Enzymes Of Fatty Acid Metabolism Research Articles

Vitamin B5 is a context-dependent dietary regulator of nociception.

Chronic pain has an enormous impact on the quality of life of billions of patients, families, and caregivers worldwide. Current therapies do not adequately address pain for most patients. A basic understanding of the conserved genetic framework controlling pain may help us develop better, non-addictive pain therapies. Here we identify new conserved and druggable analgesic targets using tissue-specific functional genomic screening of candidate "pain" genes in the fly. From these efforts we describe 23 new pain genes for further consideration. This included Acsl, a fatty acid-metabolizing enzyme and mammalian orthologs are involved in arachidonic acid metabolism. Acsl knockdown and mutant larvae showed delayed nocifensive responses to localized and global noxious heat. Mechanistically, knockdown of Acsl reduced dendritic branching of nociceptive neurons. Surprisingly, the pain phenotype in these animals could be rescued through dietary intervention with vitamin B5, highlighting the interplay between genetics, metabolism and nutrient environment to establish sensory perception thresholds. Together, our functional genomic screening within the sensory nociceptor has identified new nociception genes that provide a better understanding of pain biology and can help guide the development of new painkillers.

Role of ACSBG1 in brain lipid metabolism and X-linked adrenoleukodystrophy pathogenesis: Insights from a knockout mouse model.

The "bubblegum" acyl-CoA synthetase (ACSBG1) is a pivotal player in lipid metabolism during the development of the mouse brain, facilitating the activation of long-chain fatty acids (LCFAs) and their integration into essential lipid species crucial for brain function. Through its enzymatic activity, ACSBG1 converts LCFAs into acyl-CoA derivatives, supporting vital processes like membrane formation, myelination, and energy production. Its regulatory role significantly influences neuronal growth, synaptic plasticity, and overall brain development, highlighting its importance in maintaining lipid homeostasis and proper brain function. Originally discovered in the fruit fly brain, ACSBG1 attracted attention for its potential implication in X-linked adrenoleukodystrophy (XALD) pathogenesis. Studies using Drosophila melanogaster lacking the ACSBG1 homolog, bubblegum, revealed adult neurodegeneration with elevated levels of very long-chain fatty acids (VLCFA). To explore ACSBG1's role in fatty acid (FA) metabolism and its relevance to XALD, we created an ACSBG1 knockout (Acsbg1-/-) mouse model and examined its impact on lipid metabolism during mouse brain development. Phenotypically, Acsbg1-/- mice resembled wild type (w.t.) mice. Despite its primary expression in tissues affected by XALD, brain, adrenal gland and testis, ACSBG1 depletion did not significantly reduce total ACS enzyme activity in these tissues when using LCFA or VLCFA as substrates. However, analysis unveiled intriguing developmental and compositional changes in FA levels associated with ACSBG1 deficiency. In the adult mouse brain, ACSBG1 expression peaked in the cerebellum, with lower levels observed in other brain regions. Developmentally, ACSBG1 expression in the cerebellum was initially low during the first week of life but increased dramatically thereafter. Cerebellar FA levels were assessed in both w.t. and Acsbg1-/- mouse brains throughout development, revealing notable differences. While saturated VLCFA levels were typically high in XALD tissues and in fruit flies lacking ACSBG1, cerebella from Acsbg1-/- mice displayed lower saturated VLCFA levels, especially after about 8 days of age. Additionally, monounsaturated ω9 FA levels exhibited a similar trend as saturated VLCFA, while ω3 polyunsaturated FA levels were elevated in Acsbg1-/- mice. Further analysis of specific FA levels provided additional insights into potential roles for ACSBG1. Notably, the decreased VLCFA levels in Acsbg1-/- mice primarily stemmed from changes in C24:0 and C26:0, while reduced ω9 FA levels were mainly observed in C18:1 and C24:1. ACSBG1 depletion had minimal effects on saturated long-chain FA or ω6 polyunsaturated FA levels but led to significant increases in specific ω3 FA, such as C20:5 and C22:5. Moreover, the impact of ACSBG1 deficiency on the developmental expression of several cerebellar FA metabolism enzymes, including those required for synthesis of ω3 polyunsaturated FA, was assessed; these FA can potentially be converted into bioactive signaling molecules like eicosanoids and docosanoids. In conclusion, despite compelling circumstantial evidence, it is unlikely that ACSBG1 directly contributes to the pathology of XALD. Instead, the effects of ACSBG1 knockout on processes regulated by eicosanoids and/or docosanoids should be further investigated.

