Identification of Differentially Expressed Genes During Proliferative Response of the Liver Induced by Follistatin

Medina, Johan; Yamada, Satoko; Kojima, Itaru

doi:10.1507/endocrj.k09e-224

Cited by 3 publications

(2 citation statements)

References 41 publications

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“…Many studies of the biologic activity of this protein have been limited to gene therapy approaches using adeno-associated viral delivery (Takabe et al, 2003;Kota et al, 2009;Medina et al, 2009;Foley et al, 2010). These investigations have shown that follistatin has potent antiinflammatory activities, wound-healing properties, and muscle hypertrophy and hyperplasia-stimulating effects in rodents and nonhuman primates (Kogure et al, 1995;Wankell et al, 2001;Fuwii et al, 2005;Fumagalli et al, 2007;Tsuchida, 2008;Zimber et al, 2011;de Kretser et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Several groups have reported potent beneficial effects of follistatin administration in various indications, such as inflammation, liver repair, fibrosis, wound healing, hair regrowth, and muscle disorders, including muscular dystrophy (Kogure et al, 1995;Wankell et al, 2001;Fuwii et al, 2005;Fumagalli et al, 2007;Tsuchida, 2008;Zimber et al, 2011;de Kretser et al, 2012). Many of these disorders require systemic wide pharmacological effects, and as a result, several groups have focused on the use of gene therapy in the form of adeno-associated virus to obtain protein exposure levels required for activity in animal models of disease (Takabe et al, 2003;Kota et al, 2009;Medina et al, 2009;Foley et al, 2010). These studies have yielded promising proof-ofconcept data for the therapeutic potential for follistatin; however, from a practical perspective, the use of follistatinadeno-associated virus as a bona fide human therapeutic is squelched by a tenuous clinical and regulatory path.…”

Section: Introductionmentioning

confidence: 99%

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An Engineered Human Follistatin Variant: Insights into the Pharmacokinetic and Pharmocodynamic Relationships of a Novel Molecule with Broad Therapeutic Potential

Datta‐Mannan

Yaden

Krishnan

et al. 2012

J Pharmacol Exp Ther

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Human follistatin is a regulatory glycoprotein with widespread biologic functions, including antiinflammatory activities, woundhealing properties, and muscle-stimulating effects. The role of follistatin in a wide range of biologic activities shows promise for potential clinical application, which has prompted considerable interest in the investigation of the protein as a potential diseasemodifying agent. In spite of this potential, the development of follistatin as a broad use biotherapeutic has been severely hindered by a poor understanding and characterization of its pharmacokinetic/pharmacodynamic (PK/PD) relationships. Therefore, to better define these relationships, we performed in-depth analyses of the PK/PD relationships of native follistatin-315 (FST315). Our data indicate that the intrinsic PK/PD properties of native FST315 are poorly suited for acting as a parentally administered biotherapeutic with broad systemic effects. Here, we leveraged protein engineering to modify the PK characteristics of the native molecule by fusing FST315 to a murine IgG 1 Fc and removing the intrinsic heparan sulfate-binding activity of follistatin. The engineered variant molecule had~100-and 1600-fold improvements in terminal half-life and exposure, respectively. In contrast to the native FST315, the variant showed a robust, dose-dependent pharmacological effect when administered subcutaneously on a weekly basis in mouse models of muscle atrophy and degeneration. These studies highlight the underappreciated and critical relationship between optimizing multiple physical and chemical properties of follistatin on its overall PK/PD profile. Moreover, our findings provide the first documented strategy toward the development of a follistatin therapeutic with potential use in patients affected with skeletal muscle diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An Engineered Human Follistatin Variant: Insights into the Pharmacokinetic and Pharmocodynamic Relationships of a Novel Molecule with Broad Therapeutic Potential

