ABSTRACT FROM AUTHOR]

TMEM106B is an endolysosomal transmembrane protein not only associated with multiple neurological disorders including frontotemporal dementia, Alzheimer's disease, and hypomyelinating leukodystrophy but also potentially involved in COVID-19. Additionally, recent studies have identified amyloid fibrils of C-terminal TMEM106B in both aged healthy and neurodegenerative brains. However, so far little is known about physiological functions of TMEM106B in the endolysosome and how TMEM106B is involved in a wide range of human conditions at molecular levels. Here, we performed lipidomic analysis of the brain of TMEM106B-deficient mice. We found that TMEM106B deficiency significantly decreases levels of two major classes of myelin lipids, galactosylceramide and its sulfated derivative sulfatide. Subsequent co-immunoprecipitation assay showed that TMEM106B physically interacts with galactosylceramidase. We also found that galactosylceramidase activity was significantly increased in TMEM106B-deficient brains. Thus, our results suggest that TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism and have implications for TMEM106B-associated diseases. Unbiased lipidomic and proteomic analyses reveal that TMEM106B, an endolysosomal protein associated with many neurological disorders including frontotemporal dementia, regulates myelin lipid metabolism by interacting with galactosylceramidase. [ABSTRACT FROM AUTHOR]

In the intricate landscape of the tumor microenvironment, tumor-associated macrophages (TAMs) emerge as a ubiquitous cellular component that profoundly affects the oncogenic process. The microenvironment of hepatocellular carcinoma (HCC) is characterized by a pronounced infiltration of TAMs, underscoring their pivotal role in modulating the trajectory of the disease. Amidst the evolving therapeutic paradigms for HCC, the strategic reprogramming of metabolic pathways presents a promising avenue for intervention, garnering escalating interest within the scientific community. Previous investigations have predominantly focused on elucidating the mechanisms of metabolic reprogramming in cancer cells without paying sufficient attention to understanding how TAM metabolic reprogramming, particularly lipid metabolism, affects the progression of HCC. In this review article, we intend to elucidate how TAMs exert their regulatory effects via diverse pathways such as E2F1-E2F2-CPT2, LKB1-AMPK, and mTORC1-SREBP, and discuss correlations of TAMs with these processes and the characteristics of relevant pathways in HCC progression by consolidating various studies on TAM lipid uptake, storage, synthesis, and catabolism. It is our hope that our summary could delineate the impact of specific mechanisms underlying TAM lipid metabolic reprogramming on HCC progression and provide useful information for future research on HCC and the development of new treatment strategies. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (Mtb), the tuberculosis-causing agent, exhibits diverse genetic lineages, with known links to virulence. While genomic and transcriptomic variations between modern and ancient Mtb lineages have been explored, the role of small non-coding RNA (sRNA) in post-translational gene regulation remains largely uncharted. In this study, Mtb Lineage 1 (L1) Sabahan strains (n = 3) underwent sRNA sequencing, revealing 351 sRNAs, including 23 known sRNAs and 328 novel ones identified using ANNOgesic. Thirteen sRNAs were selected based on the best average cut-off value of 300, with RT-qPCR revealing significant expression differences for sRNA 1 (p = 0.0132) and sRNA 29 (p = 0.0012) between Mtb L1 and other lineages (L2 and L4, n = 3) (p > 0.05). Further characterization using RACE (rapid amplification of cDNA ends), followed by target prediction with TargetRNA3 unveils that sRNA 1 (55 base pairs) targets Rv0506, Rv0697, and Rv3590c, and sRNA 29 (86 base pairs) targets Rv33859c, Rv3345c, Rv0755c, Rv0107c, Rv1817, Rv2950c, Rv1181, Rv3610c, and Rv3296. Functional characterization with Mycobrowser reveals these targets involved in regulating intermediary metabolism and respiration, cell wall and cell processes, lipid metabolism, information pathways, and PE/PPE. In summary, two novel sRNAs, sRNA 1 and sRNA 29, exhibited differential expression between L1 and other lineages, with predicted roles in essential Mtb functions. These findings offer insights into Mtb regulatory mechanisms, holding promise for the development of improved tuberculosis treatment strategies in the future. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is a prevalent complication of diabetes mellitus characterized by cardiac dysfunction and myocardial remodeling. Farrerol (FA), an active ingredient in Rhododendron with various pharmacological activities, has an unclear specific role in DCM. Therefore, this study aims to investigate the effects of FA on DCM rats and elucidate its mechanism. The type 2 diabetes mellitus (T2DM) model was induced in adult male Sprague-Dawley rats by administering a high-fat diet for 8 weeks along with STZ injection. Subsequent to successful modeling, FA and the positive drug Dapagliflozin (Dapa) were orally administered via gavage for an additional 8-week period. After administration, the rats' body weight, fasting blood glucose, fasting insulin, and blood lipid profiles were quantified. Cardiac function was assessed through evaluation of cardiac function parameters, histopathological examination and measurement of myocardial enzyme markers were conducted to assess myocardial injury and fibrosis, Oil red O staining was utilized to evaluate myocardial lipid accumulation, wheat germ agglutinin (WGA) staining was used for assessing cardiomyocyte hypertrophy, and Western blot analysis was used to detect the proteins expression level of AMP-activated protein kinase (AMPK) pathway. The rat cardiomyocyte H9c2 were induced with palmitic acid to establish an in vitro cell model of myocardial lipid toxicity. Subsequently, the cells were subjected to treatment with FA and AMPK inhibitor Compound C, followed by assessment of lipid formation and expression levels of proteins related to the AMPK signaling pathway. The findings demonstrated that both FA and Dapa exhibited efficacy in ameliorating diabetic symptoms, cardiac dysfunction, myocardial fibrosis, cardiomyocyte hypertrophy, and lipid accumulation in T2DM rats. Additionally, they were found to enhance AMPK phosphorylation and PPARα expression while down-regulating CD36. Similarly, FA was observed to inhibit lipid formation in H9c2 and activate the AMPK signaling pathway. However, the improved effect of FA on lipotoxic cardiomyocytes induced by palmitic acid was partially reversed by Compound C. Therefore, the activation of the AMPK signaling pathway by FA may enhance cardiac lipid metabolism, thereby improving cardiac dysfunction and myocardial fibrosis in DCM rats. [ABSTRACT FROM AUTHOR]