Transcriptome analysis of Acinetobacter calcoaceticus HX09 strain with outstanding crude-oil-degrading ability.

Microbial remediation plays a pivotal role in the elimination of petroleum pollutants, making it imperative to investigate the capabilities of microorganisms in degrading petroleum. The present study describes the isolation of a promising strain, Acinetobacter sp. HX09, from petroleum-contaminated water. GC-MS analysis revealed a remarkable removal efficiency for short and medium-chain alkanes, with a rate of approximately 64% after a 7-days incubation at 30 °C. Transcriptome analysis of HX09 exhibited a predominant upregulation in gene expression levels by the induce of crude oil. Notably, genes such as alkane 1-monooxygenase, dehydrogenases and fatty acid metabolic enzymes exhibited fold changes range from 3.16 to 1.3. Based on the alkB gene sequences in HX09, the Phyre2 algorithm generated a three-dimensional structure that exhibited similarity to segments of acyl coenzyme desaturases and acyl lipid desaturases. Furthermore, three biodegradation-related gene clusters were predicted in HX09 based on the reference genome sequence. These findings contribute to our understanding of the hydrocarbon-degrading mechanisms employed by Acinetobacter species and facilitate the development of effective remediation strategies for crude oil- polluted environments.

HIF3A gene disruption causes abnormal alveoli structure and early neonatal death.

Transcriptional response to changes in oxygen concentration is mainly controlled by hypoxia-inducible transcription factors (HIFs). Besides regulation of hypoxia-responsible gene expression, HIF-3α has recently been shown to be involved in lung development and in the metabolic process of fat tissue. However, the precise mechanism for such properties of HIF-3α is still largely unknown. To this end, we generated HIF3A gene-disrupted mice by means of genome editing technology to explore the pleiotropic role of HIF-3α in development and physiology. We obtained adult mice carrying homozygous HIF3A gene mutations with comparable body weight and height to wild-type mice. However, the number of litters and ratio of homozygous mutation carriers born from the mating between homozygous mutant mice was lower than expected due to sporadic deaths on postnatal day 1. HIF3A gene-disrupted mice exhibited abnormal configuration of the lung such as a reduced number of alveoli and thickened alveolar walls. Transcriptome analysis showed, as well as genes associated with lung development, an upregulation of stearoyl-Coenzyme A desaturase 1, a pivotal enzyme for fatty acid metabolism. Analysis of fatty acid composition in the lung employing gas chromatography indicated an elevation in palmitoleic acid and a reduction in oleic acid, suggesting an imbalance in distribution of fatty acid, a constituent of lung surfactant. Accordingly, administration of glucocorticoid injections during pregnancy resulted in a restoration of normal alveolar counts and a decrease in neonatal mortality. In conclusion, these observations provide novel insights into a pivotal role of HIF-3α in the preservation of critically important structure and function of alveoli beyond the regulation of hypoxia-mediated gene expression.

Voluntary Wheel Running Reduces Cardiometabolic Risks in Female Offspring Exposed to Lifelong High-Fat, High-Sucrose Diet.