Datta‐Mannan

Yaden

Krishnan

et al. 2012

J Pharmacol Exp Ther

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Activin A induces growth arrest through a SMAD- dependent pathway in hepatic progenitor cells

et al. 2014

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BackgroundActivin A, an important member of transforming growth factor-β superfamily, is reported to inhibit proliferation of mature hepatocyte. However, the effect of activin A on growth of hepatic progenitor cells is not fully understood. To that end, we attempted to evaluate the potential role of activin A in the regulation of hepatic progenitor cell proliferation.ResultsUsing the 2-acetaminofluorene/partial hepatectomy model, activin A expression decreased immediately after partial hepatectomy and then increased from the 9th to 15th day post surgery, which is associated with the attenuation of oval cell proliferation. Activin A inhibited oval cell line LE6 growth via activating the SMAD signaling pathway, which manifested as the phosphorylation of SMAD2/3, the inhibition of Rb phosphorylation, the suppression of cyclinD1 and cyclinE, and the promotion of p21WAF1/Cip1 and p15INK4B expression. Treatment with activin A antagonist follistatin or blocking SMAD signaling could diminish the anti-proliferative effect of activin A. By contrast, inhibition of the MAPK pathway did not contribute to this effect. Antagonizing activin A activity by follistatin administration enhanced oval cell proliferation in the 2-acetylaminofluorene/partial hepatectomy model.ConclusionActivin A, acting through the SMAD pathway, negatively regulates the proliferation of hepatic progenitor cells.

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Regulation of Hepatic Follistatin Expression at Rest and during Exercise in Mice

Peppler

Castellani

Root-McCaig

et al. 2019

Medicine &Amp; Science in Sports &Amp; Exercise

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Introduction Follistatin (FST) is a protein with numerous biological roles and was recently identified as an exercise-inducible hepatokine; however, the signals that regulate this are not well understood. The purpose of this study was to delineate potential endocrine factors that may regulate hepatic FST at rest and during exercise. Methods This study used four experiments. First, male and female C57BL/6J mice remained sedentary or were subjected to a single bout of exercise at moderate or exhaustive intensity with liver collected immediately post. Second, mice were injected with glucagon (1 mg·kg−1, 60 min), epinephrine (2 mg·kg−1, 30 min), glucagon then epinephrine, or saline. Third, mice were pretreated with propranolol (20–60 mg·kg−1, 30 min) before epinephrine injection. Fourth, glucagon receptor wild type (Gcgr +/+ ) or knockout (Gcgr −/− ) mice were pretreated with saline or propranolol (20 mg·kg−1, 30 min) and were subjected to a single bout of exhaustive exercise with liver collected immediately post or after 2 h recovery. In all experiments liver FST mRNA expression was measured, and in experiment four FST protein content was measured. Results A single bout of treadmill exercise performed at an exhaustive but not moderate-intensity increased FST expression, as did injection of glucagon or epinephrine alone and when combined. Pretreatment of mice with propranolol attenuated the epinephrine-induced increase in FST expression. The exercise-induced increase in FST expression was attenuated in Gcgr−/− mice, with no effect of propranolol. Gcgr−/− mice had higher protein content of FST, but there was no effect of exercise or propranolol. Conclusions These data suggest that both glucagon and epinephrine regulate hepatic FST expression at rest; however, only glucagon is required for the exercise-induced increase.

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Identification of Differentially Expressed Genes During Proliferative Response of the Liver Induced by Follistatin

Cited by 3 publications

References 41 publications

An Engineered Human Follistatin Variant: Insights into the Pharmacokinetic and Pharmocodynamic Relationships of a Novel Molecule with Broad Therapeutic Potential

An Engineered Human Follistatin Variant: Insights into the Pharmacokinetic and Pharmocodynamic Relationships of a Novel Molecule with Broad Therapeutic Potential

Activin A induces growth arrest through a SMAD- dependent pathway in hepatic progenitor cells

Regulation of Hepatic Follistatin Expression at Rest and during Exercise in Mice

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