A single intraportal administration of follistatin accelerates liver regeneration in partially hepatectomized rats

Kogure, Kimitaka; Omata, Waka; Kanzaki, Makoto; Zhang, You Qing; Yasuda, Hiroshi; Mine, Tetsuya; Kojima, Itaru

doi:10.1016/0016-5085(95)90212-0

Cited by 99 publications

(73 citation statements)

References 16 publications

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“…It was shown that activin A inhibits hepatocyte proliferation, and administration of the activin A antagonist follistatin led to acceleration of liver regeneration after partial hepatectomy (21). During liver regeneration, activin A and its receptors display a characteristic time-dependent expression: activin A receptors are down-regulated immediately after partial hepatectomy.…”

Section: Discussionmentioning

confidence: 99%

Endothelial transcription factor KLF2 negatively regulates liver regeneration via induction of activin A

Manavski

Abel

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Endothelial cells (ECs) not only are important for oxygen delivery but also act as a paracrine source for signals that determine the balance between tissue regeneration and fibrosis. Here we show that genetic inactivation of flow-induced transcription factor Krüppel-like factor 2 (KLF2) in ECs results in reduced liver damage and augmentation of hepatocyte proliferation after chronic liver injury by treatment with carbon tetrachloride (CCl4). Serum levels of GLDH3 and ALT were significantly reduced in CCl4-treated EC-specific KLF2-deficient mice. In contrast, transgenic overexpression of KLF2 in liver sinusoidal ECs reduced hepatocyte proliferation. KLF2 induced activin A expression and secretion from endothelial cells in vitro and in vivo, which inhibited hepatocyte proliferation. However, loss or gain of KLF2 expression did not change capillary density and liver fibrosis, but significantly affected hepatocyte proliferation. Taken together, the data demonstrate that KLF2 induces an antiproliferative secretome, including activin A, which attenuates liver regeneration.

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Section: Discussionmentioning

confidence: 99%

Endothelial transcription factor KLF2 negatively regulates liver regeneration via induction of activin A

Manavski

Abel

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Following partial hepatectomy, follistatin expression was up-regulated after 24-48 h, the time period in which hepatocyte replication was increased [42] . Administration of exogenous follistatin after partial hepatectomy accelerated liver regeneration but led to impaired restoration of normal tissue architecture and compromised liver function [122][123][124] . Administration of follistatin in CCl4-treated rats attenuated the formation of liver fibrosis [125] .…”

Section: Follistatinmentioning

confidence: 99%

Activins and follistatins: Emerging roles in liver physiology and cancer

Kreidl

Öztürk²,

Metzner³

et al. 2009

WJH

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Activins are secreted proteins belonging to the TGF-β family of signaling molecules. Activin signals are crucial for differentiation and regulation of cell proliferation and apoptosis in multiple tissues. Signal transduction by activins relies mainly on the Smad pathway, although the importance of crosstalk with additional pathways is increasingly being recognized. Activin signals are kept in balance by antagonists at multiple levels of the signaling cascade. Among these, follistatin and FLRG, two members of the emerging family of follistatin-like proteins, can bind secreted activins with high affinity, thereby blocking their access to cell surface-anchored activin receptors. In the liver, activin A is a major negative regulator of hepatocyte proliferation and can induce apoptosis. The functions of other activins expressed by hepatocytes have yet to be more clearly defined. Deregulated expression of activins and follistatin has been implicated in hepatic diseases including inflammation, fibrosis, liver failure and primary cancer. In particular, increased follistatin levels have been found in the circulation and in the tumor tissue of patients suffering from hepatocellular carcinoma as well as in animal models of liver cancer. It has been argued that up-regulation of follistatin protects neoplastic hepatocytes from activin-mediated growth inhibition and apoptosis. The use of follistatin as biomarker for liver tumor development is impeded, however, due to the presence of elevated follistatin levels already during preceding stages of liver disease. The current article summarizes our evolving understanding of the multi-faceted activities of activins and follistatins in liver physiology and cancer.

