- Background: At sexual maturity, the liver of laying hens undergoes many metabolic changes to support vitellogenesis. - We reanalyzed some data from a previously published article comparing 38-week old versus 10-week old hens to give a more integrative view of the functions stimulated in the liver at sexual maturity and to move beyond current physiological knowledge. - Results: Of the 516 genes previously shown to be overexpressed in the liver of laying hens, 475 were intracellular fold changes), while only 36 were predicted to be secreted fold changes) and 5 had no related information on their cellular location. - Using a 20 K chicken oligoarray, a total of 582 probes were shown to be over-expressed in the liver of 38-week sexually mature hens versus 10-week juvenile hens (Layer ISA brown, Hendrix Genetics, 1.2 to 67 fold-differences) [11]. - Thus, the objective of the present article was to give an integrative and straightforward over- view of the functions related to the proteins that were shown to be overexpressed in the liver at sexual maturity of hens. - To give this integrative view of the functions associated with the liver at sexual maturity of hens, we distinguished proteins that are confined to the liver (membrane/cell localization) from those that are secreted in the blood stream such as yolk precursors, and others that may have a more systemic effect and/or an effect at another physiological site than the liver.. - Using a 20 K chicken oligoarray corresponding to 12,595 different chicken probes, a total of 582 probes had been shown to be over-expressed in the liver at sexual matur- ity of hens [11] (Additional file 1, column A-C). - It is noteworthy that these genes have a basal expression in the liver of immature pullets. - Using this last genome annotation, we re- analyzed the full list of genes shown to be overexpressed in the liver of mature hens to remove redundancies and to update accession numbers. - This preliminary work allowed us to restrict the initial list of 582 genes to 516 genes (Additional file 1) that are overexpressed in the liver of laying hens (1.2 to 67-fold changes). - Distribution between secreted/non secreted proteins Some expressed proteins are secreted in the blood stream to support physiological processes at distant sites (including vitellogenesis at the ovary site) while others are restricted to the intracellular compartment of the liver. - They include avidin- related protein 6-like (fold change =10.5) that is localized in the W chromosome (female-specific chromosome).. - Of the 36 overexpressed genes that are pre- dicted to be secreted (Additional file 2, lines 491–526), only 18 are recovered in the yolk (Table 2) [13–15]. - As expected, vitellogenins, components of very low-density lipoproteins (apovitellenin, apolipoprotein B), and riboflavin-binding protein, which are highly abundant in egg yolk are also highly overexpressed in the liver of laying hens. - First, the liver of laying hens appears as a peripheral clock tissue. - ML/IL ratio: ratio of gene expression in the liver of 38-week laying hens (ML) to the expression in the liver of 10-week juvenile pullets (IL). - is expressed in the liver of laying hens. - Remarkably, all these proteins are highly overexpressed in the liver of laying hens while they lack expression (or ex- hibit a very low expression) in the liver of human species (Additional file 2, column G).. - The potential role of the liver to regulate thyroid hormone availability is evidenced by the overexpression of plasma glutamate carboxypepti- dase precursor (CPQ, fold change = 8.37) that is secreted and that may play a role in the release of thyroxine hormones (T4/T3) from their thyroglobulin precursor.. - Both proteins are essentially expressed in the thyroid but not in liver in human (Additional file 2, column G).. - These genes encode two membrane proteins (glutamyl aminopeptidase, ENPEP (fold change = 1.99), angiotensin II receptor associated protein, AGTRAP (fold change = 1.95) that participate in the renin-angiotensin system to regulate blood pressure.. - The multimerin 1 (MMRN1, fold change = 1.87), which is secreted to play a role in the storage and the stabilization of factor V in platelets and in thrombin ac- tivation (coagulation) (Additional file 2) was shown to be upregulated in this study.. - We hypothesize that phosphoethanolamine/phosphocholine phosphatase (PHOSPHO1, fold change = 1.35) and bone morphogenic protein 7 (BMP7, fold change = 1.63) that both lack expression in the liver of human, and fibroblast growth factor 23 (FGF23, fold change = 1.78), which is almost exclusively expressed in the liver in human species, may be partly involved in bone remodeling.. - The aim of the present study was to de- scribe the adaptation of the liver molecular repertoire at sexual maturity in the domestic fowl, by targeting over-expressed genes in sexually mature hens in com- parison to juveniles, based on previous published data obtained by high-throughput approach [11]. - Sexual maturity in laying hens is associated with clock genes overexpression in the liver. - Such an effect of the diet on the expression of clock genes in the liver of laying hens and other peripheral organs (jejunum) have been pub- lished recently, showing that the expression of