Proliferation of hepatic stellate cells is inhibited by phosphorylation of CREB on serine 133.

Houglum, K; Lee, K S; Chojkier, Mario

doi:10.1172/jci119291

Cited by 78 publications

(76 citation statements)

References 47 publications

(67 reference statements)

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“…In activated HSCs, COUP-TFII is induced. 3 How necdin and Wnt10b cross-inter- (35) and may be a negative regulator of the necdin-Wnt pathway identified by the present study. Although we identified necdin to be upstream of Wnt, how other preadipocyte-selective or anti-adipogenic genes regulate necdin expression in HSCs, is unknown at the present time.…”

mentioning

confidence: 70%

The Necdin-Wnt Pathway Causes Epigenetic Peroxisome Proliferator-activated Receptor γ Repression in Hepatic Stellate Cells

Zhu

Wang

Tsukamoto

2010

Journal of Biological Chemistry

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Hepatic stellate cells (HSCs), vitamin A-storing liver pericytes, undergo myofibroblastic trans-differentiation or "activation" to participate in liver wound healing. This cellular process involves loss of regulation by adipogenic transcription factors such as peroxisome proliferator-activated receptor ␥ (PPAR␥). Necdin, a melanoma antigen family protein, promotes neuronal and myogenic differentiation while inhibiting adipogenesis. The present study demonstrates that necdin is selectively expressed in HSCs among different liver cell types and induced during their activation in vitro and in vivo. Silencing of necdin with adenovirally expressed shRNA, reverses activated HSCs to quiescent cells in a manner dependent on PPAR␥ and suppressed canonical Wnt signaling. Promoter analysis, site-directed mutagenesis, and chromatin immunoprecipitation demonstrate that Wnt10b, a canonical Wnt induced in activated HSCs, is a direct target of necdin. Necdin silencing abrogates three epigenetic signatures implicated in repression of PPAR␥: increased MeCP2 (methyl CpG binding protein 2) and HP-1␣ co-repressor recruitments to Ppar␥ promoter and enhanced H3K27 dimethylation at the exon 5 locus, again in a manner dependent on suppressed canonical Wnt. These epigenetic effects are reproduced by antagonism of canonical Wnt signaling with Dikkopf-1. Our results demonstrate a novel necdinWnt pathway, which serves to mediate antiadipogenic HSC trans-differentiation via epigenetic repression of PPAR␥. Hepatic stellate cells (HSCs)2 are desmin-positive mesenchymal cells located in the subendothelial (perisinusoidal) space of hepatic sinusoids. They store vitamin A, function as hepatic pericytes, communicate with hepatocytes via a gap junction and the release of soluble factors, and produce the components of the normal matrix milieu of the perisinusoidal space. HSCs also actively participate in matrix remodeling and wound healing through their production of matrix metalloproteinases and extracellular matrix proteins and are considered as one of the principal cell types responsible for the genesis of liver fibrosis (1). The most unique feature of the manner in which HSCs participate in liver fibrogenesis is their myofibroblastic transdifferentiation (activation) characterized by depletion of vitamin A storage, cell proliferation, induction of matrix genes, and acquisition of the myofibroblastic phenotype via induction of ␣-smooth muscle actin. Although major classes of mediators are identified for HSC trans-differentiation, including soluble factors (cytokines, hormones, and lipid mediators), reactive oxygen species, and altered extracellular matrix milieu (1), the fundamental understanding of cell lineage and cell fate regulation of HSCs is elusive. In this regard, Asahina et al. (2) has demonstrated recently the mesenchymal origin of fetal HSCs and "submesothelial cell" as a potential precursor for HSCs. Intriguingly, HSCs express markers for cell types derived from multipotent mesenchymal progenitor cells such as neural cells, chondrocyt...

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confidence: 70%

The Necdin-Wnt Pathway Causes Epigenetic Peroxisome Proliferator-activated Receptor γ Repression in Hepatic Stellate Cells

Zhu

Wang

Tsukamoto

2010

Journal of Biological Chemistry

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“…PKA and CaMKs may act synergistically, and in different cell types both kinases are known to phosphorylate a cAMPresponsive element-binding protein at Ser 133 (24,31,33 (Fig. 2B) or absence (data not shown) of extracellular Ca 2ϩ , and ACTH stimulates aldosterone production in Ca 2ϩ -free medium (Fig.…”

Section: Discussionmentioning

confidence: 98%

Regulation of aldosterone production from zona glomerulosa cells by ANG II and cAMP: evidence for PKA-independent activation of CaMK by cAMP

