Gene Expression Profiles In Liver Research Articles

Transcriptomic and Methylomic Analyses Show Significant Shifts in Biosynthetic Processes and Reduced Intrapopulation Gene Expression Variance in PAH-Adapted Atlantic Killifish.

Environmental contaminants pose a significant selection pressure across taxa, potentiating evolved resistance to chemicals. However, rapid evolution may alter molecular and physiological homeostasis leading to trade-offs. To elucidate molecular underpinnings of evolved chemical resistance, we compared liver gene expression and methylation profiles in polycyclic aromatic hydrocarbon (PAH)-adapted Atlantic killifish (Fundulus heteroclitus) in the Republic site (RP), Elizabeth River, Virginia with PAH-sensitive Kings Creek (KC) fish. We found 1607 differentially expressed and 2252 alternatively spliced genes between RP and KC, with highly enriched genes involving lipid and amino acid metabolism, respectively. While 308 genes had differentially methylated regions, only 13 of these genes were differentially expressed. The aryl hydrocarbon receptor 2b gene (ahr2b) was differentially methylated and expressed, as well as alternatively spliced signifying its critical role in mediating PAH tolerance. Notably, the intrapopulation coefficient of variation (CoV) was lower in 82% of 17,566 expressed genes in RP fish compared to KC fish. Among other pathways, these genes with low CoV were highly enriched in bioenergetic processes inferring reduced metabolic physiological variation as a population in RP fish. Altered metabolic gene expression and overall reduced gene expression variance in RP fish warrant further studies on fitness trade-offs including altered susceptibility to other stressors associated with rapid adaptation to anthropogenic pressures.

Loss of Bicra/Gltscr1 leads to a defect in fetal liver macrophages responsible for erythrocyte maturation in mice.

GLTSCR1, a protein encoded by the Bicra gene, is a defining subunit of the SWI/SNF (also called mammalian BAF) chromatin remodeling subcomplex called GBAF/ncBAF. To determine the role of GLTSCR1 during mouse development, we generated a Bicra germline knockout mouse using CRISPR/Cas9. Mice with homozygous loss of Bicra were born at Mendelian ratios but were small, pale and died within 24 hours after birth. Histology indicated blood-related defects including defective erythroblastic islands and irregularly sized red blood cells. Gene expression profiling of fetal livers pinpointed a defect in liver resident macrophages involved in the last stage of erythrocyte maturation, resulting in accumulation of nucleated erythrocytes in Bicra-/- pups. Together, these results demonstrate that Bicra is critical for fetal liver macrophage function during development.

Assessing Alcohol Genes Targets in Mouse Liver

Background: Alcohol is a risk factor for liver diseases. There is a correlation between alcohol consumption and fatty liver disease. Experiences have shown gene expression alteration in the liver following alcohol consumption. Since the molecular mechanism of connection between alcohol consumption and fatty liver disease needs a clear perspective, this study aims to explore the significant genes that are targeted by alcohol in the liver of mice.Methods: Gene expression profiles of mice livers fed with alcohol were retrieved from the Gene Expression Omnibus (GEO) database and compared with the control samples. Data are pre-evaluated with the GEO2R program, and the significant differentially expressed genes (DEGs) are analyzed via gene expression evaluations and regulatory network assessment. Results: Among the 25619 dysregulated genes, 78 significant DEGs were pointed out. Gene expression analysis showed that most extremely dysregulated genes are up-regulated and belong to the cytochrome P450 genes family. Finally, cytochrome P450 and glutathione S-transferase genes family, as well as hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 4, were introduced as the critical targeted genes.Conclusion: In conclusion, detoxification of xenobiotics, cellular metabolism and homeostasis, the pathogenesis of some liver diseases, synthesis of several prostaglandins and steroid hormones, and inflammation fibrosis in the liver are possibly associated with alcohol consumption.