Maternal and postnatal overnutrition has been linked to an increased risk of cardiometabolic diseases in offspring. This study investigated the impact of adult-onset voluntary wheel running to counteract cardiometabolic risks in female offspring exposed to a life-long high-fat, high-sucrose (HFHS) diet. Dams were fed either an HFHS or a low-fat, low-sucrose (LFLS) diet starting from 8 wk before pregnancy and continuing throughout gestation and lactation. Offspring followed their mothers' diets. At 15 wk of age, they were divided into sedentary (Sed) or voluntary wheel running (Ex) groups, resulting in four groups: LFLS/Sed ( n = 10), LFLS/Ex ( n = 5), HFHS/Sed ( n = 6), HFHS/Ex ( n = 5). Cardiac function was assessed at 25 wk, with tissue collection at 26 wk for mitochondrial respiratory function and protein analysis. Data were analyzed using two-way ANOVA. Although maternal HFHS diet did not affect the offspring's body weight at weaning, continuous HFHS feeding postweaning resulted in increased body weight and adiposity, irrespective of the exercise regimen. HFHS/Sed offspring showed increased left ventricular wall thickness and elevated expression of enzymes involved in fatty acid transport (CD36, FABP3), lipogenesis (DGAT), glucose transport (GLUT4), oxidative stress (protein carbonyls, nitrotyrosine), and early senescence markers (p16, p21). Their cardiac mitochondria displayed lower oxidative phosphorylation (OXPHOS) efficiency and reduced expression of OXPHOS complexes and fatty acid metabolism enzymes (ACSL5, CPT1B). However, HFHS/Ex offspring mitigated these effects, aligning more with LFLS/Sed offspring. Adult-onset voluntary wheel running effectively counteracts the detrimental cardiac effects of a lifelong HFHS diet, improving mitochondrial efficiency, reducing oxidative stress, and preventing early senescence. This underscores the significant role of physical activity in mitigating diet-induced cardiometabolic risks.

Effects of paternal arachidonic acid supplementation on offspring behavior and hypothalamus inflammation markers in the mouse.

Arachidonic acid (AA) is involved in inflammation and plays a role in growth and brain development in infants. We previously showed that exposure of mouse sires to AA for three consecutive generations induces a cumulative change in fatty acid (FA) involved in inflammation and an increase in body and liver weight in the offspring. Here, we tested the hypothesis that paternal AA exposure changes the progeny's behavioral response to a proinflammatory insult, and asked whether tissue-specific FA are associated with that response. Male BALB/c mice were supplemented daily with three doses of AA for 10 days and crossed to non-supplemented females (n = 3/dose). Two-month-old unsupplemented male and female offspring (n = 6/paternal AA dose) were exposed to Gram-negative bacteria-derived lipopolysaccharides (LPS) or saline control two hours prior to open field test (OFT) behavioral analysis and subsequent sacrifice. We probed for significant effects of paternal AA exposure on: OFT behaviors; individual FA content of blood, hypothalamus and hypothalamus-free brain; hypothalamic expression profile of genes related to inflammation (Tnfa, Il1b, Cox1, Cox2) and FA synthesis (Scd1, Elovl6). All parameters were affected by paternal AA supplementation in a sex-specific manner. Paternal AA primed the progeny for behavior associated with increased anxiety, with a marked sex dimorphism: high AA doses acted as surrogate of LPS in males, realigning a number of OFT behaviors that in females were differential between saline and LPS groups. Progeny hypothalamic Scd1, a FA metabolism enzyme with documented pro-inflammatory activity, showed a similar pattern of differential expression between saline and LPS groups at high paternal AA dose in females, that was blunted in males. Progeny FA generally were not affected by LPS, but displayed non-linear associations with paternal AA doses. In conclusion, we document that paternal exposure to AA exerts long-term behavioral and biochemical effects in the progeny in a sex-specific manner.

Liver ACSM3 deficiency mediates metabolic syndrome via a lauric acid-HNF4α-p38 MAPK axis.

