Fat storage-inducing transmembrane proteins: beyond mediating lipid droplet formation.

Fat storage-inducing transmembrane proteins (FITMs) were initially identified in 2007 as members of a conserved endoplasmic reticulum (ER) resident transmembrane protein gene family, and were found to be involved in lipid droplet (LD) formation. Recently, several studies have further demonstrated that the ability of FITMs to directly bind to triglyceride and diacylglycerol, and the diphosphatase activity of hydrolyzing fatty acyl-CoA, might enable FITMs to maintain the formation of lipid droplets, engage in lipid metabolism, and protect against cellular stress. Based on the distribution of FITMs in tissues and their important roles in lipid droplet biology and lipid metabolism, it was discovered that FITMs were closely related to muscle development, adipocyte differentiation, and energy metabolism. Accordingly, the abnormal expression of FITMs was not only associated with type 2 diabetes and lipodystrophy, but also with cardiac disease and several types of cancer. This study reviews the structure, distribution, expression regulation, and functionality of FITMs and their potential relationships with various metabolic diseases, hoping to provide inspiration for fruitful research directions and applications of FITM proteins. Moreover, this review will provide an important theoretical basis for the application of FITMs in the diagnosis and treatment of related diseases.

Serine peptidase inhibitor Kazal type III (SPINK3) promotes BRL-3A cell proliferation by targeting the PI3K-AKT signaling pathway.

The serine protease inhibitor, Kazal type III (SPINK3), is a trypsin inhibitor associated with liver disease, which highly overexpresses in a variety of cancers. In one of our previous studies of our laboratory, Spink3 was observed to be significantly upregulated in rat liver regeneration (LR) via a gene expression profile. For the current study, rat hepatocyte BRL-3A cells were treated by gene addition/interference, and the addition of the exogenous rat recombinant protein SPINK3. It was revealed that both the overexpression of endogenous Spink3 and addition of exogenous rat recombinant SPINK3 (rrSPINK3) significantly promoted the cell proliferation of BRL-3A cells, whereas cell proliferation was inhibited when Spink3 was interfered. Furthermore, quantitative reverse transcription polymerase chain reaction and western blot results revealed that three signaling pathways, including extracellular-signal-regulated kinase 1/2 (ERK1/2), Janus kinase (JAK)-signal transducer and activator of transcription (STAT), and phosphatidylinositol-3-kinase (PI3K)-protein kinase B (AKT), as well as their related genes, were altered following endogenous Spink3 addition/interference. Also, the PI3K-AKT and SRC-p38 pathways and their related genes were modified following exogenous SPINK3 treatment. Among them, the common signaling pathway was PI3K-AKT pathway. We concluded that SPINK3 could activate the PI3K-AKT pathway by enhancing the expression of AKT1 to regulate the proliferation of BRL-3A cells. This study may contribute to shedding light on the potential mechanisms of SPINK3 that regulate the proliferation of BRL-3A cells.

Comparative Analysis of Expression Profiles of Reg Signaling Pathways-Related Genes Between AHF and HCC.

Regenerating islet-derived protein (Reg) could participate in the occurrence of diabetes mellitus, inflammation, tumors, and other diseased or damaged tissues. However, the correlation of Reg with acute hepatic failure (AHF) and hepatocellular carcinoma (HCC) is poorly defined. To reveal the expression profiles of Reg family and their possible regulatory roles in AHF and HCC, rat models of HCC and AHF were separately established, and Rat Genome 230 2.0 was used to detect expression profiles of Reg-mediated signaling pathways-associated genes from liver tissues in AHF and HCC. The results showed that a total of 79 genes were significantly changed. Among these genes, 67 genes were the AHF-specific genes, 45 genes were the HCC-specific genes, and 33 genes were the common genes. Then, K-means clustering classified these genes into 4 clusters based on the gene expression similarity, and DAVID analysis showed that the above altered genes were mainly associated with stress response, inflammatory response, and cell cycle regulation. Thereafter, IPA software was used to analyze potential effects of these genes, and the predicted results suggested that the Reg-mediated JAK/STAT, NF-κB, MAPK (ERK1/2, P38 and JNK), PLC, and PI3K/AKT signaling pathways may account for the activated inflammation and cell proliferation, and the attenuated apoptosis and cell death during the occurrence of AHF and HCC.