Metabolic dysfunction-associated steatohepatitis reduces interferon and macrophage liver gene signatures in patients with chronic hepatitis B

Background & AimsChronic HBV patients with concomitant metabolic dysfunction-associated steatohepatitis (MASH) have been shown to develop more advanced fibrosis faster with more severe liver disease as compared to patients with chronic HBV alone. However, our understanding of the underlying mechanisms is limited. Here we study how MASH co-morbidity impact immune activity in the liver of patients with chronic HBV infection. MethodsBulk RNA sequencing was performed on liver biopsies from patients with only MASH (n=10), only HBeAg-negative chronic HBV (ENEG; n=11), combined MASH/ENEG (n=9) and healthy controls (n=9). Biopsies with no or minimal fibrosis (≤F2) were selected to avoid confounding effects of fibrosis. We compared whole transcriptome data from patients with MASH/ENEG to those with ENEG alone to determine the impact of MASH co-morbidity on chronic hepatitis B. ResultsThere is a high degree of overlap of liver gene expression profiles in patients with only ENEG versus those with only MASH compared to healthy controls, suggesting a largely shared mechanism of liver dysfunction and immune activity for these distinct conditions. In patients with ENEG, MASH co-morbidity significantly reduced interferon pathway activity (NES=2.03, p.adj=0.0251), the expression of ISGs (e.g., IFIT2, IFI27, IFITM1, IFI6), and macrophage gene signatures (e.g., MARCO, CD163, CD5L, CD63), when compared to patients with ENEG alone. ConclusionsTranscriptomic profiling of the liver suggests that MASH negatively impacts ISGs expression in the liver of patients with ENEG, which may affect antiviral immune pathways, viral replication and inflammatory responses resulting in an increased risk of advanced fibrosis in patients with chronic hepatitis B. Our study provides valuable insights for guiding future research aimed at developing effective, tailored strategies for managing patients with both conditions. Impact and implicationsIn recent decades, obesity and associated health issues have reached epidemic levels, with steatotic liver disease affecting up to 30% of adults in developed countries, and this trend is also observed among chronic hepatitis B patients. Given the high and rising prevalence of steatotic liver disease and its frequent co-occurrence in chronic hepatitis B patients, it is essential to understand how conditions such as metabolic dysfunction-associated steatohepatitis (MASH) impact immune responses in the liver. This study provides unique insights into the impact of MASH on HBV antiviral immune activity in the liver of patients with chronic hepatitis B. The rising number of patients with both conditions affects treatment outcomes and highlights the urgent need for novel, tailored therapeutic strategies. Our study holds significant relevance for guiding future research on developing treatment strategies for patients with both MASH and chronic hepatitis B.

Toxic effects of freshwater grouper (Acrossocheilus fasciatus) eggs on poultry: Morphological and transcriptomic insights into hepatic toxicity

Fish egg poisoning is a serious and neglected public menace that kills hundreds of people and numerous poultry each year. Freshwater groupers (Acrossocheilus fasciatus) are common food fish in the southeastern regions of China. Their toxic eggs are regarded as a significant public health concern. The molecular mechanisms of egg-toxin toxicity in freshwater grouper to poisoned organisms are elusive. In this study, black-boned chicks were exposed to toxic eggs from freshwater grouper at a lethal dose. The hepatic morphology of the intoxicated chick was assessed. An analysis of the liver gene expression profile was conducted by comparing samples exposed to toxic eggs with control samples using RNA-Seq. The result revealed that an increase in vacuolation and congestion was observed in chicks with toxic eggs exposure. The transcriptome analysis revealed 5421 genes with differential expression, comprising 2810 up-regulated and 2611 down-regulated genes. The genes were primarily linked to energy metabolism, cell apoptosis, cell adhesion, exogenous microbial infection, and cell junction. The most strongly upregulated genes were cholecystokinin (CCK), cholecystokinin A receptor (CCKAR), and unc-80 homolog, NALCN activator (UNC80), and the most downregulated genes were glycine amidinotransferase (GATM), fatty acid desaturase 2 (FADS2), and hexokinase 2 (HKDC1). GO term with the highest enrichment of DEGs is nucleosome assembly. According to KEGG pathways, the three most significant metabolic pathways in the liver are DNA replication, retinol metabolism, and steroid biosynthesis. The results could be crucial for comprehending the negative biological impacts of egg-toxin and its toxic mechanisms. The outcome could provide potential biomarkers of egg-toxin exposure in hepatic, which might be useful for manufacturing an antidote to egg-toxin and providing valuable insights for ecotoxicity studies.