Background: The complexity of cancer is intricately linked to its multifaceted biological processes, including the roles of the tumor microenvironment (TME) as well as genetic and metabolic regulation. Histone lactylation has recently emerged as a novel epigenetic modification mechanism that plays a pivotal role in regulating cancer initiation, proliferation, invasion, and metastasis. Objective: This review aims to elucidate the role of histone lactylation in modulating various aspects of tumor biology, including DNA repair mechanisms, glycolytic metabolic abnormalities, functions of non-tumor cells in the TME, and the promotion of tumor inflammatory responses and immune escape. Additionally, the review explores potential therapeutic strategies targeting histone lactylation. Methods: A comprehensive literature review was performed, analyzing recent findings on histone lactylation and its impact on cancer biology. This involved a systematic examination of studies focusing on biochemical pathways, cellular interactions, and clinical implications related to histone lactylation. Results: Histone lactylation was identified as a critical regulator of tumor cell DNA repair mechanisms and glycolytic metabolic abnormalities. It also significantly influences the functions of non-tumor cells within the TME, promoting tumor inflammatory responses and immune escape. Moreover, histone lactylation acts as a multifunctional biological signaling molecule impacting immune responses within the TME. Various cell types within the TME, including T cells and macrophages, were found to regulate tumor growth and immune escape mechanisms through lactylation. Conclusion: Histone lactylation offers a novel perspective on tumor metabolism and its role in cancer development. It presents promising opportunities for the development of innovative cancer therapies. This review underscores the potential of histone lactylation as a therapeutic target, paving the way for new strategies in cancer treatment. [ABSTRACT FROM AUTHOR]