Metabolic syndrome combines major risk factors for cardiovascular disease, making deeper insight into its pathogenesis important. We here explore the mechanistic basis of metabolic syndrome by recruiting an essential patient cohort and performing extensive gene expression profiling. The mitochondrial fatty acid metabolism enzyme acyl-CoA synthetase medium-chain family member 3 (ACSM3) was identified to be significantly lower expressed in the peripheral blood of metabolic syndrome patients. In line, hepatic ACSM3 expression was decreased in mice with metabolic syndrome. Furthermore, Acsm3 knockout mice showed glucose and lipid metabolic abnormalities, and hepatic accumulation of the ACSM3 fatty acid substrate lauric acid. Acsm3 depletion markedly decreased mitochondrial function and stimulated signaling via the p38 MAPK pathway cascade. Consistently, Acsm3 knockout mouse exhibited abnormal mitochondrial morphology, decreased ATP contents, and enhanced ROS levels in their livers. Mechanistically, Acsm3 deficiency, and lauric acid accumulation activated nuclear receptor Hnf4α-p38 MAPK signaling. In line, the p38 inhibitor Adezmapimod effectively rescued the Acsm3 depletion phenotype. Together, these findings show that disease-associated loss of ACSM3 facilitates mitochondrial dysfunction via a lauric acid-HNF4a-p38 MAPK axis, suggesting a novel therapeutic vulnerability in systemic metabolic dysfunction.

Identification of pre-diagnostic lipid sets associated with liver cancer risk using untargeted lipidomics and chemical set analysis: A nested case-control study within the ATBC cohort.

In pre-disposed individuals, a reprogramming of the hepatic lipid metabolism may support liver cancer initiation. We conducted a high-resolution mass spectrometry based untargeted lipidomics analysis of pre-diagnostic serum samples from a nested case-control study (219 liver cancer cases and 219 controls) within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Out of 462 annotated lipids, 158 (34.2%) were associated with liver cancer risk in a conditional logistic regression analysis at a false discovery rate (FDR) <0.05. A chemical set enrichment analysis (ChemRICH) and co-regulatory set analysis suggested that 22/28 lipid classes and 47/83 correlation modules were significantly associated with liver cancer risk (FDR <0.05). Strong positive associations were observed for monounsaturated fatty acids (MUFA), triacylglycerols (TAGs) and phosphatidylcholines (PCs) having MUFA acyl chains. Negative associations were observed for sphingolipids (ceramides and sphingomyelins), lysophosphatidylcholines, cholesterol esters and polyunsaturated fatty acids (PUFA) containing TAGs and PCs. Stearoyl-CoA desaturase enzyme 1 (SCD1), a rate limiting enzyme in fatty acid metabolism and ceramidases seems to be critical in this reprogramming. In conclusion, our study reports pre-diagnostic lipid changes that provide novel insights into hepatic lipid metabolism reprogramming may contribute to a pro-cell growth and anti-apoptotic tissue environment and, in turn, support liver cancer initiation.

Maternal protein deficiency impairs peroxisome biogenesis and leads to oxidative stress and ferroptosis in liver of fetal growth restriction offspring

Maternal protein malnutrition leads to liver dysfunction and increases susceptibility to nonalcoholic fatty liver disease in adult fetal growth restriction (FGR) offspring, yet the underlying mechanism remains unknown. Peroxisomes play vital roles in fatty acid β-oxidation (FAO) and detoxification of reactive oxygen species (ROS). Using a well-defined rat model, the peroxins (PEXs), fatty acid metabolic enzymes, and oxidase stress regulators were investigated in the liver of FGR offspring. The results revealed that PEX3, 11b, 14, and 19 were obviously reduced in the fetal liver and lasted to adulthood, suggesting a decrease in the biogenesis and division of peroxisomes. FA metabolism enzymes and ferroptosis regulators were deregulated. To further investigate this association, small interfering RNA was employed to achieve knockdown (KD) of PEX14 in BRL cells (a rat hepatocyte line). PEX14 KD led to dysregulation of PEXs and long-chain FAs accumulation. PEX14 deficiency caused ROS accumulation and lipid peroxidation, finally induced regulated cell death (including apoptosis, autophagy, and ferroptosis). Double knock down (DKD) of PEX14 and fatty acyl-CoA reductase 1 (FAR1) revealed that PEX14 KD-induced ferroptosis was related with enhanced FAR1 level. DKD of PEX14 and Atg5 further confirmed that PEX14 KD-induced cell death was partly autophagy-dependent. Overall, these data demonstrate a vital role for PEX14 in maintaining peroxisome function and liver physiology, and suggest that hepatocyte peroxisome defects partly explain liver dysplasia and lipid metabolism disorders in fetal original liver disease.