Comparative Screening of the Liver Gene Expression Profiles from Type 1 and Type 2 Diabetes Rat Models.

Experimental animal models of diabetes can be useful for identifying novel targets related to disease, for understanding its physiopathology, and for evaluating emerging antidiabetic treatments. This study aimed to characterize two rat diabetes models: HFD + STZ, a high-fat diet (60% fat) combined with streptozotocin administration (STZ, 35 mg/kg BW), and a model with a single STZ dose (65 mg/kg BW) in comparison with healthy rats. HFD + STZ- induced animals demonstrated a stable hyperglycemia range (350-450 mg/dL), whereas in the STZ-induced rats, we found glucose concentration values with a greater dispersion, ranging from 270 to 510 mg/dL. Moreover, in the HFD + STZ group, the AUC value of the insulin tolerance test (ITT) was found to be remarkably augmented by 6.2-fold higher than in healthy animals (33,687.0 ± 1705.7 mg/dL/min vs. 5469.0 ± 267.6, respectively), indicating insulin resistance (IR). In contrast, a more moderate AUC value was observed in the STZ group (19,059.0 ± 3037.4 mg/dL/min) resulting in a value 2.5-fold higher than the average exhibited by the control group. After microarray experiments on liver tissue from all animals, we analyzed genes exhibiting a fold change value in gene expression <-2 or >2 (p-value <0.05). We found 27,686 differentially expressed genes (DEG), identified the top 10 DEGs and detected 849 coding genes that exhibited opposite expression patterns between both diabetes models (491 upregulated genes in the STZ model and 358 upregulated genes in HFD + STZ animals). Finally, we performed an enrichment analysis of the 849 selected genes. Whereas in the STZ model we found cellular pathways related to lipid biosynthesis and metabolism, in the HFD + STZ model we identified pathways related to immunometabolism. Some phenotypic differences observed in the models could be explained by transcriptomic results; however, further studies are needed to corroborate these findings. Our data confirm that the STZ and the HFD + STZ models are reliable experimental models for human T1D and T2D, respectively. These results also provide insight into alterations in the expression of specific liver genes and could be utilized in future studies focusing on diabetes complications associated with impaired liver function.

Transcriptomics and Metabolomics Reveal Tomato Consumption Alters Hepatic Xenobiotic Metabolism and Induces Steroidal Alkaloid Metabolite Accumulation in Mice.

Tomato consumption is associated with many health benefits including lowered risk for developing certain cancers. It is hypothesized that tomato phytochemicals are transported to the liver and other tissues where they alter gene expression in ways that lead to favorable health outcomes. However, the effects of tomato consumption on mammalian liver gene expression and chemical profile are not well defined. The study hypothesizes that tomato consumption would alter mouse liver transcriptomes and metabolomes compared to a control diet. C57BL/6J mice (n = 11-12/group) are fed a macronutrient matched diet containing either 10% red tomato, 10% tangerine tomato, or no tomato powder for 6 weeks after weaning. RNA-Seq followed by gene set enrichment analyses indicates that tomato type and consumption, in general, altered expression of phase I and II xenobiotic metabolism genes. Untargeted metabolomics experiments reveal distinct clustering between control and tomato fed animals. Nineteen molecular formulas (representing 75 chemical features) are identified or tentatively identified as steroidal alkaloids and isomers of their phase I and II metabolites; many of which are reported for the first time in mammals. These data together suggest tomato consumption may impart benefits partly through enhancing detoxification potential.

Porphyra haitanensis glycoprotein regulates glucose homeostasis: targeting the liver.

In this study, we investigated the effects of glycoprotein (PG)-mediated regulation of Porphyra haitanensis on liver glucose metabolism in hyperglycemic mouse models, and sought to establish the underlying mechanism, as determined by the changes in liver gene expression and metabolic profiles. The results showed that 30-300 mg kg-1 PG upregulated the expression of the liver genes Ins1, Ins2, Insr, Gys2, Gpi1, Gck, and downregulated the expression of G6pc, G6pc2, and G6pc3, in a concentration-dependent manner. 300 mg kg-1 PG downregulated the concentrations of glucose-related metabolites in the liver, but upregulated lactic acid, 2-aminoacetic acid, and glucose-1-phosphate concentrations. It was assumed that PG regulated liver glucose metabolism by enriching insulin secretion, glycolysis/gluconeogenesis, and the AMPK signaling pathway, and promoting insulin secretion, glycogen synthesis, and glycolysis. Our findings supported the development of P. haitanensis and its glycoproteins as novel natural antidiabetic compounds that regulated blood glucose homeostasis.

