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Zf9, a Kruppel-like transcription factor up-regulated in vivo during early hepatic fibrosis.

ABSTRACT: Wound repair in the liver induces altered gene expression in stellate cells (resident mesenchymal cells) in a process known as "activation." A zinc finger transcription factor cDNA, zf9, was cloned from rat stellate cells activated in vivo. Zf9 expression and biosynthesis are increased markedly in activated cells in vivo compared with cells from normal rats ("quiescent" cells). The factor is localized to the nucleus and the perinuclear zone in activated but not quiescent cells. Zf9 mRNA also is expressed widely in nonhepatic adult rat tissues and the fetal liver. The zf9 nucleotide sequence predicts a member of the Kruppel-like family with a unique N-terminal domain rich in serine-proline clusters and leucines. The human zf9 gene maps to chromosome 10P near the telomere. Zf9 binds specifically to a DNA oligonucleotide containing a GC box motif. The N-terminal domain of Zf9 (amino acids 1-201) is transactivating in the chimeric GAL4 hybrid system. In Drosophila schneider cells, full length Zf9 transactivates a reporter construct driven by the SV40 promoter/enhancer, which contains several GC boxes. A physiologic role for Zf9 is suggested by its transactivation of a collagen alpha1(I) promoter reporter. Transactivation of collagen alpha1(I) by Zf9 is context-dependent, occurring strongly in stellate cells, modestly in Hep G2 cells, and not at all in D. schneider cells. Our results suggest that Zf9 may be an important signal in hepatic stellate cell activation after liver injury.

SUBMITTER: Ratziu V

PROVIDER: S-EPMC21367 | biostudies-literature | 1998 Aug

REPOSITORIES: biostudies-literature

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Zf9, a Kruppel-like transcription factor up-regulated in vivo during early hepatic fibrosis.

Ratziu V V Lalazar A A Wong L L Dang Q Q Collins C C Shaulian E E Jensen S S Friedman S L SL

Proceedings of the National Academy of Sciences of the United States of America 19980801 16

Wound repair in the liver induces altered gene expression in stellate cells (resident mesenchymal cells) in a process known as "activation." A zinc finger transcription factor cDNA, zf9, was cloned from rat stellate cells activated in vivo. Zf9 expression and biosynthesis are increased markedly in activated cells in vivo compared with cells from normal rats ("quiescent" cells). The factor is localized to the nucleus and the perinuclear zone in activated but not quiescent cells. Zf9 mRNA also is ...[more]

PMID: 9689109

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Project description:UnlabelledKruppel-like factor 6 (KLF6), a zinc finger transcription factor and tumor suppressor, is induced as an immediate-early gene during hepatic stellate cell (HSC) activation. The paradoxical induction of a tumor suppressor in HSCs during proliferation led us to explore the biology of wildtype KLF6 (KLF6(WT) ) and its antagonistic, alternatively spliced isoform KLF6(SV1) in cultured HSCs and animal models. The animal models generated include a global heterozygous KLF6 mouse (Klf6+/-), and transgenic mice expressing either hKLF6(WT) or hKLF6(SV1) under the control of the Collagen α2 (I) promoter to drive HSC-specific gene expression following injury. The rat Klf6 transcript has multiple splice forms that are homologous to those of the human KLF6 gene. Following a transient increase, all rat Klf6 isoforms decreased in response to acute carbon tetrachloride (CCl(4)) liver injury and culture-induced activation. After acute CCl(4), Klf6+/- mice developed significantly increased fibrosis and enhanced fibrogenic messenger RNA (mRNA) and protein expression. In contrast, HSC-specific transgenic mice overexpressing KLF6(WT) or KLF6(SV1) developed significantly diminished fibrosis with reduced expression of fibrogenic genes. Chromatin IP and quantitative reverse-transcription polymerase chain reaction in mouse HSCs overexpressing KLF6(WT) demonstrated KLF6(WT) binding to GC boxes in promoters of Colα1 (I), Colα2 (I), and beta-platelet-derived growth factor receptor (β-Pdgfr) with reduced gene expression, consistent with transcriptional repression by KLF6. Stellate cells overexpressing either KLF6(WT) or KLF6(SV1) were more susceptible to apoptotic stress based on poly (ADP-ribose) polymerase (PARP) cleavage.ConclusionKLF6 reduces fibrogenic activity of HSCs by way of two distinct mechanisms, direct transcriptional repression of target fibrogenic genes and increased apoptosis of activated HSCs. These results suggest that following its initial induction, sustained down-regulation of KLF6 in liver injury may allow de-repression of fibrogenic genes and decreased stellate cell clearance by inhibiting apoptosis.

Project description:AimTo investigate the effects of blueberry on hepatic fibrosis and NF-E2-related factor 2 (Nrf2) transcription factor in rats.MethodsForty-five male Sprague-Dawley rats were randomly divided into control group (A); CCl(4)-induced hepatic fibrosis group (B); blueberry prevention group (C); Dan-shao-hua-xian capsule (DSHX) prevention group (D); and blueberry + DSHX prevention group (E). Liver fibrosis was induced in rats by subcutaneous injection of CCl(4) and a high-lipid/low-protein diet for 8 wk (except the control group). The level of hyaluronic acid (HA) and alanine aminotransferase (ALT) in serum was examined. The activity of superoxide dismutase (SOD), glutathione-S-transferase (GST) and malondialdehyde (MDA) in liver homogenates was determined. The degree of hepatic fibrosis was evaluated by hematoxylin and eosin and Masson staining. Expression of Nrf2 and NADPH quinone oxidoreductase 1 (Nqo1) was detected by real-time reversed transcribed-polymerase chain reaction, immunohistochemical techniques, and western blotting.ResultsCompared with group B, liver indices, levels of serum HA and ALT of groups C, D and E were reduced (liver indices: 0.038 +/- 0.008, 0.036 +/- 0.007, 0.036 +/- 0.005 vs 0.054 +/- 0.009, P < 0.05; HA: 502.33 +/- 110.57 ng/mL, 524.25 +/- 255.42 ng/mL, 499.25 +/- 198.10 ng/mL vs 828.50 +/- 237.83 ng/mL, P < 0.05; ALT: 149.44 +/- 16.51 U/L, 136.88 +/- 10.07 U/L, 127.38 +/- 11.03 U/L vs 203.25 +/- 31.62 U/L, P < 0.05), and SOD level was significantly higher, but MDA level was lower, in liver homogenates (SOD: 1.36 +/- 0.09 U/mg, 1.42 +/- 0.13 U/mg, 1.50 +/- 0.15 U/mg vs 1.08 +/- 0.19 U/mg, P < 0.05; MDA: 0.294 +/- 0.026 nmol/mg, 0.285 +/- 0.025 nmol/mg, 0.284 +/- 0.028 nmol/mg vs 0.335 +/- 0.056 nmol/mg, P < 0.05). Meanwhile, the stage of hepatic fibrosis was significantly weakened (P < 0.05). Compared with group A, the activity of GST liver homogenates and expression levels of Nrf2 and Nqo1 in group B were elevated (P < 0.05). The expression level of Nrf2 and Nqo1 in groups C, D, and E were increased as compared with group B, but the difference was not significant.ConclusionBlueberry has preventive and protective effects on CCl(4)-induced hepatic fibrosis by reducing hepatocyte injury and lipid peroxidation. However, these effects may not be related to the activation of Nrf2 during long-term of CCl(4).

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Zf9, a Kruppel-like transcription factor up-regulated in vivo during early hepatic fibrosis.

Publications

Zf9, a Kruppel-like transcription factor up-regulated in vivo during early hepatic fibrosis.

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