LINC00116-encoded microprotein mitoregulin regulates fatty acid metabolism at the mitochondrial outer membrane

LINC00116 encodes a microprotein first identified as Mitoregulin (MTLN), where it was reported to localize to the inner membrane of mitochondria to regulate fatty acid oxidation and oxidative phosphorylation. These initial discoveries were followed by reports with differing findings about its molecular functions and submitochondrial localization. To clarify the apparent discrepancies, we constructed multiple orthogonal methods of determining the localization of MTLN, including split GFP-based reporters that enable efficient and reliable topology analyses for microproteins. These methods unequivocally demonstrate MTLN primarily localizes to the outer membrane of mitochondria, where it interacts with enzymes of fatty acid metabolism including CPT1B and CYB5B. Loss of MTLN causes the accumulation of very long-chain fatty acids (VLCFAs), especially docosahexaenoic acid (DHA). Intriguingly, loss of MTLN protects mice against western diet/fructose-induced insulin-resistance, suggests a protective effect of VLCFAs in this context. MTLN thus serves as an attractive target to control the catabolism of VLCFAs.

Effect on lipoxygenase pathway and flavor stabilization of postharvest strawberries by intense pulsed light treatment

A non-thermal pretreatment method was developed to improve the flavor stability of strawberries using an intense pulsed light during postharvest storage. The physicochemical properties, volatile organic compounds (free and bound), enzyme activities, and key gene expressions were investigated during 7-day storage. A 23.67% decrease in the decay ratio was obtained in IPL-treated with 2.0 Hz frequency for 60 s compared to the control. A more stable surface color was obtained at the end of the storage period. A total of 21 f-VOCs and 13 b-VOCs were quantitatively identified. IPL treatment promoted the contents of free aldehydes, esters, and ketones. The content of (E)− 2-heptenal in the IPL-treated strawberries was 1.90 times higher than that in control. The variation in the total content of b-VOCs was less than 31.61% that in the control group. Correspondingly, IPL treatment inhibited the activities of fatty acid metabolism enzymes and decreased LOX activity by 26.3% after storage. Aroma-related genes, including FaLOX, FaADH, and FaAAT, were down-regulated in the metabolism of specific VOCs following IPL treatment. This work provided evidence about the practical application of IPL in inhibiting the activity of enzyme in the LOX pathway, thereby improving the flavor stability of strawberries under non-thermal process conditions.

Effects of folic acid supplementation on chronic atrophic gastritis based on MTHFR C677T polymorphism.

It has been shown the methylenetetrahydrofolate reductase (MTHFR) 677TT (rs 1801133) genotype predicts histopathological alterations in the incisura of patients with chronic atrophic gastritis (CAG). MTHFR is a crucial enzyme in fatty acid (FA) metabolism. This study aimed to evaluate the influence of FA supplementation in CAG patients without Helicobacter pylori infection and the MTHFR C677T (rs 1801133) genotype as a potential CAG predictor. A total of 96 CAG patients, aged 21 to 72 years old, were enrolled in this study. After 6 months of treatment, histopathological outcomes were compared among patients treated with weifuchun (WFC) (1.44 g 3 times per os per day), those treated with WFC and FA (5 mg once daily), and those treated with WFC, FA, and vitamin B12 (VB12) (0.5 mg 3 times per day) based on the Operative Link on Gastritis/Intestinal Metaplasia assessment staging systems. Atrophic lesions in patients treated with WFC and FA improved more than in patients treated only with WFC therapy (78.1% vs 53.3%, P = .04). Atrophic or intestinal metaplasia (IM) lesions in the incisura of patients with the TT genotype were better than those in patients with the CC/CT genotype (P = .02). The treatment of CAG patients with 5 mg of FA supplements daily for 6 months improved their gastric atrophy status, especially for the Operative Link on Gastritis/Intestinal Metaplasia assessment stages I/II. Moreover, our study is the first to reveal that patients with the MTHFR 677TT genotype require more timely and effective FA treatment than those with the CC/CT genotype.

