Function (Oxford, England)最新文献

{"title":"Driver Mutations of Pancreatic Cancer Affect Ca²⁺ Signaling and ATP Production.","authors":"Kinga B Stopa, Filip Łoziński, Agnieszka A Kusiak, Jacek Litewka, Daria Krzysztofik, Sylwester Mosiołek, Jan Morys, Paweł E Ferdek, Monika A Jakubowska","doi":"10.1093/function/zqad035","DOIUrl":"10.1093/function/zqad035","url":null,"abstract":"<p><p>Glandular pancreatic epithelia of the acinar or ductal phenotype may seem terminally differentiated, but they are characterized by remarkable cell plasticity. Stress-induced trans-differentiation of these cells has been implicated in the mechanisms of carcinogenesis. Current consensus links pancreatic ductal adenocarcinoma with onco-transformation of ductal epithelia, but under the presence of driver mutations in <i>Kras</i> and <i>Trp53</i>, also with trans-differentiation of pancreatic acini. However, we do not know when, in the course of cancer progression, physiological functions are lost by mutant acinar cells, nor can we assess their capacity for the production of pancreatic juice components. Here, we investigated whether two mutations-Kras^G12D and Trp53^R172H-present simultaneously in acinar cells of KPC mice (model of oncogenesis) influence cytosolic Ca²⁺ signals. Since Ca²⁺ signals control the cellular handling of digestive hydrolases, any changes that affect intracellular signaling events and cell bioenergetics might have an impact on the physiology of the pancreas. Our results showed that physiological doses of acetylcholine evoked less regular Ca²⁺ oscillations in KPC acinar cells compared to the control, whereas responses to supramaximal concentrations were markedly reduced. Menadione elicited Ca²⁺ signals of different frequencies in KPC cells compared to control cells. Finally, Ca²⁺ extrusion rates were significantly inhibited in KPC cells, likely due to the lower basal respiration and ATP production. Cumulatively, these findings suggest that driver mutations affect the signaling capacity of pancreatic acinar cells even before the changes in the epithelial cell morphology become apparent.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10413928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10006228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure and Function of RhoBTB1 Required for Substrate Specificity and Cullin-3 Ubiquitination.","authors":"Gaurav Kumar,&nbsp;Shi Fang,&nbsp;Daria Golosova,&nbsp;Ko-Ting Lu,&nbsp;Daniel T Brozoski,&nbsp;Ibrahim Vazirabad,&nbsp;Curt D Sigmund","doi":"10.1093/function/zqad034","DOIUrl":"10.1093/function/zqad034","url":null,"abstract":"<p><p>We identified Rho-related BTB domain containing 1 (RhoBTB1) as a key regulator of phosphodiesterase 5 (PDE5) activity, and through PDE5, a regulator of vascular tone. We identified the binding interface for PDE5 on RhoBTB1 by truncating full-length RhoBTB1 into its component domains. Co-immunoprecipitation analyses revealed that the C-terminal half of RhoBTB1 containing its two BTB domains and the C-terminal domain (B1B2C) is the minimal region required for PDE5 recruitment and subsequent proteasomal degradation via Cullin-3 (CUL3). The C-terminal domain was essential in recruiting PDE5 as constructs lacking this region could not participate in PDE5 binding or proteasomal degradation. We also identified Pro³⁵³ and Ser³⁶³ as key amino acid residues in the B1B2C region involved in CUL3 binding to RhoBTB1. Mutation of either of these residues exhibited impaired CUL3 binding and PDE5 degradation, although the binding to PDE5 was preserved. Finally, we employed ascorbate peroxidase 2 (APEX2) proximity labeling using a B1B2C-APEX2 fusion protein as bait to capture unknown RhoBTB1 binding partners. Among several B1B2C-binding proteins identified and validated, we focused on SET domain containing 2 (SETD2). SETD2 and RhoBTB1 directly interacted, and the level of SETD2 increased in response to pharmacological inhibition of the proteasome or Cullin complex, CUL3 deletion, and RhoBTB1-inhibition with siRNA. This suggests that SETD2 is regulated by the RhoBTB1-CUL3 axis. Future studies will determine whether SETD2 plays a role in cardiovascular function.