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“…11 Furthermore, blockade of the action of endogenous activin A accelerated liver regeneration and resulted in the appearance of nuclear labeling several hours earlier than in control rats. 25 Therefore, activin A expressed in the remnant liver after partial Recent studies in our laboratory showed that EGF DNA fragmentation was also examined in HL-60 cells stimulated the production of follistatin, an activintreated with A23187 as a posbinding protein, by cultured hepatocytes. 22 As fol- clear morphology, including moderate chromatin condensation.…”

Section: Effect Of Norepinephrine On Follistatin Productionmentioning

confidence: 99%

Norepinephrine reverses the effects of activin A on DNA synthesis and apoptosis in cultured rat hepatocytes

et al. 1996

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apoptosis of cultured rat hepatocytes. (HEPATOLOGY Activin A, an autocrine factor produced by hepato-1996;23:288-293.) cytes, inhibits mitogen-stimulated DNA synthesis and induces apoptotic death of cultured rat hepatocytes. Several lines of evidence indicate that norepinephrine (NE), as a comitogenic growth factor, alters the balance beCellular proliferation is controlled by positive and tween growth stimulation and inhibition and acts as a negative growth regulators. Hepatocytes provide an trigger for the initiation of hepatocyte proliferation. In ideal system for the study of cell growth because of the present study, we examined whether NE modulated special characteristics: they exist in a quiescent state the effects of activin A on rat hepatocytes in primary in the normal adult animal, yet they are capable of culture. Activin A, at a concentration of 10 09 mol/L, extensive, coordinated proliferation following partial blocked the effect of epidermal growth factor (EGF) on hepatectomy. 1,2 Control of cell growth during liver re- DNA synthesis, that was assessed by measuring [ 3 H]generation has been studied extensively both in vivo thymidine incorporation and nuclear labeling, almost and in vitro and synthesis of various growth stimulacompletely, and NE reversed the inhibitory effect of activin A on DNA synthesis. This effect of NE was dose-tors of hepatocyte growth is induced during liver regendependent, being significant at concentrations of 10 06 eration. Transforming growth factor a that shares the mol/L and above, but was overcome by higher concentra-same receptors as epidermal growth factor (EGF), is tions of activin A, and was attenuated by prazosin, but synthesized as an autocrine factor in parenchymal liver not by yohimbine or propranolol. NE exerted its effect cells, 3 while hepatocyte growth factor is delivered via during the first 24 hours of culture, but was ineffective the endocrine mechanism and is synthesized in nonwhen added after 24 hours. EGF augmented the release parenchymal cells, 4-7 that subsequently synthesize of follistatin, an activin-binding protein known to block transforming growth factor b, a potent inhibitor of hethe action of activin A, by hepatocytes and NE did not patocyte growth. 8 Norepinephrine (NE), as a comitoaffect the amount of follistatin they released. In addition genic growth factor, has the potential to enhance the to inhibiting DNA synthesis by hepatocytes cultured with EGF, activin A induced death of hepatocytes cul-mitogenic effects of various growth stimulators. Blocktured in the absence of EGF. The nuclear morphology ade of a 1 -adrenergic receptors by prazosin attenuated of cells cultured with activin A alone was strikingly the DNA synthesis peak seen during liver regenerachanged compared with untreated control cells and tion, 9 that shows clearly that a 1 -adrenergic agonists marked identation of the nuclear membranes and mod-play a critical role during the early stage of liver regenerate chromatin condensation were observed. Fragmen-eration. NE also reduced ...

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A single intraportal administration of follistatin accelerates liver regeneration in partially hepatectomized rats

Cited by 99 publications

References 16 publications

Endothelial transcription factor KLF2 negatively regulates liver regeneration via induction of activin A

Endothelial transcription factor KLF2 negatively regulates liver regeneration via induction of activin A

Activins and follistatins: Emerging roles in liver physiology and cancer

Norepinephrine reverses the effects of activin A on DNA synthesis and apoptosis in cultured rat hepatocytes

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