Transcriptomic and lipid profiling analysis reveals a functional interplay between testosterone and growth hormone in hypothyroid liver.

Preclinical and clinical studies suggest that hypothyroidism might cause hepatic endocrine and metabolic disturbances with features that mimic deficiencies of testosterone and/or GH. The absence of physiological interactions between testosterone and GH can be linked to male differentiated liver diseases. Testosterone plays relevant physiological effects on somatotropic-liver axis and liver composition and the liver is a primary organ of interactions between testosterone and GH. However, testosterone exerts many effects on liver through complex and poorly understood mechanisms. Testosterone impacts liver functions by binding to the Androgen Receptor, and, indirectly, through its conversion to estradiol, and cooperation with GH. However, the role of testosterone, and its interaction with GH, in the hypothyroid liver, remains unclear. In the present work, the effects of testosterone, and how they impact on GH-regulated whole transcriptome and lipid composition in the liver, were studied in the context of adult hypothyroid-orchiectomized rats. Testosterone replacement positively modulated somatotropic-liver axis and impacted liver transcriptome involved in lipid and glucose metabolism. In addition, testosterone enhanced the effects of GH on the transcriptome linked to lipid biosynthesis, oxidation-reduction, and metabolism of unsaturated and long-chain fatty acids (FA). However, testosterone decreased the hepatic content of cholesterol esters and triacylglycerols and increased fatty acids whereas GH increased neutral lipids and decreased polar lipids. Biological network analysis of the effects of testosterone on GH-regulated transcriptome confirmed a close connection with crucial proteins involved in steroid and fatty acid metabolism. Taken together, this comprehensive analysis of gene expression and lipid profiling in hypothyroid male liver reveals a functional interplay between testosterone and pulsed GH administration.

Inulin-enriched Megamonas funiformis ameliorates metabolic dysfunction-associated fatty liver disease by producing propionic acid

Accumulated evidence supports the beneficial role of inulin in alleviating metabolic dysfunction-associated fatty liver disease (MAFLD) by modulating gut microbiota. However, the underlying mechanisms are not fully understood. Here we used high-fat diet (HFD)-induced laying hen model of MAFLD to investigate the effect of inulin on ameliorating MAFLD and found that the inulin-enriched Megamonas genus was inversely correlated with hepatic steatosis-related parameters. Oral administration of a newly isolated commensal bacterium by culturomics, M. funiformis CML154, to HFD-fed hens and mice ameliorated MAFLD, changed liver gene expression profiles, and increased intestinal propionate concentration. Further evidence demonstrated that the anti-MAFLD effect of M. funiformis CML154 is attributed to propionate-mediated activation of the APN-AMPK-PPARα signaling pathway, thereby inhibiting fatty acid de novo synthesis and promoting β-oxidation. These findings establish the causal relationships among inulin, M. funiformis, and MAFLD, and suggest that M. funiformis CML154 is a probiotic candidate for preventative or therapeutic intervention of MAFLD.

An entropy weight method to integrate big omics and mechanistically evaluate DILI.

DILI accounts for more than half of acute liver failure cases in the United States and is a major health care issue for the public worldwide. As investigative toxicology is playing an evolving role in the pharmaceutical industry, mechanistic insights into drug hepatotoxicity can facilitate drug development and clinical medication. By integrating multisource datasets including gene expression profiles of rat livers from open TG-GATE database and DrugMatrix, drug labels from FDA Liver Toxicity Knowledge Base, and clinical reports from LiverTox, and with the employment of bioinformatic and computational tools, this study developed an approach to characterize and predict DILI based on the molecular understanding of the processes (toxicity pathways). A panel of 11 pathways widely covering biological processes and stress responses was established using a training set of six positive and one negative DILI drugs from open TG-GATEs. An entropy weight method-based model was developed to weight responsive genes within a pathway, and an interpretable machine-learning (ML) model XGBoot-SHAP was trained to rank the importance of pathways to the panel activity. The panel activity was proven to differentiate between injured and noninjured sample points and characterize DILI manifestation using six training drugs. Next, the model was tested using an additional 89 drugs (61 positives + 28 negatives), and a precision of 86% and higher can be achieved. This study provides a novel approach to mechanisms-driven prediction modeling, as well as big data integration for insights into pharmacology and other human biology areas.