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10413933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10400406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal Epidermal Growth Factor Promotes Neonatal Claudin-2 Dependent Increases in Small Intestinal Calcium Permeability.","authors":"Megan R Beggs,&nbsp;Kennedi Young,&nbsp;Allen Plain,&nbsp;Debbie D O'Neill,&nbsp;Ahsan Raza,&nbsp;Veit Flockerzi,&nbsp;Henrik Dimke,&nbsp;R Todd Alexander","doi":"10.1093/function/zqad033","DOIUrl":"10.1093/function/zqad033","url":null,"abstract":"<p><p>A higher concentration of calcium in breast milk than blood favors paracellular calcium absorption enabling growth during postnatal development. We aimed to determine whether suckling animals have greater intestinal calcium permeability to maximize absorption and to identify the underlying molecular mechanism. We examined intestinal claudin expression at different ages in mice and in human intestinal epithelial (Caco-2) cells in response to hormones or human milk. We also measured intestinal calcium permeability in wildtype, <i>Cldn2</i> and <i>Cldn12</i> KO mice and Caco-2 cells in response to hormones or human milk. Bone mineralization in mice was assessed by μCT. Calcium permeability across the jejunum and ileum of mice were 2-fold greater at 2 wk than 2 mo postnatal age. At 2 wk, <i>Cldn2</i> and <i>Cldn12</i> expression were greater, but only <i>Cldn2</i> KO mice had decreased calcium permeability compared to wildtype. This translated to decreased bone volume, cross-sectional thickness, and tissue mineral density of femurs. Weaning from breast milk led to a 50% decrease in <i>Cldn2</i> expression in the jejunum and ileum. Epidermal growth factor (EGF) in breast milk specifically increased only CLDN2 expression and calcium permeability in Caco-2 cells. These data support intestinal permeability to calcium, conferred by claudin-2, being greater in suckling mice and being driven by EGF in breast milk. Loss of the CLDN2 pathway leads to suboptimal bone mineralization at 2 wk of life. Overall, EGF-mediated control of intestinal claudin-2 expression contributes to maximal intestinal calcium absorption in suckling animals.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1e/06/zqad033.PMC10413934.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10006231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Responses of Normal Rat Kidneys to a High Salt Intake.","authors":"Satoshi Shimada, Brian R Hoffmann, Chun Yang, Theresa Kurth, Andrew S Greene, Mingyu Liang, Ranjan K Dash, Allen W Cowley","doi":"10.1093/function/zqad031","DOIUrl":"10.1093/function/zqad031","url":null,"abstract":"<p><p>In this study, novel methods were developed, which allowed continuous (24/7) measurement of arterial blood pressure and renal blood flow in freely moving rats and the intermittent collection of arterial and renal venous blood to estimate kidney metabolic fluxes of O₂ and metabolites. Specifically, the study determined the effects of a high salt (HS; 4.0% NaCl) diet upon whole kidney O₂ consumption and arterial and renal venous plasma metabolomic profiles of normal Sprague-Dawley rats. A separate group of rats was studied to determine changes in the cortex and outer medulla tissue metabolomic and mRNAseq profiles before and following the switch from a 0.4% to 4.0% NaCl diet. In addition, targeted mRNA expression analysis of cortical segments was performed. Significant changes in the metabolomic and transcriptomic profiles occurred with feeding of the HS diet. A progressive increase of kidney O₂ consumption was found despite a reduction in expression of most of the mRNA encoding enzymes of TCA cycle. A novel finding was the increased expression of glycolysis-related genes in Cx and isolated proximal tubular segments in response to an HS diet, consistent with increased release of pyruvate and lactate from the kidney to the renal venous blood. Data suggests that aerobic glycolysis (eg, Warburg effect) may contribute to energy production under these circumstances. The study provides evidence that kidney metabolism responds to an HS diet enabling enhanced energy production while protecting from oxidative stress and injury. Metabolomic and transcriptomic analysis of kidneys of Sprague-Dawley rats fed a high salt diet.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10413938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10134598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"APOE4, Age, and Sex Regulate Respiratory Plasticity Elicited by Acute Intermittent Hypercapnic-Hypoxia.","authors":"Jayakrishnan Nair, Joseph F Welch, Alexandria B Marciante, Tingting Hou, Qing Lu, Emily J Fox, Gordon S Mitchell","doi":"10.1093/function/zqad026","DOIUrl":"10.1093/function/zqad026","url":null,"abstract":"<p><strong>Rationale: </strong>Acute intermittent hypoxia (AIH) shows promise for enhancing motor recovery in chronic spinal cord injuries and neurodegenerative diseases. However, human trials of AIH have reported significant variability in individual responses.</p><p><strong>Objectives: </strong>Identify individual factors (eg, genetics, age, and sex) that determine response magnitude of healthy adults to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH).</p><p><strong>Methods: </strong>In 17 healthy individuals (age = 27 ± 5 yr), associations between individual factors and changes in the magnitude of AIHH (15, 1-min O2 = 9.5%, CO2 = 5% episodes) induced changes in diaphragm motor-evoked potential (MEP) amplitude and inspiratory mouth occlusion pressures (P0.1) were evaluated. Single nucleotide polymorphisms (SNPs) in genes linked with mechanisms of AIH induced phrenic motor plasticity (<i>BDNF, HTR2A, TPH2, MAOA, NTRK2</i>) and neuronal plasticity (apolipoprotein E, <i>APOE</i>) were tested. Variations in AIHH induced plasticity with age and sex were also analyzed. Additional experiments in humanized (h)<i>ApoE</i> knock-in rats were performed to test causality.</p><p><strong>Results: </strong>AIHH-induced changes in diaphragm MEP amplitudes were lower in individuals heterozygous for <i>APOE4</i> (i.e., <i>APOE3</i>/<i>4</i>) compared to individuals with other <i>APOE</i> genotypes (<i>P</i> = 0.048) and the other tested SNPs. Males exhibited a greater diaphragm MEP enhancement versus females, regardless of age (<i>P</i> = 0.004). Additionally, age was inversely related with change in P0.1 (<i>P</i> = 0.007). In h<i>ApoE4</i> knock-in rats, AIHH-induced phrenic motor plasticity was significantly lower than h<i>ApoE3</i> controls (<i>P</i> < 0.05).</p><p><strong>Conclusions: </strong><i>APOE4</i> genotype, sex, and age are important biological determinants of AIHH-induced respiratory motor plasticity in healthy adults.</p><p><strong>Addition to knowledge base: </strong>AIH is a novel rehabilitation strategy to induce functional recovery of respiratory and non-respiratory motor systems in people with chronic spinal cord injury and/or neurodegenerative disease. Figure 5 Since most AIH trials report considerable inter-individual variability in AIH outcomes, we investigated factors that potentially undermine the response to an optimized AIH protocol, AIHH, in healthy humans. We demonstrate that genetics (particularly the lipid transporter, <i>APOE</i>), age and sex are important biological determinants of AIHH-induced respiratory motor plasticity.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/78/79/zqad026.PMC10413930.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10019366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Skeletal Muscle Consequences of Phosphatidylethanolamine Synthesis Deficiency.","authors":"Sophie Grapentine,&nbsp;Rathnesh K Singh,&nbsp;Marica Bakovic","doi":"10.1093/function/zqad020","DOIUrl":"10.1093/function/zqad020","url":null,"abstract":"<p><p>The maintenance of phospholipid homeostasis is increasingly being implicated in metabolic health. Phosphatidylethanolamine (PE) is the most abundant phospholipid on the inner leaflet of cellular membranes, and we have previously shown that mice with a heterozygous ablation of the PE synthesizing enzyme, Pcyt2 (<i>Pcyt2^+/-</i>), develop obesity, insulin resistance, and NASH. Skeletal muscle is a major determinant of systemic energy metabolism, making it a key player in metabolic disease development. Both the total PE levels and the ratio of PE to other membrane lipids in skeletal muscle are implicated in insulin resistance; however, the underlying mechanisms and the role of Pcyt2 regulation in this association remain unclear. Here, we show how reduced phospholipid synthesis due to Pcyt2 deficiency causes <i>Pcyt2^+/-</i> skeletal muscle dysfunction and metabolic abnormalities. <i>Pcyt2^+/-</i> skeletal muscle exhibits damage and degeneration, with skeletal muscle cell vacuolization, disordered sarcomeres, mitochondria ultrastructure irregularities and paucity, inflammation, and fibrosis. There is intramuscular adipose tissue accumulation, and major disturbances in lipid metabolism with impaired FA mobilization and oxidation, elevated lipogenesis, and long-chain fatty acyl-CoA, diacylglycerol, and triacylglycerol accumulation. <i>Pcyt2^+/-</i> skeletal muscle exhibits perturbed glucose metabolism with elevated glycogen content, impaired insulin signaling, and reduced glucose uptake. Together, this study lends insight into the critical role of PE homeostasis in skeletal muscle metabolism and health with broad implications on metabolic disease development.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/0c/ed/zqad020.PMC10278983.