Transdifferentiation of Rat Hepatic Stellate Cells Results in Leptin Expression

Potter, James J.; Womack, Lawrence; Mezey, Esteban; Anania, Frank A.

doi:10.1006/bbrc.1997.8193

Cited by 165 publications

(52 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…16 In severe obesity, however, vascular endothelium is likely to be exposed to much higher concentrations resulting from local leptin release. 17,18 Of note, leptin correlates with the severity of hypertensive retinopathy 3 and stimulates proliferation of renal glomerular cells leading to kidney damage, glomerulosclerosis and proteinuria. 19 Thus, the endothelial effects of leptin might also play a role in the pathogenesis of hypertension-associated complications in obese patients.…”

Section: Discussionmentioning

confidence: 99%

Modulation by leptin of proliferation and apoptosis in vascular endothelial cells

et al. 2002

View full text Add to dashboard Cite

AIM: Plasma leptin concentrations not only correlate with body fat mass, but also with the degree of hypertensive retinopathy. The present study was designed to further examine, whether leptin's proliferative, proangiogenic activity relates to a yet uncovered anti-apoptotic effect. RESULTS: Leptin (10 -50 nmol=l) concentration-dependently reduced apoptosis in HUVECs (human umbilical vein endothelial cells), HAVECs (human adult vein endothelial cells) and HMECs (human microvascular endothelial cells) by 20% (P 0.05). These findings were supported by increased expression of the apoptosis inhibitor bcl-2 ( þ 55%, P 0.05) as well as by differential modulation of the respective cell cycle checkpoint genes=proteins p53 ( 7 20%, P 0.01), p21 WAF-1=Cip1 ( 7 23%, P 0.05) and the Retinoblastoma protein ( þ 123%, P 0.01). CONCLUSION: bcl-2 dependent anti-apoptotic action might contribute to leptin's proangiogenic activity and thereby promote the development of vascular proliferative disease in obesity.

show abstract

Section: Discussionmentioning

confidence: 99%

Modulation by leptin of proliferation and apoptosis in vascular endothelial cells

et al. 2002

View full text Add to dashboard Cite

show abstract

“…Arguments for this notion included: 1) quiescent HSC store substantial amounts of triglycerides besides vitamin A-like adipocytes (4); 2) both quiescent HSC and adipocytes express type IV collagen, whereas activated HSC and preadipocytes express interstitial collagens; 3) cytokines (TNF-␣ and leptin) or growth factors (EGF/TGF␣ and TGF␤), which are known to inhibit adipocyte differentiation, also activate HSCs (5); and 4) adipocyte-specific genes such as leptin are expressed by HSCs (6). Indeed, the expression of PPAR␥, a master regulator for adipocyte differentiation (7), is reduced in activated HSCs (8), and the ligands for this nuclear receptor inhibit HSC activation in vitro (9,10).…”

mentioning

confidence: 99%

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

Zhu

Wang

Tsukamoto

2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

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...

show abstract

“…8 Like neuroendocrine cells, HSC synthesize a variety of catecholamines and express adrenoreceptors, 9 as well as receptors for other neurohumoral factors, such as acetylcholine, 10 neuropeptide Y, 11 angiotensin, 12 somatostatin, 13 and leptin. 14 These features have prompted speculation that HSC might be derived from neural precursors during development. 3 Recent research demonstrates overlap between the signals that regulate the fates of neural and myofibroblastic cells within the gastrointestinal tract.…”

mentioning

confidence: 99%

Role for Hedgehog signaling in hepatic stellate cell activation and viability

Sicklick

Choi

et al. 2005

Laboratory Investigation

171

150

View full text Add to dashboard Cite

Hepatic stellate cells (HSC) have a complex phenotype that includes both neural and myofibroblastic features. The Hedgehog (Hh) pathway has been shown to direct the fate of neural and myofibroblastic cells during embryogenesis and during tissue remodeling in adults. Therefore, we hypothesized that Hh signaling may regulate the fate of HSC in adults. In this study, we find that freshly isolated stellate cells from adult PatchedlacZ transgenic mice exhibit b-galactosidase activity, indicating Hh pathway activity. Transcripts of Hh ligands, the Hh pathway receptor, and Hh-regulated transcription factors are expressed by stellate cells from mice, rats, and humans. Transfection experiments in a cell line using a Hh-inducible luciferase reporter demonstrate constitutive Hh pathway activity. Moreover, neutralizing antibodies to Hh increase apoptosis, while viability is restored by treatment with Hh ligand. In vitro treatment of primary stellate cells with cyclopamine (Cyc), a pharmacologic inhibitor of the Hh pathway, inhibits activation and slightly decreases cell survival, while a single injection of Cyc into healthy adult mice reduces activation of HSC by more than 50% without producing obvious liver damage. Our findings reveal a novel mechanism, namely the Hh pathway, that regulates the activation and viability of HSC.

show abstract

Transdifferentiation of Rat Hepatic Stellate Cells Results in Leptin Expression

Cited by 165 publications

References 35 publications

Modulation by leptin of proliferation and apoptosis in vascular endothelial cells

Modulation by leptin of proliferation and apoptosis in vascular endothelial cells

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

Role for Hedgehog signaling in hepatic stellate cell activation and viability

Contact Info

Product

Resources

About