HDL functionality is dependent on hepatocyte stress defense factors Nrf1 and Nrf2.

High density lipoproteins (HDL) promote homeostasis and counteract stressful tissue damage that underlie cardiovascular and other diseases by mediating reverse cholesterol transport, reducing inflammation, and abrogating oxidative damage. However, metabolically stressful conditions associated with atherosclerosis can impair these effects. Hepatocytes play a major role in the genesis and maturation of circulating HDL, and liver stress elicits marked regulatory changes to circulating HDL abundance and composition, which affect its functionality. The mechanisms linking liver stress to HDL function are incompletely understood. In this study, we sought to determine whether stress defending transcription factors nuclear factor erythroid 2 related factor-1 (Nrf1) and -2 (Nrf2) promote hepatocyte production of functional HDL. Using genetically engineered mice briefly fed a mild metabolically stressful diet, we investigated the effect of hepatocyte-specific deletion of Nrf1, Nrf2, or both on circulating HDL cholesterol, protein composition, and function. Combined deletion, but not single gene deletion, reduced HDL cholesterol and apolipoprotein A1 levels as well as the capacity of HDL to accept cholesterol undergoing efflux from cultured macrophages and to counteract tumor necrosis factor α-induced inflammatory effect on cultured endothelial cells. This coincided with substantial alteration to the HDL proteome, which correlated with liver gene expression profiles of corresponding proteins. Thus, our findings show complementary actions by hepatocyte Nrf1 and Nrf2 play a role in shaping HDL abundance and composition to promote production of functionally viable HDL. Consequently, our study illuminates the possibility that enhancing stress defense programming in the liver may improve atheroprotective and perhaps other health promoting actions of HDL.

Trajectories of liver fibrosis and gene expression profiles in NAFLD associated with diabetes.

Understanding the mechanisms linking steatosis to fibrosis is needed to establish a promising therapy against nonalcoholic fatty liver disease (NAFLD). This study aims to clarify clinical features and hepatic gene expression signatures that predict and contribute to liver fibrosis development during the long-term real-world histological course of NAFLD subjects with and without diabetes. A pathologist scored 342 serial liver biopsy samples from 118 subjects clinically diagnosed with NAFLD during a 3.8 years (SD 3.45, maximum 15 years) course of clinical treatment (UMIN; Clinical Trials Registry, no. UMIN000035231). At the initial biopsy, 26 subjects had simple fatty liver, and 92 had nonalcoholic steatohepatitis (NASH). In the trend analysis, the Fibrosis-4 index (P < 0.001) and its components at baseline predicted the future fibrosis progression. In the generalized linear mixed model, an increase in HbA1c, but not BMI, was significantly associated with fibrosis progression (0.17 [0.009-0.326]; P = 0.038) for NAFLD subjects with diabetes. In gene set enrichment analyses, the pathways involved in hepatocytes zone 3, central liver sinusoidal endothelial cell (LSEC), stellate cells, and plasma cells were coordinately altered in association with fibrosis progression and HbA1c elevation. Therefore, in NAFLD subjects with diabetes, HbA1c elevation is significantly associated with liver fibrosis progression, independent of weight gain, which may be a valuable therapeutic target to prevent the pathological progression of NASH. Gene expression profiles suggest that diabetes-induced hypoxia and oxidative stress injure LSEC injury in zone 3, which may mediate inflammation and stellate cell activation, leading to liver fibrosis.

