Adipogenic Transcriptional Regulation of Hepatic Stellate Cells

Hepatic stellate cells (HSC) undergo transdifferentiation (activation) from lipid-storing pericytes to myofibroblastic cells to participate in liver fibrogenesis. Our recent work demonstrates that depletion of peroxisome proliferator-activated receptor γ (PPARγ) constitutes one of the key molecular events for HSC activation and that ectopic expression of this nuclear receptor achieves the phenotypic reversal of activated HSC to the quiescent cells. The present study extends these findings to test a novel hypothesis that adipogenic transcriptional regulation is required for the maintenance of HSC quiescence. Comparative analysis of quiescent and activated HSC in culture reveals higher expression of putative adipogenic transcription factors such as CCAAT/enhancer-binding protein (C/EBP) α, C/EBPβ, C/EBPδ, PPARγ, liver X receptor α, sterol regulatory element-binding protein 1c and of adipocyte-specific genes in the quiescent cells. Conversely, activated HSC have increased expression of PPARβ, a transcription factor known to promote fatty acid oxidation. A treatment of activated HSC with the adipocyte differentiation mixture (isobutylmethylxanthine, dexamethasone, and insulin) or ectopic expression of PPARγ or SREBP-1c in these cells, induces a panel of adipogenic transcription factors, reduces PPARβ, and causes the phenotypic reversal to quiescent HSC. These results support the importance of adipogenic transcriptional regulation in HSC quiescence and provide a new framework for identifying novel molecular targets for the treatment of liver cirrhosis. Hepatic stellate cells (HSC) undergo transdifferentiation (activation) from lipid-storing pericytes to myofibroblastic cells to participate in liver fibrogenesis. Our recent work demonstrates that depletion of peroxisome proliferator-activated receptor γ (PPARγ) constitutes one of the key molecular events for HSC activation and that ectopic expression of this nuclear receptor achieves the phenotypic reversal of activated HSC to the quiescent cells. The present study extends these findings to test a novel hypothesis that adipogenic transcriptional regulation is required for the maintenance of HSC quiescence. Comparative analysis of quiescent and activated HSC in culture reveals higher expression of putative adipogenic transcription factors such as CCAAT/enhancer-binding protein (C/EBP) α, C/EBPβ, C/EBPδ, PPARγ, liver X receptor α, sterol regulatory element-binding protein 1c and of adipocyte-specific genes in the quiescent cells. Conversely, activated HSC have increased expression of PPARβ, a transcription factor known to promote fatty acid oxidation. A treatment of activated HSC with the adipocyte differentiation mixture (isobutylmethylxanthine, dexamethasone, and insulin) or ectopic expression of PPARγ or SREBP-1c in these cells, induces a panel of adipogenic transcription factors, reduces PPARβ, and causes the phenotypic reversal to quiescent HSC. These results support the importance of adipogenic transcriptional regulation in HSC quiescence and provide a new framework for identifying novel molecular targets for the treatment of liver cirrhosis. Transdifferentiation of vitamin A-storing hepatic stellate cells (HSC) 1The abbreviations used are: HSC, hepatic stellate cell(s); PPAR, peroxisome proliferator-activated receptor; SREBP, sterol regulatory element-binding protein; C/EBP, CCAAT/enhancer-binding protein; LXR, liver X receptor; MDI, isobutylmethylxanthine, dexamethazone, and insulin; FAS, fatty acid synthase; ACC, acetyl-CoA carboxylase; TGF, transforming growth factor; MOI, multiplicity of infection; PBS, phosphate-buffered saline; SCAP, SREBP cleavage-activating protein; GFP, green fluorescent protein.1The abbreviations used are: HSC, hepatic stellate cell(s); PPAR, peroxisome proliferator-activated receptor; SREBP, sterol regulatory element-binding protein; C/EBP, CCAAT/enhancer-binding protein; LXR, liver X receptor; MDI, isobutylmethylxanthine, dexamethazone, and