Physiological genomics最新文献

{"title":"Lost in translation? Evidence for a muted proteomic response to thermal stress in a stenothermal Antarctic fish and possible evolutionary mechanisms.","authors":"W Wesley Dowd, Dietmar Kültz","doi":"10.1152/physiolgenomics.00051.2024","DOIUrl":"10.1152/physiolgenomics.00051.2024","url":null,"abstract":"<p><p>Stenothermal Antarctic notothenioid fishes are noteworthy for their history of isolation in extreme cold and their corresponding lack of the canonical heat shock response. Despite extensive transcriptomic studies, the mechanistic basis for stenothermy has not been fully elucidated. Given that the proteome better represents an organism's physiology, the possibility exists that some aspects of stenothermy arise posttranscriptionally. Here, Antarctic emerald rockcod (<i>Trematomus bernacchii</i>) were sampled after exposure to chronic and/or acute high temperatures, followed by a thorough assessment of proteomic responses in the brain, gill, and kidney. Few cellular stress response proteins were induced, and overall responses were modest in terms of the numbers of differentially expressed proteins and their fold changes. Inconsistencies in protein induction across treatments and tissues are suggestive of dysregulation, rather than an adaptive response. Changes in regulation of the translational machinery in Antarctic notothenioids could explain these patterns. Some components of translational regulatory pathways are highly conserved [e.g., Ser-52, eukaryotic translation initiation factor 2α (eIF2α)], but other proteins comprising the cellular \"integrated stress response,\" specifically, the eIF2α kinases general control nonderepressible 2 (GCN2) and PKR-like endoplasmic reticulum kinase (PERK), may have evolved along different trajectories in Antarctic fishes. Taken together, these observations suggest a novel hypothesis for stenothermy and the absence of a coordinated cellular stress response in Antarctic fishes.<b>NEW & NOTEWORTHY</b> Antarctic fishes have some of the lowest known heat tolerances among vertebrates, but the molecular mechanisms underlying this pattern are not fully understood. By combining detailed analyses of protein expression patterns in several tissues under various heat treatments with a broader evolutionary perspective, this study offers a novel hypothesis to explain the narrow range of temperature tolerance in this extraordinary group of fishes.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"721-740"},"PeriodicalIF":2.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of SNP-SNP interactions of surfactant protein genes with severity of respiratory syncytial virus infection in children.","authors":"Chintan K Gandhi, Lynnlee C Depicolzuane, Chixiang Chen, Catherine M Roberts, Natalie Sicher, Katelyn Johnson Wegerson, Neal J Thomas, Rongling Wu, Joanna Floros","doi":"10.1152/physiolgenomics.00045.2024","DOIUrl":"10.1152/physiolgenomics.00045.2024","url":null,"abstract":"<p><p>The severity of respiratory syncytial virus (RSV) may be linked to host genetic susceptibility. Surfactant protein (SP) genetic variants have been associated with RSV severity, but the impact of single-nucleotide polymorphism (SNP)-SNP interactions remains unexplored. Therefore, we used a novel statistical model to investigate the association of SNP-SNP interactions of <i>SFTP</i> genes with RSV severity in two- and three-interaction models. We analyzed available genotype and clinical data from prospectively enrolled 405 children diagnosed with RSV, categorizing them into moderate or severe RSV groups. Using Wang's statistical model, we studied significant associations of SNP-SNP interactions with RSV severity in a case-control design. We observed, first, association of three interactions with increased risk of severe RSV in a two-SNP model. One intragenic interaction was between SNPs of <i>SFTPA2</i>, and the other two were intergenic, involving SNPs of hydrophilic and hydrophobic SPs alone. We also observed, second, association of 22 interactions with RSV severity in a three-SNP model. Among these, 20 were unique, with 12 and 10 interactions associated with increased or decreased risk of RSV severity, respectively, and included at least one SNP of either <i>SFTPA1</i> or <i>SFTPA2</i>. All interactions were intergenic except one, among SNPs of <i>SFTPA1</i>. The remaining interactions were either among SNPs of hydrophilic SPs alone (<i>n</i> = 8) or among SNPs of both hydrophilic or hydrophobic SPs (<i>n</i> = 11). Our findings indicate that SNPs of all <i>SFTP</i>s may contribute to genetic susceptibility to RSV severity. However, the predominant involvement of <i>SFTPA1</i> and/or <i>SFTPA2</i> SNPs in these interactions underscores their significance in RSV severity.