Serine peptidase inhibitor Kazal type I (SPINK1) promotes BRL-3A cell proliferation via p38, ERK, and JNK pathways.

Serine peptidase inhibitor Kazal type I (SPINK1) has the similar spatial structure as epidermal growth factor (EGF); EGF can interact with epidermal growth factor receptor (EGFR) to promote proliferation in different cell types. However, whether SPINK1 can interact with EGFR and further regulate the proliferation of hepatocytes in liver regeneration remains largely unknown. In this study, we investigated the role of SPINK1 in a rat liver hepatocyte line of BRL-3A in vitro. The results showed the upregulation of endogenous Spink1 (gene addition) significantly increased not only the cell viability, cell numbers in S and G2 /M phase, but also upregulated the genes/proteins expression related to cell proliferation and anti-apoptosis in BRL-3A. In contrast, the cell number in G1 phase and the expression of pro-apoptosis-related genes/proteins were significantly decreased. The similar results were observed when the cells were treated with exogenous rat recombinant SPINK1. Immunoblotting suggested SPINK1 can interact with EGFR. By Ingenuity Pathway Analysis software, the SPINK1 signalling pathway was built; the predicted read outs were validated by qRT-PCR and western blot; and the results showed that p38, ERK, and JNK pathways-related genes/proteins were involved in the cell proliferation upon the treatment of endogenous Spink1 and exogenous SPINK1. Collectively, SPINK1 can associate with EGFR to promote the expression of cell proliferation-related and anti-apoptosis-related genes/proteins; inhibit the expression of pro-apoptosis-related genes/proteins via p38, ERK, and JNK pathways; and consequently promote the proliferation of BRL-3A cells. For the first time, we demonstrated that SPINK1 can associate with EGFR to promote the proliferation of BRL-3A cells via p38, ERK, and JNK pathways. This work has direct implications on the underlying mechanism of SPINK1 in regulating hepatocytes proliferation in vivo and liver regeneration after partial hepatectomy.

A preliminary in vivo study of the effects of OPN on rat liver regeneration induced by partial hepatectomy.

Osteopontin (OPN) is a member of Th1 cytokine secreted by activated lymphocytes and macrophages. However, it deserves to be studied whether OPN could promote cell activation or proliferation, and then facilitate hepatic self-repair during liver regeneration (LR). This study is designed to further reveal the effects of OPN on LR in vivo. Firstly, quantitative reverse transcription-PCR (qRT-PCR) and western blot (WB) were utilized to validate the expression profile of endogenous OPN in rat regenerating livers after partial hepatectomy (PH). Then OPN expression vector, two shRNA expression vectors and their respective test vectors were successfully constructed. Afterwards, test vectors were administrated into mouse livers via tail vein to find the more efficient shRNA. Furthermore, OPN expression vector and the more efficient shRNA expression vector were injected into rat regenerating livers, and then the changes in liver regeneration and hepatic microstructure were respectively detected by liver regeneration rate and HE staining, while the expressions of several marker genes were detected by qRT-PCR and WB. Endogenous OPN was strikingly up-regulated in both mRNA and protein level during LR, especially at 12 and 72 h after PH. The shRNA expression vector Opn(313) was found to be more efficient than Opn(887) in silencing the expression of Opn. Then OPN expression vector and Opn(313) were injected into rat remnant livers, and it showed that OPN overexpression aggravated hepatic necrosis and leukocytes infiltration, while OPN silencing inhibited liver regeneration rate and the expressions of PCNA and CCL2, but augmented that of BAX. In conclusion, OPN might enhance inflammation and cell proliferation, attenuate cell apoptosis, and ultimately facilitate liver regeneration at the termination stage of liver regeneration.