Negative correlation between acetyl-CoA acyltransferase 2 and cetuximab resistance in colorectal cancer.

The emergence of anti-EGFR therapy has revolutionized the treatment of colorectal cancer (CRC). However, not all patients respond consistently well. Therefore, it is imperative to conduct further research to identify the molecular mechanisms underlying the development of cetuximab resistance in CRC. In this study, we find that the expressions of many metabolism-related genes are downregulated in cetuximab-resistant CRC cells compared to their sensitive counterparts. Specifically, acetyl-CoA acyltransferase 2 (ACAA2), a key enzyme in fatty acid metabolism, is downregulated during the development of cetuximab resistance. Silencing of ACAA2 promotes proliferation and increases cetuximab tolerance in CRC cells, while overexpression of ACAA2 exerts the opposite effect. RTK-Kras signaling might contribute to the downregulation of ACAA2 expression in CRC, and ACAA2 predicts CRC prognosis in patients with Kras mutations. Collectively, our data suggest that modulating ACAA2 expression contributes to secondary cetuximab resistance in Kras wild-type CRC patients. ACAA2 expression is related to Kras mutation and demonstrates a prognostic role in CRC patients with Kras mutation. Thus, ACAA2 is a potential target in CRC with Kras mutation.

DDIT4 Downregulation by siRNA Approach Increases the Activity of Proteins Regulating Fatty Acid Metabolism upon Aspirin Treatment in Human Breast Cancer Cells

Repositioning of aspirin for a more effective breast cancer (BC) treatment requires identification of predictive biomarkers. However, the molecular mechanism underlying the anticancer activity of aspirin remains fully undefined. Cancer cells enhance de novo fatty acid (FA) synthesis and FA oxidation to maintain a malignant phenotype, and the mechanistic target of rapamycin (mTORC1) is required for lipogenesis. We, therefore, aimed to test if the expression of mTORC1 suppressor DNA damage-inducible transcript (DDIT4) affects the activity of main enzymes in FA metabolism after aspirin treatment. MCF-7 and MDA-MB-468 human BC cell lines were transfected with siRNA to downregulate DDIT4. The expression of carnitine palmitoyltransferase 1 A (CPT1A) and serine 79-phosphorylated acetyl-CoA carboxylase 1 (ACC1) were analyzed by Western Blotting. Aspirin enhanced ACC1 phosphorylation by two-fold in MCF-7 cells and had no effect in MDA-MB-468 cells. Aspirin did not change the expression of CPT1A in either cell line. We have recently reported DDIT4 itself to be upregulated by aspirin. DDIT4 knockdown resulted in 1.5-fold decreased ACC1 phosphorylation (dephosphorylation activates the enzyme), 2-fold increased CPT1A expression in MCF-7 cells, and 2.8-fold reduced phosphorylation of ACC1 following aspirin exposure in MDA-MB-468 cells. Thus, DDIT4 downregulation raised the activity of main lipid metabolism enzymes upon aspirin exposure which is an undesired effect as FA synthesis and oxidation are linked to malignant phenotype. This finding may be clinically relevant as DDIT4 expression has been shown to vary in breast tumors. Our findings justify further, more extensive investigation of the role of DDIT4 in aspirin’s effect on fatty acid metabolism in BC cells.

ZFP92, a KRAB domain zinc finger protein enriched in pancreatic islets, binds to B1/Alu SINE transposable elements and regulates retroelements and genes.