Qing-Zhi-Tiao-Gan-Tang (QZTGT) prevents nonalcoholic steatohepatitis (NASH) by expression pattern correction

Ethnopharmacological relevanceQing-Zhi-Tiao-Gan-Tang or Qing-Zhi-Tiao-Gan Decoction (QZTGT) is based on the compatibility theory of traditional Chinese medicine (TCM), that is a combination of three classical formulae for the treatment of nonalcoholic fatty liver disease (NAFLD). Its pharmacodynamic material basis is made up of quinones, flavanones, and terpenoids. Aim of the studyThis study aimed to look for a promising recipe for treating nonalcoholic steatohepatitis (NASH), a more advanced form of NAFLD, and to use a transcriptome-based multi-scale network pharmacological platform (TMNP) to find its therapy targets. Materials and methodsA classical dietary model of NASH was established using MCD (Methionine- and choline-deficient) diet-fed mice. Liver coefficients like ALT, AST, serum TC, and TG levels were tested following QZTGT administration. A transcriptome-based multi-scale network pharmacological platform (TMNP) was used to further analyze the liver gene expression profile. ResultsThe composition of QZTGT was analyzed by HPLC-Q-TOF/MS, a total of 89 compounds were separated and detected and 31 of them were found in rat plasma. QZTGT improved liver morphology, inflammation and fibrosis in a classical NASH model. Transcriptomic analysis of liver samples from NASH animal model revealed that QZTGT was able to correct gene expression. We used transcriptome-based multi-scale network pharmacological platform (TMNP) to predicted molecular pathways regulated by QZTGT to improve NASH. Further validation indicated that “fatty acid degradation”, “bile secretion” and “steroid biosynthesis” pathways were involved in the improvement of NASH phenotype by QZTGT. ConclusionsUsing HPLC-Q-TOF/MS, the compound composition of QZTGT, a Traditional Chinese prescription, was separated, analyzed and identified systematically. QZTGT mitigated NASH symptoms in a classical dietary model of NASH. Transcriptomic and network pharmacology analysis predicted the potential QZTGT regulated pathways. These pathways could be used as therapeutic targets for NASH.

Hepatic p38α MAPK controls gluconeogenesis via FOXO1 phosphorylation at S273 during glucagon signalling in mice.

Hyperglucagonaemia-stimulated hepatic glucose production (HGP) contributes to hyperglycaemia during type 2 diabetes. A better understanding of glucagon action is important to enable efficient therapies to be developed for the treatment of diabetes. Here, we aimed to investigate the role of p38 MAPK family members in glucagon-induced HGP and determine the underlying mechanisms by which p38 MAPK regulates glucagon action. p38α, β, γ and δ MAPK siRNAs were transfected into primary hepatocytes, followed by measurement of glucagon-induced HGP. Adeno-associated virus serotype 8 carrying p38α MAPK short hairpin RNA (shRNA) was injected into liver-specific Foxo1 knockout, liver-specific Irs1/Irs2 double knockout and Foxo1S273D knockin mice. Foxo1S273A knockin mice were fed a high-fat diet for 10 weeks. Pyruvate tolerance tests, glucose tolerance tests, glucagon tolerance tests and insulin tolerance tests were carried out in mice, liver gene expression profiles were analysed and serum triglyceride, insulin and cholesterol levels were measured. Phosphorylation of forkhead box protein O1 (FOXO1) by p38α MAPK in vitro was analysed by LC-MS. We found that p38α MAPK, but not the other p38 isoforms, stimulates FOXO1-S273 phosphorylation and increases FOXO1 protein stability, promoting HGP in response to glucagon stimulation. In hepatocytes and mouse models, inhibition of p38α MAPK blocked FOXO1-S273 phosphorylation, decreased FOXO1 levels and significantly impaired glucagon- and fasting-induced HGP. However, the effect of p38α MAPK inhibition on HGP was abolished by FOXO1 deficiency or a Foxo1 point mutation at position 273 from serine to aspartic acid (Foxo1S273D) in both hepatocytes and mice. Moreover, an alanine mutation at position 273 (Foxo1S273A) decreased glucose production, improved glucose tolerance and increased insulin sensitivity in diet-induced obese mice. Finally, we found that glucagon activates p38α through exchange protein activated by cAMP 2 (EPAC2) signalling in hepatocytes. This study found that p38α MAPK stimulates FOXO1-S273 phosphorylation to mediate the action of glucagon on glucose homeostasis in both health and disease. The glucagon-induced EPAC2-p38α MAPK-pFOXO1-S273 signalling pathway is a potential therapeutic target for the treatment of type 2 diabetes.