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9713067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precision Medicine in Pancreatitis: The Future of Acute Pancreatitis Care.","authors":"Andras Garami, Peter Hegyi","doi":"10.1093/function/zqad015","DOIUrl":"10.1093/function/zqad015","url":null,"abstract":"<p><p>Acute pancreatitis (AP) continues to present a substantial burden to patients and healthcare personnel. Despite its occasionally severe progression and high mortality rate, there is no specific therapy that could be routinely applied in patients with AP. Here, we review treatment possibilities in AP, describe how the treatment approaches have changed in pancreatic cancer as an analogy, and point out potential causes for the failure of clinical trials on AP. We highlight that instead of attempting to discover generalized treatment options that could be used in any AP patient, it is time for a paradigm shift in the treatment of AP, which would help to focus more on individual patients or specific patient subpopulations when designing clinical trials and therapeutic approaches (similarly as in pancreatic cancer). Since the recruitment of specific patient subpopulations with AP could take excessive time if clinical centers work separately, the development of precision medicine in AP would require to establish an expert committee, eg, Pancreatitis Precision Medicine Interest Group, which could organize and coordinate the activities of the joined centers. With the joined forces of expert clinicians and leading centers, a new era could start in the treatment of AP, in which personalized treatment options could be discovered and introduced to efficiently reduce the burden of the disease on patients and healthcare workers.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9f/1d/zqad015.PMC10165548.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9479234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Refining the Treatment of Pancreatic Cancer From Big Data to Improved Individual Survival.","authors":"Peter Bailey, Xu Zhou, Jingyu An, Teresa Peccerella, Kai Hu, Christoph Springfeld, Markus Büchler, John P Neoptolemos","doi":"10.1093/function/zqad011","DOIUrl":"10.1093/function/zqad011","url":null,"abstract":"<p><p>Pancreatic cancer is one of the most lethal cancers worldwide, most notably in Europe and North America. Great strides have been made in combining the most effective conventional therapies to improve survival at least in the short and medium term. The start of treatment can only be made once a diagnosis is made, which at this point, the tumor volume is already very high in the primary cancer and systemically. If caught at the earliest opportunity (in circa 20% patients) surgical resection of the primary followed by combination chemotherapy can achieve 5-year overall survival rates of 30%-50%. A delay in detection of even a few months after symptom onset will result in the tumor having only borderline resectabilty (in 20%-30% of patients), in which case the best survival is achieved by using short-course chemotherapy before tumor resection as well as adjuvant chemotherapy. Once metastases become visible (in 40%-60% of patients), cure is not possible, palliative cytotoxics only being able to prolong life by few months. Even in apparently successful therapy in resected and borderline resectable patients, the recurrence rate is very high. Considerable efforts to understand the nature of pancreatic cancer through large-scale genomics, transcriptomics, and digital profiling, combined with functional preclinical models, using genetically engineered mouse models and patient derived organoids, have identified the critical role of the tumor microenvironment in determining the nature of chemo- and immuno-resistance. This functional understanding has powered fresh and exciting approaches for the treatment of this cancer.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9b/ed/zqad011.PMC10165547.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9479231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia Resistance Is an Inherent Phenotype of the Mouse Flexor Digitorum Brevis Skeletal Muscle.","authors":"Adam J Amorese, Everett C Minchew, Michael D Tarpey, Andrew T Readyoff, Nicholas C Williamson, Cameron A Schmidt, Shawna L McMillin, Emma J Goldberg, Zoe S Terwilliger, Quincy A Spangenburg, Carol A Witczak, Jeffrey J Brault, E Dale Abel, Joseph M McClung, Kelsey H Fisher-Wellman, Espen E Spangenburg","doi":"10.1093/function/zqad012","DOIUrl":"10.1093/function/zqad012","url":null,"abstract":"<p><p>The various functions of skeletal muscle (movement, respiration, thermogenesis, etc.) require the presence of oxygen (O₂). Inadequate O₂ bioavailability (ie, hypoxia) is detrimental to muscle function and, in chronic cases, can result in muscle wasting. Current therapeutic interventions have proven largely ineffective to rescue skeletal muscle from hypoxic damage. However, our lab has identified a mammalian skeletal muscle that maintains