Transcriptional activation by growth hormone of HNF-6-regulated hepatic genes, a potential mechanism for improved liver repair during biliary injury in mice

Wang, Minhua; Chen, Michael; Zheng, Guoqiang; Dillard, Barney; Tallarico, Mike; Ortiz, Zorayda; Holterman, Ai Xuan

doi:10.1152/ajpgi.00581.2007

Cited by 20 publications

(28 citation statements)

References 48 publications

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“…6). As expected from our laboratory's previous work in GH-treated liver (40,41), HNF6 gene expression was appropriately increased in large (by 1.5-fold) and small BEC (by 1.7-fold) relative to PBS control (Fig. 6A).…”

Section: Effects Of Increasing In Vivo Hnf6 Expression On Target Genesupporting

confidence: 85%

“…With respect to ntcp, transient transfection of CMV-HNF6 expression vectors in HepG2 cell lines did not activate ntcp reporter gene constructs (data not shown). Furthermore, prior AdHNF6 liver infection by tail vein injection did not enhance whole liver ntcp or mrp2 expression (40), suggesting that ntcp and mrp2 gene response cannot be directly attributed to simple HNF6 transcriptional effects on their promoters. Since HNF commonly participate in a transcriptional network with the proper complement of HNF and cross-interaction among HNFs controlling the target gene profile, BEC upregulation of ntcp and mrp2 expression following AdHNF6 infection could be due to potential molecular synergistic interactions between HNF6 and HNF1a/HNF4a/Foxa2, perhaps through the recruitment of coactivators to orchestrate target gene activation.…”

Section: Discussionmentioning

confidence: 91%

“…Since the above data showed that SV40LG and SV40SM cells have differential expression of Foxa2, HNF1a, and HNF4a transcription factors, we next sought to characterize the baseline expression of HNF6, Foxa2, HNF1a, and HNF4a target genes. As control target genes for HNF6, we assayed glucokinase (GK, previously shown to be positively regulated by HNF6) (22) and TGFb2R (shown to be negatively regulated by HNF6) (31,40) and did not find differences in their baseline expression (Fig. 2).…”

Section: Ajp-gastrointest Liver Physiolmentioning

confidence: 99%

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Differential transcriptional characteristics of small and large biliary epithelial cells derived from small and large bile ducts

Glaser

Wang

Ueno

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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Biliary epithelial cells (BEC) are morphologically and functionally heterogeneous. To investigate the molecular mechanism for their diversities, we test the hypothesis that large and small BEC have disparity in their target gene response to their transcriptional regulator, the biliary cell-enriched hepatocyte nuclear factor HNF6. The expression of the major HNF (HNF6, OC2, HNF1b, HNF1a, HNF4a, C/EBPb, and Foxa2) and representative biliary transport target genes that are HNF dependent were compared between SV40-transformed BEC derived from large (SV40LG) and small (SV40SM) ducts, before and after treatment with recombinant adenoviral vectors expressing HNF6 (AdHNF6) or control LacZ cDNA (AdLacZ). Large and small BEC were isolated from mouse liver treated with growth hormone, a known transcriptional activator of HNF6, and the effects on selected target genes were examined. Constitutive Foxa2, HNF1a, and HNF4a gene expression were 2.3-, 12.4-, and 2.6-fold, respectively, higher in SV40SM cells. This was associated with 2.7-and 4-fold higher baseline expression of HNF1a-and HNF4a-regulated ntcp and oatp1 genes, respectively. Following AdHNF6 infection, HNF6 gene expression was 1.4-fold higher (P ϭ 0.02) in AdHNF6 SV40SM relative to AdHNF6 SV40LG cells, with a corresponding higher Foxa2 (4-fold), HNF1a (15-fold), and HNF4a (6-fold) gene expression in AdHNF6-SV40SM over AdHNF6-SV40LG. The net effects were upregulation of HNF6 target gene glucokinase and of Foxa2, HNF1a, and HNF4a target genes oatp1, ntcp, and mrp2 over AdLacZ control in both cells, but with higher levels in AdH6-SV40SM over AdH6-SV40LG of glucokinase, oatp1, ntcp, and mrp2 (by 1.8-, 3.4-, 2.4-, and 2.5-fold, respectively). In vivo, growth hormone-mediated increase in HNF6 expression was associated with similar higher upregulation of glucokinase and mrp2 in cholangiocytes from small vs. large BEC. Small and large BEC have a distinct profile of hepatocyte transcription factor and cognate target gene expression, as well as differential strength of response to transcriptional regulation, thus providing a potential molecular basis for their divergent function. heterogeneity; bile transport; hepatocyte nuclear factors; hepatocyte nuclear factor 6