Analysis of the ways and methods of signaling pathways in regulating cell cycle of NIH3T3 at transcriptional level.

BACKGROUND: To analyze the ways and methods of signaling pathways in regulating cell cycle progression of NIH3T3 at transcriptional level, we modeled cell cycle of NIH3T3 and found that G1 phase of NIH3T3 cell cycle was at 5-15 h after synchronization, S phase at 15-21 h, G2 phase at 21-22 h, M phase at 22-25 h. RESULTS: Mouse Genome 430 2.0 microarray was used to detect the gene expression profiles of the model, and results showed remarkable changes in the expressions of 64 cell cycle genes and 960 genes associated with other physiological activity during the cell cycle of NIH3T3. For the next step, IPA software was used to analyze the physiological activities, cell cycle genes-associated signal transduction activities and their regulatory roles of these genes in cell cycle progression, and our results indicated that the reported genes were involved in 17 signaling pathways in the regulation of cell cycle progression. Newfound genes such as PKC, RAS, PP2A, NGR and PI3K etc. belong to the functional category of molecular mechanism of cancer, cyclins and cell cycle regulation HER-2 signaling in breast cancer signaling pathways. These newfound genes could promote DNA damage repairment and DNA replication progress, regulate the metabolism of protein, and maintain the cell cycle progression of NIH3T3 modulating the reported genes CCND1 and C-FOS. CONCLUSION: All of the aforementioned signaling pathways interacted with the cell cycle network, indicating that NIH3T3 cell cycle was regulated by a number of signaling pathways.

Expression profiles uncover the correlation of OPN signaling pathways with rat liver regeneration at cellular level.

Osteopontin (OPN) could participate in the occurrence of multiple liver diseases via promoting inflammation, cell activation, proliferation, and migration. However, the correlation of OPN with liver regeneration (LR) is poorly defined. Previous studies from us and others revealed that OPN was probably involved in the activation and proliferation of various hepatic cell types during LR. In this study, to further investigate the underlined mechanism of OPN in regulating LR, eight hepatic cell types were isolated and purified from rat regenerative livers at 10 time points. The gene expression profiles of above hepatic cells were assayed by Rat Genome 230 2.0 chips, and then IPA software was used to uncover the correlations of gene expression changes with physiological activities. The findings demonstrated that the majority of the OPN pathway-related genes were up-regulated in hepatocytes (HCs), pit cells (PCs), oval cells (OCs), and biliary epithelial cells (BECs) but down-regulated in other four cell types including sinusoidal endothelial cells (SECs), Kupffer cells (KCs), dendritic cells (DCs), and hepatic stellate cells (HSCs). Thereafter, functional enriched analysis by IPA indicated that OPN signaling pathway might promote cell proliferation, activation, migration, and inflammation in HCs, OCs, BECs, and PCs, and slightly boost proliferation and migration of SECs and KCs but inhibit inflammation response and chemotaxis in SECs and KCs and almost all physiological processes in DCs and HSCs. Morever, apoptosis, cell death, and necrosis were remarkably inhibited through JAK/STAT, ERK1/2, and NF-kB branches in almost every cell type. These above results suggest that OPN signaling pathway is closely related to HCs, OCs, BECs, and PCs but has less regulatory effect on SECs, KCs, HSCs, and DCs during rat LR.

Thrombopoietin Signaling Pathway Regulates Hepatocyte Activation in Rat Liver Regeneration.

Thrombopoietin (THPO) signaling pathway regulates cell activation and many other physiological activities. To study its role in liver regeneration (LR), hepatocytes were isolated from rat regenerating livers and gene expression profile was detected using the Rat Genome 230 2.0 Array. Spectral function (E t ) and information correlation coefficient (ICC) were used to analyze gene synergy based on gene expression changes. The results showed that 35 genes related to THPO signaling pathway were significantly changed during rat LR. Functional analysis with ICC showed that five genes, STAT3, PLSCR1, CTGF, PRLR, and LCP1, played a key role in hepatocyte activation. Fourteen channels of THPO signaling pathway participated in regulating hepatocyte activation during rat LR.