clock genes are trained in response to a specific sequence of feeding but also depends on the composition of the diet [21, 22].. - In the study published by Bourin et al. - NRIP1 gene encodes the nuclear receptor interacting protein 1, that is localized in the nucleus, and that is a positive regulator of the circadian clock gene expression. - The biological significance of such an overexpression in the liver of laying hens needs to be explored further and may depend on the reproductive status of animals (clock gene entrainment/physiological requirements associated with reproduction). - mammals, pregnancy and the transition from pregnancy to lactation have been shown to regulate clock gene ex- pression in the liver of mice [28, 29]. - Because at sexual maturity the liver of birds is intimately associated with vitellogenesis, it might not be surprising to observe a regu- lation of clock genes expression in the liver of laying hens as compared with pullets.. - The liver of laying hens contributes to interorgan communication. - In parallel to the expression of clock genes, the stimula- tion of photoreceptors will participate in the release of gonadotropin hormones (GnRH). - The liver was previously reported to express prolactin receptor (PRLR) [32], which is further confirmed in the study presented here (fold change = 6.84 in laying hens versus juvenile pullets). - Prostaglandins have a preponderant role in the uterus, by controlling ovi- position [5]. - However, the biological significance of the high overexpression of this receptor in the liver remains to be elucidated. - of the liver to hormone biosynthesis (at a much lesser extent as compared with the ovary), and catabolism (SULT gene). - A liver-gonad communication may be also mediated by PAQR7 (fold change = 6.33), PGRMC2 (fold change = 1.54) and UPRT (fold change = 1.84) localized in the plasma membrane and the nucleus. - The brain will in turn control the liver metabolism and that of other organs and tissues [39] via secretion of hormones and neurotransmitters in the blood. - In addition, the upregulation of PLXNB2 gene encoding a non-secreted protein in the liver could contribute to the regulation of neuronal migration to the liver at sexual maturity. - The liver of laying hens undergoes increased protein synthesis. - Nucleo- tide synthesis also increased in the liver at sexual matur- ity with GMPS (fold change = 1.32) and CMPK1 (fold change =1.54) genes regulating purine and pyrimidine synthesis, CMPK1 contributing to pyrimidine nucleotide transport as well as THUMPD2 (fold change = 1.43) to tRNA methylation. - The enhancement of genes regulating glycosyltranferases like GCNT4 (fold change = 1.60), EXTL2 (fold change =1.41) and B3GNT2 (fold change =3.69) are also evidenced in the present study.. - Other genes such as SEC16A (fold change =1.36) and SCAMP1 (fold change =1.78) contrib- uting to the transport of secreted proteins are upregulated and might participate in the secretion of hepatic proteins in the bloodstream.. - STMN1 over-expression in the liver of laying hens is conceivable, as stathmin plays a critical role in mitosis [47].. - NID1, fold change =2.77. - DRAXIN, fold change = 3.08. - MYFGF, fold change =1.34. - THNS2, fold change =1.53. - ADAMTS5, fold change =1.72 and MYOC, fold change =1.48) and are likely to contribute to the development and increased activity of the liver of laying hens.. - In the present study, 6 members of the anti- oxidant system are over-expressed at sexual maturity (CAT, CYB5A, MSRB3, GLRX, STK25 and TXNDC11, Additional file 2) and could represent a signature of the increased metabolic rate of the liver. - In addition, we found several enzymes involved in the catabolism of steroids, proteins and hor- mones but also detoxifying molecules such as TEF (fold change = 1.46) and SULT (fold change = 5.47) genes, which may be paralleled with the major role of the liver in clear- ing toxic compounds from the blood [20], to maintain body homeostasis. - Finally, three immune response related genes have been shown to be overexpressed in the liver of laying hens and may be markers for a chronic inflammatory environment (IFNRL1, fold change = 2.02. - The increased basal metabolism of the liver of laying hens supports egg yolk formation. - Different transcripts of glucose transporters of the GLUT family were identified in the liver of broiler chickens [64, 65]. - Although the GLUT4 gene is absent from the chicken genome, a homolog of GLUT4 named GLUT12 has been recently shown to be expressed in the liver of chickens [65]. - INPP5K is over expressed in the liver of mature hens (fold change = 1.35) and is defined as a specific regulator of insulin signaling in skeletal muscle. - In the present study (Additional file 2), many genes involved in fatty acid synthesis are over-expressed at sexual maturity (FAR1, ACSBG2, ELOVL2, HADHB, ELOVL1, PEX11A, ACSM3, LPPR5, ACPL2, PECR. - Similarly, the expression of some genes involved in the intracellular fatty acids binding and lipid transport [67] is also stimulated (FABP3, OSBPL3, TEX2, DBI, COL4A3BP, TTPA, MTTPL, Additional file 2). - In parallel, genes underlying mecha- nisms of lipid degradation (PNPLA3, AIG1, ABDH2, PLA2G12A) as well as beta oxidation (HAO2, ACADL, DECR1, CPT2) are up regulated in