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Section: Effects Of Increasing In Vivo Hnf6 Expression On Target Genesupporting

confidence: 85%

Section: Discussionmentioning

confidence: 91%

Section: Ajp-gastrointest Liver Physiolmentioning

confidence: 99%

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Differential transcriptional characteristics of small and large biliary epithelial cells derived from small and large bile ducts

Glaser

Wang

Ueno

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…As conclusive evidence that FSH plays a key role in sustaining cholangiocyte proliferation by an autocrine mechanism, we have knocked down the FSH gene in NRICC and demonstrated that lack of FSH in cholangiocytes leads to loss of proliferative capacity and enhanced apoptosis. In support of the growth-promoting effects of FSH on the biliary epithelium, other studies have shown that other pituitary hormones, such as growth hormone (12,63) and prolactin (58), sustain cholangiocyte proliferation. Although FSH (expressed and secreted by hepatocytes) may modulate cholangiocyte growth by a paracrine mechanism, our studies support the novel concept that FSH is a key player in the autocrine loop regulating the balance between cholangiocyte proliferation and loss.…”

Section: Discussionmentioning

confidence: 92%

Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1

Mancinelli¹,

Onori²,

Gaudio³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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mones regulate cholangiocyte hyperplasia in bile duct-ligated (BDL) rats. We studied whether follicle-stimulating hormone (FSH) regulates cholangiocyte proliferation. FSH receptor (FSHR) and FSH expression was evaluated in liver sections, purified cholangiocytes, and cholangiocyte cultures (NRICC). In vivo, normal female and male rats were treated with FSH or immediately after BDL with antide (a gonadotropin-releasing hormone antagonist blocking FSH secretion) or a neutralizing FSH antibody for 1 wk. We evaluated 1) cholangiocyte proliferation in sections and cholangiocytes and 2) changes in secretin-stimulated cAMP (functional index of cholangiocyte growth) levels, and ERK1/2 and Elk-1 phosphorylation. NRICC were stimulated with FSH before evaluation of proliferation, cAMP/IP3 levels, and ERK1/2 and Elk-1 phosphorylation. To determine whether FSH regulates cholangiocyte proliferation by an autocrine mechanism, we evaluated the effects of 1) cholangiocyte supernatant (containing FSH) on NRICC proliferation and 2) FSH silencing in NRICC before measuring proliferation and ERK1/2 and Elk-1 phosphorylation. Cholangiocytes and NRICC express FSHR and FSH and secrete FSH. In vivo administration of FSH to normal rats increased, whereas administration of antide and anti-FSH antibody to BDL rats decreased 1) ductal mass and 2) secretin-stimulated cAMP levels, proliferation, and ERK1/2 and Elk-1 phosphorylation in cholangiocytes compared with controls. In NRICC, FSH increased cholangiocyte proliferation, cAMP levels, and ERK1/2 and Elk-1 phosphorylation. (8), prolactin (58), and progesterone (25). The cAMP/ERK1/2/Elk-1 signaling has been shown to play a key role in the regulation of cholangiocyte proliferation (18,20,24,27,37). For example, whereas increased cAMP levels sustain cholangiocyte growth (20,24,27,37), decreased cAMP synthesis results in inhibition of cholangiocyte hyperplasia (24,27,37).Follicle-stimulating hormone (FSH) is the central hormone of the mammalian reproduction (55). FSH, also called gonadotropin because it stimulates the gonads, is produced from the anterior pituitary gland of the brain (60). FSH is a large glycoprotein composed of alpha and beta subunits, similar to those of luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and human chorionic gonadotropin (hCG) (1). The alpha subunits of FSH, LH, TSH, and hCG are identical, whereas the beta subunit is unique and endows each hormone with the ability to binds to its own receptor (60). FSH interacts with a receptor protein that has seven transmembrane-spanning domains; its binding is transduced into an intracellular signal via the heterotrimeric G proteins (61). Following coupling of the FSHR to G␣ s adenylyl cyclase is stimulated, followed by production of cAMP and activation of PKA, which phosphorylates structural proteins, enzymes, and transcriptional activators (32,66). Whether the FSH receptor is also linked to G␣ i has not yet been completely defined. In fact, the treatment of Sertoli cells with pertussis toxin (PTX, a G␣ i inhib...