[Synthesis and Properties of 1,11,15,25-Tetrahydroxy-4,8,18,22-Di (Bridged Dipropionate Carboxyl) Phthalocyanine Copper].

In this dissertation, we study the synthesis and character of new substituted Phthalocyanine. Due to the widely application of Pcs in the fields, such as the communication, medical treatment, chemical industry and so on, therefore, they have been a hot topic over several decades by scientists. Nowadays, scientists have prepared thousands of Pcs and their derivatives. However, along with the human society development and the progress in science and technology, the new phthalocyanine with novle characteristics are still the goal of the scientists. In this dissertion, the synthetic methods of the phthlocyanine is improved. The synthesis and characterization of 1,11,15,25-tetrahydroxy-4,8,18,22-di(bridged dipropionate carboxyl) phthalocyanines are reported in this paper. The mixtures of malonic acid and 3,6-dihydroxy-phthalonitrile was added to water under stiriing. Then, a catalyst amount of sulfuric acid was added. The first synthetic precursor, i. e., malonic acid 3,3'-bis(6-hydroxy phthalonitrile) butter, its molecular formula is C19H8N4O6. phthalocyanines was prepared by malonic acid 3,3'-bis(6-hydroxy phthalonitrile) butter and dihydrate zinc acetate, copper acetate monohydrate in n-amyl alcohol, using DBU as a catalyst under the 135 °C, molecular formula of phthalocyanine complexes is C38H16N8O12M. The product was characterized by Ultraviolet-visible (UV/Vis) Spectrum absorption and fluorescence, The results are agreement with the proposed structures. And electrochemical properties were studied.

Correlation analysis between gene expression profile of high-fat emulsion-induced non-alcoholic fatty liver and liver regeneration in rat.

To explore the relevance of non-alcoholic fatty liver disease (NAFLD) to liver regeneration (LR), rat models of non-alcoholic steatohepatitis (NASH) and LR were established, respectively, then Rat Genome 230 2.0 Array was used to detect the gene expression abundance of them, and the reliabilities of the array data were confirmed by real-time RT-PCR. As a result, the expression of 93 genes was significantly changed during NAFLD occurrence and 948 genes in LR. Hierarchical clustering indicated that the expression profiles of the above two events were quite different. K-means cluster classified their expression patterns into four clusters, and gene expression trends of clusters 1, 2 were similar in NAFLD and LR, while clusters 3, 4 were contrary with the gene expression changes of LR more abundant. DAVID classifications and functional enrichment analysis found that lipid metabolism and carbohydrate metabolism were stronger in NAFLD than in LR, but some other physiological activities including inflammation/immune response, cell adhesion, and migration, cell proliferation and differentiation in NAFLD were weaker than in LR. IPA further indicated that lipid metabolism, inflammation response, and cellular development were highly associated with NAFLD, and thus identified some potential biomarkers for NAFLD.

High expression of GPR50 promotes the proliferation, migration and autophagy of hepatocellular carcinoma cells in vitro.

G protein-coupled receptors (GPCRs) play important roles in tumorigenesis and the development of hepatocellular carcinoma (HCC). GPR50 is an orphan GPCR. Previous studies have indicated that GPR50 could protect against breast cancer development and decrease tumor growth in a xenograft mouse model. However, its role in HCC remains indistinct. To detect the role and the regulation mechanism of GPR50 in HCC, GPR50 expression was analyzed in HCC patients (gene expression omnibus database (GEO) (GSE45436)) and detected in HCC cell line CBRH-7919, and the results showed that GPR50 was significantly up-regulated in HCC patients and CBRH-7919 cell line compared to the corresponding normal control. Gpr50 cDNA was transfected into HCC cell line CBRH-7919, and we found that Gpr50 promoted the proliferation, migration, and autophagy of CBRH-7919. The regulation mechanism of GPR50 in HCC was detected by isobaric tags for relative and absolute quantification (iTRAQ) analysis, and we found that GPR50 promoted HCC was closely related to CCT6A and PGK1. Taken together, GPR50 may promote HCC progression via CCT6A-induced proliferation and PGK1-induced migration and autophagy, and GPR50 could be an important target for HCC.