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a protein that regulates low-density lipoprotein (LDL) cholesterol metabolism by binding to the hepatic LDL receptor (LDLR), ultimately leading to its lysosomal degradation and an increase in LDL cholesterol (LDLc) levels. Treatment strategies have been developed based on blocking PCSK9 with specific antibodies (alirocumab, evolocumab) and on blocking its production with small regulatory RNA (siRNA) (inclisiran). Clinical trials evaluating these drugs have confirmed their high efficacy in reducing serum LDLc levels and improving the prognosis in patients with atherosclerotic cardiovascular diseases. Most studies have focused on the action of PCSK9 on LDLRs and the subsequent increase in LDLc concentrations. Increasing evidence suggests that the adverse cardiovascular effects of PCSK9, particularly its atherosclerotic effects on the vascular wall, may also result from mechanisms independent of its effects on lipid metabolism. PCSK9 induces the expression of pro-inflammatory cytokines contributing to inflammation within the vascular wall and promotes apoptosis, pyroptosis, and ferroptosis of cardiomyocytes and is thus involved in the development and progression of heart failure. The elimination of PCSK9 may, therefore, not only be a treatment for hypercholesterolaemia but also for atherosclerosis and other cardiovascular diseases. The mechanisms of action of PCSK9 in the cardiovascular system are not yet fully understood. This article reviews the current understanding of the mechanisms of PCSK9 action in the cardiovascular system and its contribution to cardiovascular diseases. Knowledge of these mechanisms may contribute to the wider use of PCSK9 inhibitors in the treatment of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

In understanding stress response mechanisms in fungi, cold stress has received less attention than heat stress. However, cold stress has shown its importance in various research fields. The following study examined the cold stress response of six Pseudogymnoascus spp. isolated from various biogeographical regions through a proteomic approach. In total, 2541 proteins were identified with high confidence. Gene Ontology enrichment analysis showed diversity in the cold stress response pathways for all six Pseudogymnoascus spp. isolates, with metabolic and translation-related processes being prominent in most isolates. 25.6% of the proteins with an increase in relative abundance were increased by more than 3.0-fold. There was no link between the geographical origin of the isolates and the cold stress response of Pseudogymnoascus spp. However, one Antarctic isolate, sp3, showed a distinctive cold stress response profile involving increased flavin/riboflavin biosynthesis and methane metabolism. This Antarctic isolate (sp3) was also the only one that showed decreased phospholipid metabolism in cold stress conditions. This work will improve our understanding of the mechanisms of cold stress response and adaptation in psychrotolerant soil microfungi, with specific attention to the fungal genus Pseudogymnoascus. [ABSTRACT FROM AUTHOR]

Abstract Cerebral palsy (CP) is a prevalent neurological disorder that imposes a significant burden on children, families, and society worldwide. Recently, the RhoB p.S73F mutation was identified as a de novo mutation associated with CP. However, the mechanism by which the RhoB p.S73F mutation causes CP is currently unclear. In this study, rabbit models were generated to mimic the human RhoB p.S73F mutation using the SpG-BE4max system, and exhibited the typical symptoms of human CP, such as periventricular leukomalacia and spastic-dystonic diplegia. Further investigation revealed that the RhoB p.S73F mutation could activate ACAT1 through the LYN pathway, and the subsequently altered lipid levels may lead to neuronal and white matter damage resulting in the development of CP. This study presented the first mammalian model of genetic CP that accurately replicates the RhoB p.S73F mutation in humans, provided further insights between RhoB and lipid metabolism, and novel therapeutic targets for human CP.

Abstract Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vulnerabilities to be targeted or used as biomarkers with clinical value. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation which is facilitated by the presence of polyunsaturated fatty acids (PUFA). Here we identify fatty acid desaturases 1 and 2 (FADS1/2), which are responsible for PUFA biosynthesis, to be highly expressed in a subset of TNBC with a poorer prognosis. Lipidomic analysis, coupled with functional metabolic assays, showed that FADS1/2 high-expressing TNBC are susceptible to ferroptosis-inducing agents and that targeting FADS1/2 by both genetic interference and pharmacological approach renders those tumors ferroptosis-resistant while unbalancing PUFA/MUFA ratio by the supplementation of exogenous PUFA sensitizes resistant tumors to ferroptosis induction. Last, inhibiting lipid droplet (LD) formation and turnover suppresses the buffering capacity of LD and potentiates iron-dependent cell death. These findings have been validated in vitro and in vivo in mouse- and human-derived clinically relevant models and in a retrospective cohort of TNBC patients.