proper physiological function in an environment depleted of O₂. Using mouse models of <i>in vivo</i> hindlimb ischemia and <i>ex vivo</i> anoxia exposure, we observed the preservation of force production in the flexor digitorum brevis (FDB), while in contrast the extensor digitorum longus (EDL) and soleus muscles suffered loss of force output. Unlike other muscles, we found that the FDB phenotype is not dependent on mitochondria, which partially explains the hypoxia resistance. Muscle proteomes were interrogated using a discovery-based approach, which identified significantly greater expression of the transmembrane glucose transporter GLUT1 in the FDB as compared to the EDL and soleus. Through loss-and-gain-of-function approaches, we determined that GLUT1 is necessary for the FDB to survive hypoxia, but overexpression of GLUT1 was insufficient to rescue other skeletal muscles from hypoxic damage. Collectively, the data demonstrate that the FDB is uniquely resistant to hypoxic insults. Defining the mechanisms that explain the phenotype may provide insight towards developing approaches for preventing hypoxia-induced tissue damage.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2023-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/80/55/zqad012.PMC10165545.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10130679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Do Endogenously Produced and Dietary ω-3 Fatty Acids Act Differently?","authors":"Philip C Calder","doi":"10.1093/function/zqad009","DOIUrl":"10.1093/function/zqad009","url":null,"abstract":"Omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) are a family of fatty acids distinguished by the presence of the double bond closest to the methyl terminus of the acyl chain being on carbon number 3 counting from the methyl terminal carbon. There are several members of the ω-3 PUFA family. Usually, the most common ω-3 PUFA in the human diet is α-linolenic acid (ALA; 18:3ω-3), an essential fatty acid made in plants from the ω-6 PUFA linoleic acid (LA; 18:2ω-3) by an enzymatic conversion catalyzed by delta-15 desaturase (Figure 1). Animals do not possess the latter enzyme, so they cannot make ALA. Nevertheless, once consumed in the diet, ALA can be converted by animals into long-chain, more unsaturated ω-3 PUFAs, including eicosapentaenoic acid (EPA; 20:5ω-3), docosapentaenoic acid (DPA; 22:5ω-3), and docosahexaenoic acid (DHA: 22:6ω-3) (Figure 1). EPA and DHA are biologically active, influencing cell membrane structure, intracellular signaling pathways, gene expression, and lipid mediator synthesis.1 DPA is less well studied but seems to have similar actions to EPA and DHA. Amongst dietary sources, EPA and DHA are found in the highest amounts in fatty fish; they are also present in fish oil-type supplements. EPA and DHA are linked to many health benefits, including reducing the risk of cardiovascular disease and mortality2; these effects are due to beneficial modification of a number of risk factors.3 There is also evidence that EPA and DHA might reduce the risk of developing nonalcoholic fatty liver disease, through effects on hepatic carbohydrate and fat metabolism and on inflammation.4 In general, case-control studies and longitudinal cohort studies provide stronger evidence for the benefits of EPA and DHA on disease outcomes, with findings from randomized controlled trials in patients at risk of, or already with, disease being inconsistent. Circulating and cell and tissue EPA, DPA, and DHA could come directly from the diet or from endogenous biosynthesis starting with ALA as substrate and using the pathway shown in Figure 1. In people with very low or no intake of seafood and not using supplements that contain EPA, DPA, and DHA, it seems likely that much of the body’s EPA, DPA, and DHA are produced through endogenous biosynthesis.5 Thus, a major role of ALA is as a precursor to its more bioactive ω-3 PUFA derivatives. Endogenous biosynthesis is likely to be downregulated when there is more EPA, DPA, and DHA in the diet.6 However, the relative contributions of diet and endogenous biosynthesis to EPA, DPA, and DHA levels in any compartment or pool within the body are not known. Furthermore, whether the origin of these fatty acids affects their biological action is not well studied. A recent paper published in Function starts to address these questions using murine models.7 Daniel et al.7 use wild-type C57Bl/6 mice and fat-1 mice. The latter are transgenic mice expressing the fat-1 gene from Caenorhabditis elegans, which encodes an enzyme with ","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9479233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}