The Forkhead Transcription Factor FoxO1 Regulates Proliferation and Transdifferentiation of Hepatic Stellate Cells

Adachi, Masayuki; Osawa, Yosuke; Uchinami, Hiroshi; Kitamura, Tadahiro; Accili, Domenico; Brenner, David A.

doi:10.1053/j.gastro.2007.01.033

Cited by 144 publications

(127 citation statements)

References 49 publications

(63 reference statements)

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“…Stellate cell activation and fibrogenesis are amplified in cells from mice with reduced FoxO1 activity. 87 Similar to Lhx2, the peroxisome proliferator activated receptor γ nuclear receptor downregulates stellate cell activation and reduces collagen gene expression. 88 This and related observations 89 have prompted the use of peroxisome proliferator activated receptor γ ligands in clinical trials not only in fibrosis associated with NASH, but also as a candidate antifibrotic in patients with HCV fibrosis.…”

Section: Pathways Of Stellate Cell Activation: a Moving Target Initiamentioning

confidence: 99%

Mechanisms of Hepatic Fibrogenesis

2008

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Substantial improvements in the treatment of chronic liver disease have accelerated interest in uncovering the mechanisms underlying hepatic fibrosis and its resolution. Activation of resident hepatic stellate cells into proliferative, contractile, and fibrogenic cells in liver injury remains a dominant theme driving the field. However, several new areas of rapid progress in the past 5-10 years also have taken root, including: (1) identification of different fibrogenic populations apart from resident stellate cells, for example, portal fibroblasts, fibrocytes, and bone-marrow-derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely regulated determinants of hepatic inflammation and immunity; (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, posttranscriptional, and epigenetic mechanisms; (4) recognition of disease-specific pathways of fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross-linking and scar maturation in determining reversibility; and (6) hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer, and regeneration. Clinical and translational implications of these advances have become clear, and have begun to impact significantly on the management and outlook of patients with chronic liver disease.The field of hepatic fibrosis is flourishing thanks to continued experimental advances complemented by exciting progress in the treatment of chronic liver disease. 1 Control of chronic hepatitis B and C by antiviral therapies has established that advanced fibrosis can regress in association with improved clinical outcomes, 2-4 thereby intensifying enthusiasm to uncover the mechanistic basis for hepatic fibrogenesis and its attenuation. At the same time, simple paradigms defining the cellular sources of extracellular matrix (ECM), and the roles of cytokines and paracrine interactions among resident liver cells and inflammatory cells have yielded a more nuanced understanding of how the liver responds to injury. These advances have had a collateral benefit towards understanding fibrosis in other organs, particularly the pancreas. 5 Thus, a review of the mechanisms underlying hepatic fibrosis is not only timely, but is more clinically relevant than ever. This article focuses on recent advances in the field, building on established principles from earlier reviews 6,7 while weaving in their clinical relevance, but also emphasizing the molecular subtleties that have emerged through continued progress in the field. General PrinciplesFibrosis, or scarring of the liver, is a wound-healing response that engages a range of cell types and mediators to encapsulate injury. Although even acute injury will activate mechanisms of fibrogenesis, the sustained signals associated with chronic liver disease caused by infection, Cirrhosis, the most advanced stage ...

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Section: Pathways Of Stellate Cell Activation: a Moving Target Initiamentioning

confidence: 99%

Mechanisms of Hepatic Fibrogenesis

2008

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“…Thus, these findings establish FoxO proteins as key transcriptional regulators of the PI3K-PKB pathway that control the cell cycle, which in turn modulates cell proliferation and development. Similarly, transgenic and gene deletion studies have also shown that FoxO1 plays a crucial role in liver fibrosis, a process that causes hepatic stellate cells to transdifferentiate from a quiescent phenotype to a proliferating collagen-producing myofibroblast-like phenotype (Adachi et al, 2007). Constitutively active FoxO1 has been demonstrated to inhibit hepatic stellate cell proliferation, via cell cycle arrest at the G1 phase, while dominant-negative FoxO1 promotes proliferation of hepatic stellate cells, even in the presence of the PI3K inhibitor LY294002.…”