<b>NEW & NOTEWORTHY</b> Although surfactant protein (SP) genetic variants are associated with respiratory syncytial virus (RSV) severity, the impact of single-nucleotide polymorphism (SNP)-SNP interactions of SP genes remained unexplored. Using advanced statistical models, we uncovered 22 SNP-SNP interactions associated with RSV severity, with notable involvement of <i>SFTPA1</i> and <i>SFTPA2</i> SNPs. This highlights the comprehensive role of all SPs in genetic susceptibility to RSV severity, shedding light on potential avenues for targeted interventions.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"691-697"},"PeriodicalIF":2.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142110881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Podocyte cell-specific <i>Npr1</i> is required for blood pressure and renal homeostasis in male and female mice: role of sex-specific differences.","authors":"Chandramohan Ramasamy, Kandasamy Neelamegam, Samivel Ramachandran, Huijing Xia, Daniel R Kapusta, Farhad R Danesh, Kailash N Pandey","doi":"10.1152/physiolgenomics.00137.2023","DOIUrl":"10.1152/physiolgenomics.00137.2023","url":null,"abstract":"<p><p>Atrial and brain natriuretic peptides (ANP and BNP) bind to guanylyl cyclase A/natriuretic peptide receptor A (GC-A/NPRA), stimulating natriuresis and diuresis and reducing blood pressure (BP), but the role of ANP/NPRA signaling in podocytes (highly specialized epithelial cells covering the outer surfaces of renal glomerular capillaries) remains unclear. This study aimed to determine the effect of conditional deletion of podocyte-specific <i>Npr1</i> (encoding NPRA) gene knockout (KO) in male and female mice. Tamoxifen-treated wild-type control (PD <i>Npr1</i> f/f; WT), heterozygous (PD-Cre-<i>Npr1</i> f/+; HT), and KO (PD-Cre-<i>Npr1</i> f/-) mice were fed a normal-, low-, or high-salt diet for 4 wk. Podocytes isolated from HT and KO male and female mice showed complete absence of <i>Npr1</i> mRNA and NPRA protein compared with WT mice. BP, plasma creatinine, plasma sodium, urinary protein, and albumin/creatinine ratio were significantly increased, whereas plasma total protein, albumin, creatinine clearance, and urinary sodium levels were significantly reduced in the HT and KO male and female mice compared with WT mice. These changes were significantly greater in males than in females. On a normal-salt diet, glomerular filtration rate was significantly decreased in PD <i>Npr1</i> HT and KO male and female mice compared with WT mice. Immunofluorescence of podocin and synaptopodin was also significantly reduced in HT and KO mice compared with WT mice. These observations suggest that in podocytes, ANP/NPRA signaling may be crucial in the maintenance and regulation of glomerular filtration and BP and serve as a biomarker of renal function in a sex-dependent manner.<b>NEW & NOTEWORTHY</b> Our results demonstrate that the podocyte-specific deletion of <i>Npr1</i> showed increased blood pressure (BP) and altered biomarkers of renal functions, with greater magnitudes in animals fed a high-salt diet in a sex-dependent manner. The results suggest a direct and sex-dependent effect of <i>Npr1</i> ablation in podocytes on the regulation of BP and renal function and reveal that podocytes may be considered an important target for the ANP-BNP/NPRA/cGMP signaling cascade.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"672-690"},"PeriodicalIF":2.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gill ionocyte remodeling mediates blood pH regulation in rockfish (<i>Sebastes diploproa</i>) exposed to environmentally relevant hypercapnia.","authors":"Garfield T Kwan, Alexander M Clifford, Kaelan J Prime, Till S Harter, Martin Tresguerres","doi":"10.1152/physiolgenomics.00057.2024","DOIUrl":"10.1152/physiolgenomics.00057.2024","url":null,"abstract":"<p><p>Marine fishes excrete excess H⁺ using basolateral Na⁺-K⁺-ATPase (NKA) and apical Na⁺/H⁺ exchanger 3 (NHE3) in gill ionocytes. However, the mechanisms that regulate H⁺ excretion during exposure to environmentally relevant hypercapnia (ERH) remain poorly understood. Here, we explored transcriptomic, proteomic, and cellular responses in gills of juvenile splitnose rockfish (<i>Sebastes diploproa</i>) exposed to 3 days of ERH conditions (pH ∼7.5, ∼1,600 μatm Pco₂). Blood pH was fully regulated at ∼7.75 despite a lack of significant changes in gill <i>1</i>) mRNAs coding for proteins involved in blood acid-base regulation, <i>2</i>) total NKA and NHE3 protein abundance, and <i>3</i>) ionocyte density. However, ERH-exposed rockfish demonstrated increased NKA and NHE3 abundance on the ionocyte plasma membrane coupled with wider apical membranes and greater extension of apical microvilli. The observed gill ionocyte remodeling is consistent with enhanced H⁺ excretion that maintains blood pH homeostasis during exposure to ERH and does not necessitate changes at the expression or translation levels. These mechanisms of phenotypic plasticity may allow fishes to regulate blood pH during environmentally relevant acid-base challenges and thus have important implications for both understanding how organisms respond to climate change and for selecting appropriate metrics to evaluate its impact on marine ecosystems.<b>NEW & NOTEWORTHY</b> Splitnose rockfish exposed to environmentally relevant hypercapnia utilize existing proteins (rather than generate additional machinery) to maintain homeostasis.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"661-671"},"PeriodicalIF":2.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142000558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A matter of food and substrain: obesogenic diets induce differential severity of cardiac remodeling in C57Bl/6J and C57Bl/6N substrains.","authors":"Lorena Cascarano, Hrag Esfahani, Pierre Michel, Caroline Bouzin, Chantal Dessy, Jean-Luc Balligand, Lauriane Y M Michel","doi":"10.1152/physiolgenomics.00044.2024","DOIUrl":"10.1152/physiolgenomics.00044.2024","url":null,"abstract":"<p><p>The prevalence of metabolic syndrome in cardiac diseases such as heart failure with preserved ejection fraction (HFpEF) prompts the scientific community to investigate its adverse effects on cardiac function and remodeling. However, the selection of a preclinical model of obesity-induced cardiac remodeling has proven more challenging with inconsistencies often found in very similar mouse models. Here, we investigated the implication of genetic background as well as diet composition to identify a suitable model of diet-induced cardiac alterations. C57Bl/6J and C57Bl/6N male mice were subjected to distinct obesogenic diets consisting of high-fat and moderate sucrose content (HF-S) or high-sucrose and moderate lipid content (F-HS) versus matching control diets. Five-month dietary intervention with obesogenic diets induced weight gain, adipocyte hypertrophy, and increased visceral and subcutaneous fat mass in both substrains. Obese mice showed similar impairment of glucose disposition and insulin tolerance, with both strains developing insulin resistance within 2 mo. However, echocardiographic follow-up and histological analysis confirmed that the HF-S diet increased cardiac hypertrophy, interstitial fibrosis, and left atrial area in the C57Bl/6J strain only. In contrast, the C57Bl/6N strain exhibited cardiac eccentric remodeling under control diets, possibly owing to a genetic mutation in the myosin light chain kinase 3 (<i>Mylk3</i>) gene, specific to this substrain, which was not further enhanced under obesogenic diets. Altogether, the present results highlight the importance of carefully selecting the suitable mouse strain and diets to model diet-induced cardiac remodeling. In this regard, C57Bl/6J mice develop significant cardiac remodeling in response to HF-S and seem to be a suitable model for cardiometabolic disease.<b>NEW & NOTEWORTHY</b> Metabolic syndrome is highly prevalent in cardiac pathologies. Underlying mechanisms have not been thoroughly investigated, owing to the lack of reliable preclinical model of diet-induced cardiac remodeling. Our work demonstrates that genetic variants in inbred strains influence the response to metabolic stress and identifies C57Bl/6J mice as a suitable model for cardiometabolic disease in response to high-fat diet. These findings reinforce the need to carefully select the mouse strain in relation to the imposed pathophysiologic stress.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"649-660"},"PeriodicalIF":2.