Gambaryan¹,

Butt²,

Tas³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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Aldosterone production in zona glomerulosa (ZG) cells of adrenal glands is regulated by various extracellular stimuli (K ϩ , ANG II, ACTH) that all converge on two major intracellular signaling pathways: an increase in cAMP production and calcium (Ca 2ϩ ) mobilization. However, molecular events downstream of the increase in intracellular cAMP and Ca 2ϩ content are controversial and far from being completely resolved. Here, we found that Ca 2ϩ /calmodulin-dependent protein kinases (CaMKs) play a predominant role in the regulation of aldosterone production stimulated by ANG II, ACTH, and cAMP. The specific CaMK inhibitor KN93 strongly reduced ANG II-, ACTH-, and cAMP-stimulated aldosterone production. In in vitro kinase assays and intact cells, we could show that cAMP-induced activation of CaMK, using the adenylate cyclase activator forskolin or the cAMP-analog Sp-5,6-DCIcBIMPS (cBIMPS), was not mediated by PKA. Activation of the recently identified cAMP target protein Epac (exchange protein directly activated by cAMP) by 8-pCPT-2Ј-O-Me-cAMP had no effect on CaMK activity and aldosterone production. Furthermore, we provide evidence that cAMP effects in ZG cells do not involve Ca 2ϩ or MAPK signaling. Our results suggest that ZG cells, in addition to PKA and Epac/Rap proteins, contain other as yet unidentified cAMP mediator(s) involved in regulating CaMK activity and aldosterone secretion. angiotension II; adenosine 3Ј,5Ј-cyclic monophosphate; adenosine 3Ј,5Ј-cyclic monophosphate-dependent protein kinase; Ca 2ϩ /calmodulin-dependent kinase ALL STEROID HORMONES, INCLUDING ALDOSTERONE, are synthesized from a common precursor, cholesterol. Stimulation of steroidproducing cells results in prompt mobilization of cholesterol esters from intracellular lipid droplets and their enzymatic hydrolysis to free cholesterol by cholesterol ester hydrolase (CEH) (8). Free cholesterol is then transported to the outer mitochondrial membrane (28,29,50,57), where it is transferred to the side-chain cleavage enzyme system that is localized at the inner mitochondrial membranes. The latter step is the rate-limiting step in steroidogenesis and depends on the activity and phosphorylation of the steroidogenic acute regulatory protein (StAR) (49).The steroid hormone aldosterone produced in adrenal zona glomeruloza (ZG) cells is a major regulator of intravascular volume and blood pressure. Many hormonal and paracrine factors are involved in the regulation of aldosterone production; however, under physiological conditions, the most important ones are adrenocorticotropin (ACTH), angiotensin II (ANG II), and extracellular K ϩ (19, 46). The main action of ACTH in ZG cells is connected with the activation of transmembrane G s ␣-coupled ACTH receptors and the generation of cAMP as a second messenger (11,37). Until the recent discovery of a new family of cAMP-binding proteins [exchange proteins directly activated by cAMP (Epacs)] that can directly activate small GTPases Rap1 and Rap2 (12), cAMP signaling was mainly linked to the activation of cAMP-de...

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“…Interestingly, increased cAMP has been implicated in the inhibition of markers of HSC activation. Treatment of HSC with stable analogues of cAMP, or agents that inhibit phosphodiesterases, resulted in retention of retinoid stores, suppressed SMA expression, decreased proliferation, reduced collagen expression, and blunted sensitivity to endothelin-1 [29][30][31][32][33]. Therefore, cAMP elevation may be the mechanism of action for relaxin in these cells.…”

Section: Discussionmentioning

confidence: 99%

Relaxin receptors in hepatic stellate cells and cirrhotic liver

Bennett

Dalton

Mahan

et al. 2007

Biochemical Pharmacology

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Proliferation of hepatic stellate cells is inhibited by phosphorylation of CREB on serine 133.

Cited by 78 publications

References 47 publications

The Necdin-Wnt Pathway Causes Epigenetic Peroxisome Proliferator-activated Receptor γ Repression in Hepatic Stellate Cells

The Necdin-Wnt Pathway Causes Epigenetic Peroxisome Proliferator-activated Receptor γ Repression in Hepatic Stellate Cells

Regulation of aldosterone production from zona glomerulosa cells by ANG II and cAMP: evidence for PKA-independent activation of CaMK by cAMP

Relaxin receptors in hepatic stellate cells and cirrhotic liver

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