Liver cancer is the 4th most lethal form of cancer with a poor prognosis for patients worldwide. Dysregulation of lipid metabolism is related to FA oxidation alternation which can be modified by peroxisome proliferator-activated receptor-α (PPARα). Therefore, it is important to identify the lipid metabolism-related genes regulated by PPARα in liver cancer. Hub genes related to the lipid metabolism pathway of HCC samples treated with PPARα agonist (WY-14,643) were identified through a weighted gene co-expression network analysis (WGCNA). Gene expression and clinical information were obtained from the Gene Expression Omnibus (GEO) database. The network of top main hub genes was visualized by the Cytoscape software using MCODE and CytoHubba plugins. Finally, the expression and clinical association of each hub gene were evaluated using enrichment analysis, TCGA data, GEPIA, GSCA, and q-PCR. Based on our results, the top 5 co-expressed genes including (CPT2, ACSL1, ACSL3, ACOX1, and SLC27A2) were selected as the main hub genes participating in fatty acid metabolism, fatty acid beta-oxidation, and PPAR signaling pathway. All association of higher ACSL3 expression with lower outcomes and survival rates was detected in HCC patients. Therefore, lipid metabolism-related Hub genes regulated by PPARα are potential biomarkers, and they may offer a therapeutical foundation for targeted therapy directed against the HCC antitumor strategy. [ABSTRACT FROM AUTHOR]

Hydroxylated fatty acids are important intermediates in lipid metabolism and signaling. Surprisingly, the metabolism of 4-hydroxy fatty acids remains largely unexplored. We found that both ACAD10 and ACAD11 unite two enzymatic activities to introduce these metabolites into mitochondrial and peroxisomal β-oxidation, respectively. First, they phosphorylate 4-hydroxyacyl-CoAs via a kinase domain, followed by an elimination of the phosphate to form enoyl-CoAs catalyzed by an acyl-CoA dehydrogenase (ACAD) domain. Studies in knockout cell lines revealed that ACAD10 preferentially metabolizes shorter chain 4-hydroxy fatty acids than ACAD11 (i.e. 6 carbons versus 10 carbons). Yet, recombinant proteins showed comparable activity on the corresponding 4-hydroxyacyl-CoAs. This suggests that the localization of ACAD10 and ACAD11 to mitochondria and peroxisomes, respectively, might influence their physiological substrate spectrum. Interestingly, we observed that ACAD10 is cleaved internally during its maturation generating a C-terminal part consisting of the ACAD domain, and an N-terminal part comprising the kinase domain and a haloacid dehalogenase (HAD) domain. HAD domains often exhibit phosphatase activity, but negligible activity was observed in the case of ACAD10. Yet, inactivation of a presumptive key residue in this domain significantly increased the kinase activity, suggesting that this domain might have acquired a regulatory function to prevent accumulation of the phospho-hydroxyacyl-CoA intermediate. Taken together, our work reveals that 4-hydroxy fatty acids enter mitochondrial and peroxisomal fatty acid β-oxidation via two enzymes with an overlapping substrate repertoire. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) is the most prevalent malignant tumor among women worldwide and a significant cause of cancer-related deaths in females. Recent studies have shown that lipid metabolism-related genes (LMRGs) exhibit prognostic potential in various types of tumors, including BC. Our study aimed to establish a novel model to predict the metastasis of BC. Methods: Clinical information and corresponding RNA data of patients with BC were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. Consensus clustering was performed to identify novel molecular subgroups. Estimation of Stromal and Immune Cells in Malignant Tumor Tissues using Expression, microenvironment cell populations counter, microenvironment cell populations counter, and single-sample gene set enrichment analyses were employed to determine the tumor immune microenvironment and immune status of the identified subgroups. Functional analyses, including Gene Ontology and gene set enrichment analyses, were conducted to elucidate the underlying mechanisms. A prognostic risk model was constructed using the Least Absolute Shrinkage and Selection Operator algorithm and multivariate Cox regression analysis. Results: This study identified differential gene expression between patients with BC exhibiting metastasis and those without metastasis using public databases. Using the obtained data, we established predictive models based on six LMRGs. Furthermore, consensus clustering and prognostic score grouping analysis revealed that differentially expressed LMRGs influence tumor prognosis by regulating tumor immunity. To facilitate clinical application, we developed a nomogram integrating the risk model and clinical characteristics to accurately predict the prognosis of patients with BC. Conclusion: We developed and validated a novel signature associated with LMRGs for predicting disease-free survival in patients with BC. The expression of LMRGs correlates with the immune microenvironment of patients with BC, providing new insights and improved strategies for the diagnosis and treatment of BC. [ABSTRACT FROM AUTHOR]