Overview of CircRNAs Roles and Mechanisms in Liver Fibrosis.

Liver fibrosis represents the reversible pathological process with the feature of the over-accumulation of extracellular matrix (ECM) proteins within the liver, which results in the deposition of fibrotic tissues and liver dysfunction. Circular noncoding RNAs (CircRNAs) have the characteristic closed loop structures, which show high resistance to exonuclease RNase, making them far more stable and recalcitrant against degradation. CircRNAs increase target gene levels by playing the role of a microRNA (miRNA) sponge. Further, they combine with proteins or play the role of RNA scaffolds or translate proteins to modulate different biological processes. Recent studies have indicated that CircRNAs play an important role in the occurrence and progression of liver fibrosis and may be the potential diagnostic and prognostic markers for liver fibrosis. This review summarizes the CircRNAs roles and explores their underlying mechanisms, with a special focus on some of the latest research into key CircRNAs related to regulating liver fibrosis. Results in this work may inspire fruitful research directions and applications of CircRNAs in the management of liver fibrosis. Additionally, our findings lay a critical theoretical foundation for applying CircRNAs in diagnosing and treating liver fibrosis.

The role of Kupffer cells in rat liver regeneration revealed by cell-specific microarray analysis.

Liver regeneration after partial hepatectomy is a process with various types of cells involved. The role of Kupffer cells (KCs) in liver regeneration is still controversial. In this study we isolated KCs from regenerating liver and conducted cell-specific microarray analysis. The results demonstrated that the controversial role of KCs in liver regeneration could be explained with the expression patterns of TGF-α, IL-6, TNF, and possibly IL-18 during liver regeneration. IL-18 may play an important role in negative regulation of liver regeneration. The functional profiles of gene expression in KCs also indicated that KC signaling might play a negative role in cell proliferation: signaling genes were down regulated before cell division. Immune response genes in KCs were also down regulated during liver regeneration, demonstrating similar expression profiles to that of hepatocytes. The expression patterns of key genes in these functional categories were consistent with the temporal functional profiles.

Characterization of transcriptional profiling of Kupffer cells during liver regeneration in rats.

KCs (Kupffer cells), as an important hepatic immunoregulatory cells, play a key role in LR (liver regeneration). Uncovering the transcriptional profiling of KCs after PH (partial hepatectomy) would likely clarify its implication in LR. Here, we isolated KCs by methods of Percoll density gradient centrifugation and immunomagnetic beads. Transcriptional profiles of KCs were monitored up to 168 h post-PH using microarray. By comparing the expression profile of KCs at 2-168 h post-PH with that of the control and applying the statistical and bioinformatics criteria, we found 1407 known and 927 unknown genes related to LR. K-means clustering analysis grouped these 1407 genes into robust 14 time-course clusters representing distinct patterns of regulation. Based on gene-set enrichment analysis, genes encoding products involved in cytokine signalling, inflammatory response and cell chaemotaxis were highly enriched in the cluster characterized by gradual up-regulation and then return; genes in defence response and immune response were enriched in clusters 'the general down-regulation during LR'; genes in fatty acid synthesis and sterol metabolism were preferentially distributed in the cluster 'gradual increase'; whereas genes in the categories 'lipid catabolism' and 'glycolysis' were enriched in cluster 'decrease at two intervals'. According to the above analysis, KCs were seemingly sensitive to operative stimulus; immune defence and detoxification function of KCs obviously dropped post-operatively; fatty acid synthesis were enhanced, whereas lipid catabolism and glycolysis were reduced after PH. This study provides a detailed in vivo gene expression profile of KCs, providing a framework to better understand the molecular mechanisms underlying the regeneration process at cellular level.

Analysis of the role of the integrin signaling pathway in hepatocytes during rat liver regeneration.