Gene expression networks and functionally enriched pathways involved in the response of domestic chicken to acute heat stress.

Heat stress in poultry houses, especially in warm areas, is one of the main environmental factors that restrict the growth of broilers or laying performance of layers, suppresses the immune system, and deteriorates egg quality and feed conversion ratio. The molecular mechanisms underlying the response of chicken to acute heat stress (AHS) have not been comprehensively elucidated. Therefore, the main object of the current work was to investigate the liver gene expression profile of chickens under AHS in comparison with their corresponding control groups, using four RNA-seq datasets. The meta-analysis, GO and KEGG pathway enrichment, WGCNA, machine-learning, and eGWAS analyses were performed. The results revealed 77 meta-genes that were mainly related to protein biosynthesis, protein folding, and protein transport between cellular organelles. In other words, under AHS, the expression of genes involving in the structure of rough reticulum membrane and in the process of protein folding was adversely influenced. In addition, genes related to biological processes such as "response to unfolded proteins," "response to reticulum stress" and "ERAD pathway" were differentially regulated. We introduce here a couple of genes such as HSPA5, SSR1, SDF2L1, and SEC23B, as the most significantly differentiated under AHS, which could be used as bio-signatures of AHS. Besides the mentioned genes, the main findings of the current work may shed light to the identification of the effects of AHS on gene expression profiling of domestic chicken as well as the adaptive response of chicken to environmental stresses.

Changes in transcriptomic and behavioural traits in activity and ventilation rates associated with divergent individual feed efficiency in gilthead sea bream (Sparus aurata)

Feed conversion ratio (FCR) is an important trait to target in fish breeding programs, and the aim of the present study is to underline how the genetic improvement of FCR in gilthead sea bream (Sparus aurata) drives to changes in transcriptional and behavioural patterns. Groups of fish with high (FCR+) and low (FCR-) individual FCR were established at the juvenile stage (161–315 dph) by rearing isolated fish on a restricted ration. Fish were then grouped on the basis of their individual FCR and they grew up until behavioural monitoring and gene expression analyses were done at 420 dph. The AEFishBIT datalogger (externally attached to operculum) was used for simultaneous measurements of physical activity and ventilation rates. This allowed discrimination of FCR+ and FCR- groups according to their different behaviour and energy partitioning for growth and locomotor activity. Gene expression profiling of liver and white muscle was made using customized PCR-arrays of 44 and 29 genes, respectively. Up to 15 genes were differentially expressed in liver and muscle tissues highlighting a different metabolic scope of FCR+ and FCR- fish. Hepatic gene expression profile of FCR- fish displayed a lower lipogenic activity that was concurrent with a down-regulation of markers of mitochondrial activity and oxidative stress, as well as a reallocation of body fat depots with an enhanced flux of lipids towards skeletal muscle. Muscle gene expression profile of FCR- fish matched with stimulatory and inhibitory growth signals, and an activation of energy sensors and antioxidant defence as part of the operating mechanisms for a more efficient muscle growth. These new insights contribute to phenotype the genetically mediated differences in fish FCR thanks to the combination of transcriptomic and behavioural approaches that contribute to better understand the mechanisms involved in a reliable FCR improvement of farmed gilthead sea bream.

Combined Gamma Conglutin and Lupanine Treatment Exhibits In Vivo an Enhanced Antidiabetic Effect by Modulating the Liver Gene Expression Profile.

Previous studies have individually shown the antidiabetic potential of gamma conglutin (Cγ) and lupanine from lupins. Until now, the influence of combining both compounds and the effective dose of the combination have not been assessed. Moreover, the resulting gene expression profile from this novel combination remains to be explored. Therefore, we aimed to evaluate different dose combinations of Cγ and lupanine by the oral glucose tolerance test (OGTT) to identify the higher antidiabetic effect on a T2D rat model. Later, we administered the selected dose combination during a week. Lastly, we evaluated biochemical parameters and liver gene expression profile using DNA microarrays and bioinformatic analysis. We found that the combination of 28 mg/kg BW Cγ + 20 mg/kg BW lupanine significantly reduced glycemia and lipid levels. Moreover, this treatment positively influenced the expression of Pdk4, G6pc, Foxo1, Foxo3, Ppargc1a, Serpine1, Myc, Slc37a4, Irs2, and Igfbp1 genes. The biological processes associated with these genes are oxidative stress, apoptosis regulation, and glucose and fatty-acid homeostasis. For the first time, we report the beneficial in vivo effect of the combination of two functional lupin compounds. Nevertheless, further studies are needed to investigate the pharmacokinetics and pharmacodynamics of the Cγ + lupanine combined treatment.