Section: Foxo Cell Cycle Arrest and Cell-fate Decisionsmentioning

confidence: 99%

Many forks in the path: cycling with FoxO

2008

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FoxO transcription factors are an evolutionary conserved subfamily of the forkhead transcription factors, characterized by the forkhead DNA-binding domain. FoxO factors regulate a number of cellular processes involved in cell-fate decisions in a cell-type-and environment-specific manner, including metabolism, differentiation, apoptosis and proliferation. A key mechanism by which FoxO determines cell fate is through regulation of the cell cycle machinery, and as such the cellular consequence of FoxO deregulation is often manifested through perturbation of the cell cycle. Consequently, the deregulation of FoxO factors is implicated in the development of numerous proliferative diseases, in particular cancer.

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“…The functional significance of FOXO1 expression in hepatic nonparenchymal cells is still undergoing definition: FOXO1 inhibits proliferation of hepatic stellate cells and fibrogenesis, but the activation status was not evaluated in NASH (38), and no data are available for Kupffer cells.…”

Section: Foxo1 and Insulin Resistance In Nashmentioning

confidence: 99%

Increased Expression and Activity of the Transcription Factor FOXO1 in Nonalcoholic Steatohepatitis

et al. 2008

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OBJECTIVE-Nonalcoholic fatty liver, affecting 34% of the U.S. population, is characterized by hepatic insulin resistance, which is more marked in the presence of steatohepatitis, and frequently precedes hyperglycemia. The molecular mechanisms underlying the relationship between fatty liver and insulin resistance are still undergoing definition and have not been evaluated in humans. Our aim was to evaluate the relationship between insulin resistance and the expression and regulation of forkhead boxcontaining protein O subfamily-1 (FOXO1), a transcription factor that mediates the effect of insulin on the gluconeogenic genes PEPCK and glucose-6-phosphatase catalytic subunit (G6PC). RESEARCH DESIGN AND METHODS-FOXO1, PEPCK, and G6PC mRNA levels were evaluated in 84 subjects: 26 with steatohepatitis, 28 with steatosis alone, 14 with normal liver histology without metabolic alterations, and 16 with hepatitis C virus chronic hepatitis, of whom 8 were with and 8 were without steatosis. Protein expression and regulation of FOXO1 and upstream insulin signaling were analyzed in a subset.RESULTS-Expression of PEPCK was higher in steatohepatitis compared with steatosis alone and normal liver, and it was correlated with the homeostasis model assessment of insulin resistance (HOMA-IR) index. FOXO1 mRNA levels were higher in steatohepatitis, correlated with PEPCK and G6PC mRNA and with HOMA-IR. FOXO1 upregulation was confirmed at protein levels in steatohepatitis and, in the presence of oxidative stress, was associated with decreased Ser 256 phosphorylation, decreased Akt1, and increased Jun NH 2 -terminal kinase-1 activity. Consistently, immunohistochemistry showed increased FOXO1 expression and nuclear localization in steatohepatitis. FOXO1 mRNA levels correlated with nonalcoholic steatohepatitis activity score and were modulated by drugs counteracting hepatic lipogenesis.CONCLUSIONS-FOXO1 expression and activity are increased in patients with steatohepatitis, and mRNA levels are correlated with hepatic insulin resistance.

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The Forkhead Transcription Factor FoxO1 Regulates Proliferation and Transdifferentiation of Hepatic Stellate Cells

Cited by 144 publications

References 49 publications

Mechanisms of Hepatic Fibrogenesis

Mechanisms of Hepatic Fibrogenesis

Many forks in the path: cycling with FoxO

Increased Expression and Activity of the Transcription Factor FOXO1 in Nonalcoholic Steatohepatitis

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