the liver of sexually mature hens. - These genes could be involved in the turnover of the hepatocyte cell membrane. - The synthesis and release of egg yolk pro- teins by the liver in the blood circulation, suggests the involvement of a protective system to prevent egg yolk. - From our data, SPINK4 (fold change = 1.69) was over-expressed by the liver at sexual maturity. - Similar function can be hypothesized for PAPLN (fold change = 2.74) and PCSK6 (fold change = 2.20) but also WAP four-disulfide core domain protein 8 (WFDC8), a secreted protein that is highly overexpressed in the liver of laying hens (fold change =11.88). - The liver of laying hens sustains egg fertilization. - Interestingly, four genes overexpressed in the liver at sexual maturity of hens (MFGE8, ZP1, LINC00954, OVCH2, Add- itional file 2) are prone to participate in oocyte fertilization.. - ZP1 (fold change = 15.06) is synthesized by the liver and is transported to the ovary via the blood to be inserted in the perivitelline membrane surrounding the oocyte [70]. - This protease is involved in the maturation and proteolysis of major glycoproteins composing the zona pellucida [72]. - As mentioned in the introduc- tion, sexual maturity also affects secondary sexual char- acteristics such as the comb size that is a sexual ornament, and bone structure of the hen.. - The liver of laying hens may participate in the establishment of secondary sexual characteristics. - Similarly, the gene encoding iodothyronine deiodinase 2 (DIO2) was found to be over- expressed in the liver of mature compared to juvenile hens (fold change = 1.99). - This enzyme is involved in the conversion of the prohormone thyroxine (T4) to the biologically active thy- roid hormone triiodothyronine (T3) [78]. - This latter bone con- stitutes a labile source of calcium that will be mobilized over the dark period of the ovulatory cycle [7] concomi- tantly to the increase of phosphorus in the plasma. - plasma phosphorus and that this regulation is different in the liver as opposed to the bone [81, 82]. - Additional organs are also able to synthesize FGF23, including the liver of laying hens [83]. - In the present study, we confirm that the liver of laying hens expresses a higher level of FGF23 (fold change = 1.78) that might assist the development of medullary bone by regulating circulating phosphorus [84–. - Knowing that vitamins are incorporated in the diet, we hypothesized that some of the highly overex- pressed vitamin-binding proteins in the liver at sexual maturity (RBP, TCN2, GC that transport riboflavin, co- balamin and vitamin D, respectively) may also facilitate transport/storage of these essential vitamins to accompany bone remodeling. - Many overexpressed proteins of the liver of laying hens lack functional information. - Although the deep integration of under-expressed genes may also help to better appreciate the mechanisms sup- porting the overexpressed genes and the new reproductive functions, the present work focusing on over-expressed genes in the liver of laying hens reveals new research ave- nues to study the physiological changes associated with sexual maturity of laying hens.. - In the experi- ment published by [11], the diet and the light/dark cycle as well as the rearing environment were the same for pullets and laying hens. - The list of overexpressed genes in the liver of laying hens were retrieved from NCBI Gene Expression Omnibus (GEO. - Integrative analysis of overexpressed gene in the liver of laying hens.. - The physiological significance of androgen-induced ovulation in the hen. - Overview of bone biology in the egg-laying hen. - Transcriptomic profiling of proteases and antiproteases in the liver of sexually mature hens in relation to vitellogenesis. - Rhythmic expression of circadian clock genes in the preovulatory ovarian follicles of the laying hen. - Effects of dynamic feeding low- and high-methionine diets on the variation of glucose and lipid metabolism-related genes in the liver of laying hens. - Ontogeny of circadian oscillations in the heart and liver in chicken. - Pregnancy-induced changes in the circadian expression of hepatic clock genes: implications for maternal glucose homeostasis. - Study of changes in the specific activities of enzymes of lipid and carbohydrate metabolism in the liver of the domestic fowl with the onset of sexualmaturity. - The role of the autonomic nervous liver innervation in the control of energy metabolism. - Malectin: a novel carbohydrate-binding protein of the endoplasmic reticulum and a candidate player in the early steps of protein N-glycosylation. - The role of stathmin in the regulation of the cell cycle.. - Type I interferons as ambiguous modulators of chronic inflammation in the central nervous system. - Phylogenesis and biological characterization of a new glucose transporter in the chicken (Gallus gallus), GLUT12. - The major chicken egg envelope protein ZP1 is different from ZPB and is synthesized in the liver. - On the relation between thyroid and sex gland functioning in the brown leghorn fowl. - seasonal changes in the neuroendocrine system. - BMP7 improves insulin signal transduction in the liver. - Mechanisms of action of thyroid hormones in the skeleton
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