PSIII-5 Late-Breaking: Genetic Evaluation of Energy Efficiency in Bos taurus Cows Classified by Residual Feed Intake

Abstract Genetic selection for efficiency traits is essential to improve the profitability and sustainability of livestock operations. Inefficient metabolism and energy production in animal physiology leads to excess feed consumption, resulting in higher feed costs. The objective of this study was to investigate hepatic gene expression in mature Angus-influenced cows that were classified as low or high RFI as heifers and had either a low or high ratio of calf weaning weight to mature body weight at weaning. Eleven cows were selected from the Northern Agricultural Research Center (NARC) research herd. Cows were ranked as efficient (n = 5) or inefficient (n = 6) based on their low or high residual feed intake (RFI) measured as a growing heifer and then by the ratio of calf weaning weight by mature body weight. Animals were partitioned from the bottom quartile with low RFI as a heifer and weaned with a higher proportion of the calf were classified as efficient, and animals from the top quartile with a high RFI as a heifer and a lower ratio of the calf to body weight were classified as inefficient. Liver samples were collected by needle biopsy approximately one week after weaning and snap frozen. The liver gene expression profile was measured using RNAseq. Two cows' data were not reported, one from each group, as RNA quality prevented sequencing (Efficient n = 4 and Inefficient n = 5). Over 5 million reads were mapped for each sample and were aligned to BTau 4.6.1 reference sequence using HISAT2. Differentially expressed genes were determined using the DEseq2 R package using a model based on the negative binomial distribution, and p-values were adjusted using the Benjamini-Hochberg approach. A corrected P-value of less than 0.05 defined a differentially expressed gene. Gene lists were used for gene ontology and KEGG pathway enrichment using clusterProfiler software. One novel gene was significantly differentially expressed with higher expression in the efficient group. However, no annotation currently exists for this gene. Additionally, the KEGG pathway biosynthesis of unsaturated fatty acids was significantly enriched (P &amp;lt; 0.05) with the following differentially expressed genes SCD, FADS1/2, ELOVL6, and HACD2, all being down-regulated in inefficient cows. The enrichment of this pathway is most functionally relevant, as it indicates that local liver changes could directly affect the efficient metabolism and biosynthesis of fatty acids. With encouraging, but limited results, this study provides the groundwork for future study of the heritable mechanisms contributing to the generation of more energy-efficient cows.

LOW DOSE-RATE RADIATION-SPECIFIC ALTERATIONS FOUND IN A GENOME-WIDE GENE EXPRESSION ANALYSIS OF THE MOUSE LIVER.

Life span shortening and increased incidences of cancer and non-cancer diseases were observed in B6C3F1 mice irradiated with gamma-rays at a low dose-rate (LDR) of 20mGy/d for 400d. A genome-wide gene expression profiling of livers from mice irradiated at a LDR (20mGy/d, 100-400d) was performed. LDR radiation affected specific pathways such as those related to lipid metabolism, e.g. 'Cholesterol biosynthesis' and 'Adipogenesis' in females irradiated for 200 and 300d at 20mGy/d, with increased expression of genes encoding cholesterol biosynthesis enzymes (Cyp51, Sqle, Fdps) as age and radiation dose increased. No significant alterations in the expression of these genes were observed in male mice exposed similarly. However, the genes encoding adipogenesis regulators, Srebf1 and Pparg, increased with age and radiation dose in both sexes. Comparison between LDR-irradiated and medium dose-rate (400mGy/d) male mice revealed quite different gene expression profiles. These results seem to be consistent with the increased incidence of fatty liver and obesity in female mice exposed to LDR radiation and suggest that metabolism is an important target of LDR radiation.