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141617031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of the anti-inflammatory drug budesonide on the gut microbiota and cytokine production of 13-lined ground squirrels during pre-hibernation fattening","authors":"Kirsten Grond, Jewel Zur Tulod, Courtney C. Kurtz, Khrystyne N Duddleston","doi":"10.1152/physiolgenomics.00034.2024","DOIUrl":"https://doi.org/10.1152/physiolgenomics.00034.2024","url":null,"abstract":"Physiological Genomics, Ahead of Print. <br/>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":"7 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142200692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Then and Now in Eukaryotic DNA Methylation","authors":"Richard A. Stein, Faris E. Gomaa, Pranaya Raparla, Leise Riber","doi":"10.1152/physiolgenomics.00091.2024","DOIUrl":"https://doi.org/10.1152/physiolgenomics.00091.2024","url":null,"abstract":"Physiological Genomics, Ahead of Print. <br/>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":"3 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142200691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide comparative analyses highlight selection signatures underlying saline adaptation in Chilika buffalo.","authors":"Utsav Surati, Saket K Niranjan, Rakesh Kumar Pundir, Ymberzal Koul, Vikas Vohra, Ravi Kumar Gandham, Amod Kumar","doi":"10.1152/physiolgenomics.00028.2024","DOIUrl":"10.1152/physiolgenomics.00028.2024","url":null,"abstract":"<p><p>Chilika, a native buffalo breed of the Eastern coast of India, is mainly distributed around the Chilika brackish water lake connected with the Bay of Bengal Sea. This breed possesses a unique ability to delve deep into the salty water of the lake and stay there to feed on local vegetation of saline nature. Adaptation to salinity is a genetic phenomenon; however, the genetic basis underlying salinity tolerance is still limited in animals, specifically in livestock. The present study explores the genetic evolution that unveils the Chilika buffalo's adaptation to the harsh saline habitat, including both water and food systems. For this study, whole genome resequencing data on 18 Chilika buffalo and for comparison 10 Murrah buffalo of normal habitat were generated. For identification of selection sweeps, intrapopulation and interpopulation statistics were used. A total of 709, 309, 468, and 354 genes were detected to possess selection sweeps in Chilika buffalo using the nucleotide diversity (θπ), Tajima's D, nucleotide diversity ratio (θπ-ratio), and F_ST methods, respectively. Further analysis revealed a total of 23 genes including <i>EXOC6B</i>, <i>VPS8</i>, <i>LYPD1</i>, <i>VPS35</i>, <i>CAMKMT</i>, <i>NCKAP5</i>, <i>COMMD1</i>, myosin light chain kinase 3 (<i>MYLK3</i>), and <i>B3GNT2</i> were found to be common by all the methods. Furthermore, functional annotation study of identified genes provided pathways such as MAPK signaling, renin secretion, endocytosis, oxytocin signaling pathway, etc. Gene network analysis enlists that hub genes provide insights into their interactions with each other. In conclusion, this study has highlighted the genetic basis underlying the local adaptive function of Chilika buffalo under saline environment.<b>NEW & NOTEWORTHY</b> Indian Chilika buffaloes are being maintained on extensive grazing system and have a unique ability to convert local salty vegetation into valuable human food. However, adaptability to saline habitat of Chilika buffalo has not been explored to date. Here, we identified genes and biological pathways involved, such as MAPK signaling, renin secretion, endocytosis, and oxytocin signaling pathway, underlying adaptability of Chilika buffalo to saline environment. This investigation shed light on the mechanisms underlying the buffalo's resilience in its native surroundings.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"609-620"},"PeriodicalIF":2.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141470157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic drivers of age-related changes in urinary magnesium excretion.","authors":"Wouter H van Megen, Jeroen H F de Baaij, Gary A Churchill, Olivier Devuyst, Joost G J Hoenderop, Ron Korstanje","doi":"10.1152/physiolgenomics.00119.2023","DOIUrl":"10.1152/physiolgenomics.00119.2023","url":null,"abstract":"<p><p>Although age-dependent alterations in urinary magnesium (Mg²⁺) excretion have been described, the underlying mechanism remains elusive. As heritability significantly contributes to variations in urinary Mg²⁺ excretion, we measured urinary Mg²⁺ excretion at different ages in a cohort of genetically variable Diversity Outbred (DO) mice. Compared with