Repressive KRAB domain-containing zinc-finger proteins (KRAB-ZFPs) are abundant in mammalian genomes and contribute both to the silencing of transposable elements (TEs) and to the regulation of developmental stage- and cell type-specific gene expression. Here we describe studies of zinc finger protein 92 (Zfp92), an X-linked KRAB-ZFP that is highly expressed in pancreatic islets of adult mice, by analyzing global Zfp92 knockout (KO) mice. Physiological, transcriptomic and genome-wide chromatin binding studies indicate that the principal function of ZFP92 in mice is to bind to and suppress the activity of B1/Alu type of SINE elements and modulate the activity of surrounding genomic entities. Deletion of Zfp92 leads to changes in expression of select LINE and LTR retroelements and genes located in the vicinity of ZFP92-bound chromatin. The absence of Zfp92 leads to altered expression of specific genes in islets, adipose and muscle that result in modest sex-specific alterations in blood glucose homeostasis, body mass and fat accumulation. In islets, Zfp92 influences blood glucose concentration in postnatal mice via transcriptional effects on Mafb, whereas in adipose and muscle, it regulates Acacb, a rate-limiting enzyme in fatty acid metabolism. In the absence of Zfp92, a novel TE-Capn11 fusion transcript is overexpressed in islets and several other tissues due to de-repression of an IAPez TE adjacent to ZFP92-bound SINE elements in intron 3 of the Capn11 gene. Together, these studies show that ZFP92 functions both to repress specific TEs and to regulate the transcription of specific genes in discrete tissues.

Sphingosine 1-phosphate / Acetyl CoA Carboxylase1 Axis regulates the Differentiation and Function of Tumor-associated Myeloid-Derived Suppressor Cells

Abstract The presence of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) poses a serious obstacle to cancer treatment. The bioactive lysophospholipid sphingosine 1-phosphate (S1P), which is produced by sphingosine kinases (SphK1 or SphK2), regulates tumor and T cell survival and activity. Thus, it has been targeted to improve the outcome of anti-cancer therapeutics. However, S1P has not yet been investigated in terms of how it regulates myeloid cell activity. The present study demonstrates that deletion of SphK2-mediated S1P in MDSCs favorably modifies the tumor microenvironment and renders infiltrating myeloid cells with antigen presenting phenotype, leading to increased ability to control tumor growth. Furthermore, in preclinical prostate and melanoma cancer models, the combination of PD1 antibody and SphK2 pharmacological inhibitor (ABC294640) dramatically reduced tumor growth and increased the survival of tumor bearing mice. Mechanistically, the S1P pulldown and subsequent MS-based proteomics analysis revealed that S1P binds to various proteins involved in metabolic and ribosomal biogenesis pathways. Notably, both the isoforms of Acetyl CoA Carboxylase, the rate-limiting fatty acid metabolic enzyme, binds to S1P. Furthermore, investigations using deletion, overexpression, and site-directed mutagenesis demonstrated that ACC1 activity is necessary to preserve the immunogenic capacity of SphK2 KO MDSCs. This study highlights the clinical value of manipulating MDSC suppressive activity by targeting the S1P/ACC1 axis to boost T cell-mediated tumor control and highlights the crucial function that S1P plays as an immunoregulatory mediator in MDSCs. Supported grants from NIH (R01 CA250458, R01 CA236379)

Lysophosphatidylcholine inhibits lung cancer cell proliferation by regulating fatty acid metabolism enzyme long-chain acyl-coenzyme A synthase 5.

Lung cancer is a widespread malignancy with a high death rate and disorder of lipid metabolism. Lysophosphatidylcholine (lysoPC) has anti-tumour effects, although the underlying mechanism is not entirely known. The purpose of this study aims at defining changes in lysoPC in lung cancer patients, the effects of lysoPC on lung cancer cells and molecular mechanisms. Lung cancer cell sensitivity to lysoPC was evaluated and decisive roles of long-chain acyl-coenzyme A synthase 5 (ACSL5) in lysoPC regulation were defined by comprehensively evaluating transcriptomic changes of ACSL5-downregulated epithelia. ACSL5 over-expressed in ciliated, club and Goblet cells in lung cancer patients, different from other lung diseases. LysoPC inhibited lung cancer cell proliferation, by inducing mitochondrial dysfunction, altering lipid metabolisms, increasing fatty acid oxidation and reprograming ACSL5/phosphoinositide 3-kinase/extracellular signal-regulated kinase-regulated triacylglycerol-lysoPC balance. Thus, this study provides a general new basis for the discovery of reprogramming metabolisms and metabolites as a new strategy of lung cancer precision medicine.