To explore the role of the integrin signaling pathway in hepatocytes during rat liver regeneration, the integrin signaling pathway-related gene expression profile in hepatocytes of regenerative liver was detected using Rat Genome 230 2.0 array. The chip data showed that 265 genes of the integrin signaling pathway were included by Rat Genome 230 2.0 array and 132 genes showed significant expression changes in hepatocytes of regenerative liver. The numbers of up-, down- and up/down-regulated genes were 110, 15 and 7 respectively. In addition, bioinformatics and systems biology methods were used to analyze the role of the integrin signaling pathway in hepatocytes. The analysis of gene synergy value indicated that paths 1, 8, 12, and 15 promoted hepatocyte proliferation at the priming phase of liver regeneration; paths 1, 3, 8, and 12-15 enhanced hepatocyte proliferation at the progressing phase; paths 11 and 14 promoted hepatocyte proliferation, while paths 12 and 13 reduced hepatocyte proliferation at the terminal phase. Additionally, the other 8 paths (2, 4, 5-7, 9-10, and 16) were not found to be related to liver regeneration. In conclusion, 132 genes and 8 cascades of the integrin signaling pathway participated in regulating hepatocyte proliferation during rat liver regeneration.

6 Paths of ERK5 signaling pathway regulate hepatocyte proliferation in rat liver regeneration.

Generally, extra-cellular-signal-regulated kinase 5 (ERK5) signaling pathway regulates many physiological activities, such as cell proliferation and cell differentiation. However, little is known about how ERKS signaling pathway composed of 15 paths participates in regulating hepatocyte proliferation during liver regeneration (LR). In this study, to explore the influence ERK5 signaling pathway upon hepatocytes at gene transcription level, rat genome 230 2.0 array was used to detect expression changes of 75 related genes in isolated hepatocytes from rat regenerating liver. Bioinformatics and systems biology methods were applied to analyze the precise role of ERK5 signaling pathway in regulating hepatocyte proliferation during LR. Results showed that 62 genes were contained in the array and 22 genes were significantly changed. It was found that 6 paths were related to hepatocyte proliferation during rat LR. Among them, paths 3, 6 and 13 of ERK5 signaling pathway modulated cell cycle progression by decreasing the negative influence on ERK5 and paths 3, 4, 8 and 9 by reinforcing the positive influence on ERK5. In summary, the study shows that 22 genes and 6 paths of ERK5 signaling pathway participate in regulating proliferation of hepatocytes in rat LR.

The orphan GPR50 receptor interacting with TßRI induces G1/S-phase cell cycle arrest via Smad3-p27/p21 in BRL-3A cells.

The liver has the powerful capacity to regenerate after injury or resection. In one of our previous studies, GPR50 was observed to be significantly upregulated at 6 h, following a partial hepatectomy (PH) in rat liver regeneration (LR) via gene expression profile. However, little research has been done on the regulation and mechanism of GPR50 in the liver. Herein, we observed that the overexpression of GPR50 inhibited the proliferation of BRL-3A cells. To further explore the molecular mechanisms of GPR50 in the regulation of BRL-3A cell proliferation, interaction between GPR50 and transforming growth factor-beta I (TßRI) and iTRAQTM differential proteomic analysis were elucidated, which suggested that GPR50 may interact with TßRI to activate the TGF-ß signaling pathway and arrest BRL-3A cell cycle G1/S transition. Subsequently, the potential mechanism underlying the role of GPR50 in hepatocyte growth was also explored through the addition of a signaling pathway inhibitor. These data suggested that interaction between the orphan GPR50 receptor and TßRI induced the G1/S-phase cell cycle arrest of BRL-3A cells via the Smad3-p27/p21 pathway.

The number of the genes in a functional category matters during rat liver regeneration after partial hepatectomy.