animals aged 6 mo, an increase in Mg²⁺ excretion was observed at 12 and 18 mo. Quantitative trait locus (QTL) analysis revealed an association of a locus on chromosome 10 with Mg²⁺ excretion at 6 mo of age, with <i>Oit3</i> (encoding oncoprotein-induced transcript 3; OIT3) as our primary candidate gene. To study the possible role of OIT3 in renal Mg²⁺ handling, we generated and characterized <i>Oit3</i> knockout (<i>Oit3</i>^-/-) mice. Although a slightly lower serum Mg²⁺ concentration was present in male <i>Oit3</i>^-/- mice, this effect was not observed in female <i>Oit3</i>^-/- mice. In addition, urinary Mg²⁺ excretion and the expression of renal magnesiotropic genes were unaltered in <i>Oit3</i>^-/- mice. For animals aged 12 and 18 mo, QTL analysis revealed an association with a locus on chromosome 19, which contains the gene encoding TRPM6, a known Mg²⁺ channel involved in renal Mg²⁺ reabsorption. Comparison with RNA sequencing (RNA-Seq) data revealed that <i>Trpm6</i> mRNA expression is inversely correlated with the QTL effect, implying that TRPM6 may be involved in age-dependent changes in urinary Mg²⁺ excretion in mice. In conclusion, we show here that variants in <i>Oit3</i> and <i>Trpm6</i> are associated with urinary Mg²⁺ excretion at distinct periods of life, although OIT3 is unlikely to affect renal Mg²⁺ handling.<b>NEW & NOTEWORTHY</b> Aging increased urinary magnesium (Mg²⁺) excretion in mice. We show here that variation in <i>Oit3</i>, a candidate gene for the locus associated with Mg²⁺ excretion in young mice, is unlikely to be involved as knockout of <i>Oit3</i> did not affect Mg²⁺ excretion. Differences in the expression of the renal Mg²⁺ channel TRPM6 may contribute to the variation in urinary Mg²⁺ excretion in older mice.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"634-647"},"PeriodicalIF":2.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11460537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141734914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of cholesterol homeostasis is an early signal of β-cell proteotoxicity characteristic of type 2 diabetes.","authors":"Tatyana Gurlo, Ruoshui Liu, Zhongying Wang, Jonathan Hoang, Sergey Ryazantsev, Marie Daval, Alexandra E Butler, Xia Yang, Montgomery Blencowe, Peter C Butler","doi":"10.1152/physiolgenomics.00029.2024","DOIUrl":"10.1152/physiolgenomics.00029.2024","url":null,"abstract":"<p><p>Type 2 diabetes (T2D) is a common metabolic disease due to insufficient insulin secretion by pancreatic β-cells in the context of insulin resistance. Islet molecular pathology reveals a role for protein misfolding in β-cell dysfunction and loss with islet amyloid derived from islet amyloid polypeptide (IAPP), a protein coexpressed and cosecreted with insulin. The most toxic form of misfolded IAPP is intracellular membrane disruptive toxic oligomers present in β-cells in T2D and in β-cells of mice transgenic for human IAPP (hIAPP). Prior work revealed a high degree of overlap of transcriptional changes in islets from T2D and prediabetic 9- to 10-wk-old mice transgenic for hIAPP with most changes being pro-survival adaptations and therefore of limited therapeutic guidance. Here, we investigated islets from hIAPP transgenic mice at an earlier age (6 wk) to screen for potential mediators of hIAPP toxicity that precede predominance of pro-survival signaling. We identified early suppression of cholesterol synthesis and trafficking along with aberrant intra-β-cell cholesterol and lipid deposits and impaired cholesterol trafficking to cell membranes. These findings align with comparable lipid deposits present in β-cells in T2D and increased vulnerability to develop T2D in individuals taking medications that suppress cholesterol synthesis.<b>NEW & NOTEWORTHY</b> β-Cell failure in type 2 diabetes (T2D) is characterized by β-cell misfolded protein stress due to the formation of toxic oligomers of islet amyloid polypeptide (IAPP). Most transcriptional changes in islets in T2D are pro-survival adaptations consistent with the slow progression of β-cell loss. In the present study, investigation of the islet transcriptional signatures in a mouse model of T2D expressing human IAPP revealed decreased cholesterol synthesis and trafficking as a plausible early mediator of IAPP toxicity.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"621-633"},"PeriodicalIF":2.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141470156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}