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“…HNF6 controls the expression of many liver-specific genes, which are involved in the glucose metabolism, bile homeostasis, and hepatic cell proliferation (13). The expression of HNF6 is regulated by growth hormone (GH), and the GH-HNF6 pathway has been shown to be imperative for liver protection against chronic injury through regulating the expression of genes involved in proliferation (14)(15)(16). The GH-HNF6 pathway also contributes to the gender disparity via regulating the expression of some female-predominant genes (17).…”

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confidence: 99%

Inhibition of Hepatitis B Virus Gene Expression and Replication by Hepatocyte Nuclear Factor 6

Hao

Liu

et al. 2015

J Virol

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Hepatitis B virus (HBV), a small enveloped DNA virus, chronically infects more than 350 million people worldwide and causes liver diseases from hepatitis to cirrhosis and liver cancer. Here, we report that hepatocyte nuclear factor 6 (HNF6), a liver-enriched transcription factor, can inhibit HBV gene expression and DNA replication. Overexpression of HNF6 inhibited, while knockdown of HNF6 expression enhanced, HBV gene expression and replication in hepatoma cells. Mechanistically, the SP2 promoter was inhibited by HNF6, which partly accounts for the inhibition on S mRNA. Detailed analysis showed that a cis element on the HBV genome (nucleotides [nt] 3009 to 3019) was responsible for the inhibition of the SP2 promoter by HNF6. Moreover, further analysis showed that HNF6 reduced viral pregenomic RNA (pgRNA) posttranscriptionally via accelerating the degradation of HBV pgRNA independent of La protein. Furthermore, by using truncated mutation experiments, we demonstrated that the N-terminal region of HNF6 was responsible for its inhibitory effects. Importantly, introduction of an HNF6 expression construct with the HBV genome into the mouse liver using hydrodynamic injection resulted in a significant reduction in viral gene expression and DNA replication. Overall, our data demonstrated that HNF6 is a novel host factor that can restrict HBV replication via both transcriptional and posttranscriptional mechanisms. IMPORTANCEHBV is a major human pathogen whose replication is regulated by host factors. Liver-enriched transcription factors are critical for many liver functions, including metabolism, development, and cell proliferation, and some of them have been shown to regulate HBV gene expression or replication in different manners. In this study, we showed that HNF6 could inhibit the gene expression and DNA replication of HBV via both transcriptional and posttranscriptional mechanisms. As HNF6 is differentially expressed in men and women, the current results may suggest a role of HNF6 in the gender dimorphism of HBV infection.

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Transcriptional activation by growth hormone of HNF-6-regulated hepatic genes, a potential mechanism for improved liver repair during biliary injury in mice

Abstract: activation by growth hormone of HNF-6-regulated hepatic genes, a potential mechanism for improved liver repair during biliary injury in mice.

Cited by 20 publications

References 48 publications

Differential transcriptional characteristics of small and large biliary epithelial cells derived from small and large bile ducts

Differential transcriptional characteristics of small and large biliary epithelial cells derived from small and large bile ducts

Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1

Inhibition of Hepatitis B Virus Gene Expression and Replication by Hepatocyte Nuclear Factor 6

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