Rat liver regeneration after partial hepatectomy (PH) is a good model to study the regulation of cell proliferation. We isolated hepatocytes from regenerating liver at different time points after PH and used microarray Rat Genome 230 2.0 chip to analyze the functional profiles of all up- or down-regulated genes manually and with automatic gene ontological tools. We found that the transcript expressions of PH and sham operation group were apparently different. For PH group, in the priming phase (2-12 h), signaling, transcription, response to stimulus genes predominated in up-regulated genes; in the proliferation phase (24-72 h), cell proliferation genes predominated; in the termination phase (120-168 h), differentiation and translation genes predominated; while metabolism genes predominated in the down-regulated genes at all time points (2-168 h). These functional profiles are consistent with the cellular and molecular phenomenon observed during liver regeneration, and can be closely connected with the biological process. Moreover, the results indicated that not only the quantity of specific genes but also the number of the genes in the specific functional category was regulated during liver regeneration, which means the number of similar genes in a specific functional category matters as well as the regulation of the genes. The changes of the number of the regulated cell proliferation genes and metabolism genes during liver regeneration were similar to the expression patterns of some cell division genes and metabolism genes.

Role of the autonomic nervous system in rat liver regeneration.

To study the regulatory role of autonomic nervous system in rat regenerating liver, surgical operations of rat partial hepatectomy (PH) and its operation control (OC), sympathectomy combining partial hepatectomy (SPH), vagotomy combining partial hepatectomy (VPH), and total liver denervation combining partial hepatectomy (TDPH) were performed, then expression profiles of regenerating livers at 2 h after operation were detected using Rat Genome 230 2.0 array. It was shown that the expressions of 97 genes in OC, 230 genes in PH, 253 genes in SPH, 187 genes in VPH, and 177 genes in TDPH were significantly changed in biology. The relevance analysis showed that in SPH, genes involved in stimulus response, immunity response, amino acids and K(+) transport, amino acid catabolism, cell adhesion, cell proliferation mediated by JAK-STAT, Ca(+), and platelet-derived growth factor receptor, cell growth and differentiation through JAK-STAT were up-regulated, while the genes involved in chromatin assembly and disassembly, and cell apoptosis mediated by MAPK were down-regulated. In VPH, the genes associated with chromosome modification-related transcription factor, oxygen transport, and cell apoptosis mediated by MAPK pathway were up-regulated, but the genes associated with amino acid catabolism, histone acetylation-related transcription factor, and cell differentiation mediated by Wnt pathway were down-regulated. In TDPH, the genes related to immunity response, growth and development of regenerating liver, cell growth by MAPK pathway were up-regulated. Our data suggested that splanchnic and vagal nerves could regulate the expressions of liver regeneration-related genes.

Analysis of time-course gene expression profiles of sinusoidal endothelial cells during liver regeneration in rats.

Liver regeneration (LR) after partial hepatectomy (PH) requires the coordinate contribution of different cell types. Liver sinusoidal endothelial cells (LSECs), representing the largest population of nonparenchymal cells, are proven to be crucial in LR. However, the details about their implications in regeneration are not still clear. In this study, percoll density centrifugation and immunomagentic bead methods were used to isolate LSECs with high purity and yield; global transcriptional profiles of LSECs during the regeneration were investigated by microarray. 1,629 genes were identified to be LR-related. Among them, there were 833 known genes whose expression patterns were clustered into eight classes. Gene function enrichment analysis showed that genes involved in the major LSEC functions, i.e., coagulation, phagocytosis, and transport, were highly enriched in cluster characterized by rapid induction and gradual return, suggesting the quick reestablishment of LSEC function after PH. Genes in immunity/inflammation and defense response were enriched in clusters exhibiting transient downregulation and quick recovery, possibly being associated with suppression of immunity/inflammation pathway in LSECs at early phase. Genes in glycogen synthesis and glycolysis were enriched in the clusters marked by "significant increase and gradual return" and "slight increase and then downregulation", implying an enhanced carbohydrate metabolism at early phase; detoxification-related genes were markedly distributed in the cluster with feature of rapid increase and then reduction, which was helpful in eliminating waste substance. Taken together, the measurement of gene expression profiling of LSECs and expression pattern analysis of functionally categorized genes gave insight into the mechanism of action of this cell on LR.