Revealing the mechanisms of polypyrrole (Ppy) enhancing methane production from anaerobic digestion of waste activated sludge (WAS)

Anaerobic digestion (AD) is a promising method for treating waste activated sludge (WAS), but the low methane yield limits its large-scale application. The addition of conductive nanomaterials has been demonstrated to enhance the activity of AD via promoting the direct interspecies electron transfer (DIET). In this study, novel conductive polypyrrole (Ppy) was prepared to effectively improve the AD performance of WAS. The results showed that the accumulative methane production was enhanced by 27.83% by Ppy, with both acidogenesis and methanogenesis being efficiently accelerated. The microbial community analysis indicated that the abundance of bacteria associated with acidogenesis process was significantly elevated by Ppy. Further investigation by metatranscriptomics revealed that fadE and fadN genes (to express the key enzymes in fatty acid metabolism) were highly expressed in the Ppy-driven AD, suggesting that Ppy promoted electron generation during acid production. For methanogenesis metabolism, genes related to acetate utilization and CO2 utilization methanogenesis were also up-regulated by Ppy, illustrating that Ppy facilitates the utilization of acetate and electrons by methanogenic archaea, thus potentially promoting the methanogenesis through DIET.

Identification of the Key Pathways and Genes Involved in the Wax Biosynthesis of the Chinese White Wax Scale Insect (Ericerus pela Chavannes) by Integrated Weighted Gene Coexpression Network Analysis.

The white wax secreted by the male insects of the Chinese white wax scale (CWWS) is a natural high-molecular-weight compound with important economic value. However, its regulatory mechanism of wax biosynthesis is still unclear. In this study, a weighted gene coexpression network analysis (WGCNA) was used to analyze transcriptome data of first- and second-instar females, early and late female adults, and first- and second-instar males. A total of 19 partitioned modules with different topological overlaps were obtained, and three modules were identified as highly significant for wax secretion (p < 0.05). A total of 30 hub genes were obtained through screening, among which elongation of very-long-chain fatty acids protein (ELOVL) and fatty acyl-CoA reductase (FAR) are important catalytic enzymes of fatty acid metabolism. Furthermore, their metabolic catalytic products are involved in the synthesis of wax biosynthesis. The results demonstrate that WGCNA can be used for insect transcriptome analysis and effectively screen out the key genes related to wax biosynthesis.

The PNPLA3 variant I148M reveals protective effects toward hepatocellular carcinoma in mice via restoration of omega-3 polyunsaturated fats

Alcohol consumption and high caloric diet are leading causes of progressive fatty liver disease. Genetic variant rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3 rs738409 C>G) has been repeatedly described as one of the major risk loci for alcoholic liver cirrhosis (ALC) and hepatocellular carcinoma (HCC) in humans, however, the mechanism behind this association is incompletely understood. We generated mice carrying the rs738409 variant (PNPLA3 I148M) in order to detect genotype–phenotype relationships in mice upon chow and alcohol-high fat/high sugar diet (EtOH/WD). We could clearly demonstrate that the presence of rs738409 per se is sufficient to induce spontaneous development of steatosis after 1 year in mice on a chow diet, whereas in the setting of unhealthy diet feeding, PNPLA3 I148M did not affect hepatic inflammation or fibrosis, but induced a striking lipid remodeling, microvesicular steatosis and protected from HCC formation. Using shot gun lipidomics, we detected a striking restoration of reduced long chain-polyunsaturated fatty acids (LC-PUFA)-containing TGs, docosapentaenoic acid (C22:5 n3) and omega-3-derived eicosanoids (5-HEPE, 20-HEPE, 19,20-EDP, 21-HDHA) in PNPLA3 I148M mice upon EtOH/WD. At the molecular level, PNPLA3 I148M modulated enzymes for fatty acid and TG transport and metabolism. These findings suggest (dietary) lipids as an important and independent driver of hepatic tumorigenesis. Genetic variant in PNPLA3 exerted protective effects in mice, conflicting with findings in humans. Species-related differences in physiology and metabolism should be taken into account when modeling unhealthy human lifestyle, as genetic mouse models may not always allow for translation of insight gained in humans.