insulin; FAS, fatty acid synthase; ACC, acetyl-CoA carboxylase; TGF, transforming growth factor; MOI, multiplicity of infection; PBS, phosphate-buffered saline; SCAP, SREBP cleavage-activating protein; GFP, green fluorescent protein. to vitamin A-depleted myofibroblastic cells represents a key cellular event in the genesis of cirrhosis, for which no effective medial treatments are currently available except for liver transplantation. Transdifferentiated (activated) HSC are proliferative, proinflammatory, and fibrogenic with induced ability to synthesize and deposit extracellular matrices (1Friedman S.L. J. Hepatol. 2003; 38: S38-S53Abstract Full Text Full Text PDF PubMed Google Scholar). Thus, better understanding of the mechanism underlying HSC transdifferentiation is the pivotal step toward identification of molecular targets for new and effective treatments for the disease. The most fundamental prerequisite for the understanding of HSC transdifferentiation is defining the cell type of differentiated HSC. This question relates to the origin of HSC that continues to puzzle the field. HSC are believed to serve as pericytes for hepatic capillaries called sinusoids. They represent 5–8% of total liver cells and 15–23% of nonparenchymal cells in the normal liver (2Geerts A. Semin. Liver Dis. 2001; 21: 311-335Crossref PubMed Scopus (587) Google Scholar). HSC are positive for a mesenchymal marker such as vimentin. Rodent HSC express desmin (3Yokoi Y. Namihisa T. Kuroda H. Komatsu I. Miyazaki A. Watanabe S. Usui K. Hepatology. 1984; 4: 709-714Crossref PubMed Scopus (342) Google Scholar) and glial fibrillary acidic protein (4Gard A.L. White F.P. Dutton G.R. J. Neuroimmunol. 1985; 8: 359-375Abstract Full Text PDF PubMed Scopus (153) Google Scholar), suggesting smooth muscle cell and glial cell lineage, respectively. Upon activation, both rodent and human HSC lose vitamin A and begin to express α-smooth muscle actin (5Ramadori G. Veit T. Schwogler S. Dienes H.P. Knittel T. Meyer zum Rieder H. Buschenfelde K.H. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 1990; 59: 349-357Crossref PubMed Scopus (281) Google Scholar, 6Enzan H. Himeno H. Iwamura S. Saibara T. Onishi S. Yamamoto Y. Hara H. Virchows Arch. 1994; 424: 249-256Crossref PubMed Scopus (119) Google Scholar). Interestingly, undifferentiated HSC in fetal livers that do not yet exhibit vitamin A storage also express α-smooth muscle actin (7Suskind D.L. Muench M.O. J. Hepatol. 2004; 40: 261-268Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar), supporting a smooth muscle cell lineage. Synaptophysin, which controls exocytosis and the release of neurotransmitters in neurons and neuroendocrine cells, is also expressed in both rodent and human HSC (8Cassiman D. van Pelt J. De Vos R. Lommel VanF. Desmet V. Yap S.H. Roskams T. Am. J. Pathol. 1999; 155: 1831-1839Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). Neurotrophins such as nerve growth factor, brain-derived neurotrophic factor (BDNF), neutrophin NT-3, and NT-4/5 are also expressed (9Cassiman D. Denef C. Desmet V.J. Roskams T. Hepatology. 2001; 33: 148-158Crossref PubMed Scopus (190) Google Scholar), and so are their receptors, Trk-A, B, and C (9Cassiman D. Denef C. Desmet V.J. Roskams T. Hepatology. 2001; 33: 148-158Crossref PubMed Scopus (190) Google Scholar, 10Trim N. Morgan S. Evans M. Issa R. Fine D. Afford S. Wilkins B. Iredale J. Am. J. Pathol. 2000; 156: 1235-1243Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar), further supporting the neural and glial lineage. Peroxisome proliferator-activated receptor γ (PPARγ) has been proposed as a potential molecular target for inhibition of HSC transdifferentiation (11Miyahara T. Schrum L. Rippe R. Xiong S. Yee Jr., H.F. Motomura K. Anania F.A. Willson T.M. Tsukamoto H. J. Biol. Chem. 2000; 275: 35715-35722Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar, 12Marra F. Efsen E. Romanelli R.G. Caligiuri A. Pastacaldi S. Batignani G. Bonacchi A. Caporale R. Laffi G. Pinzani M. Gentilini P. Gastroenterology. 2000; 119: 466-478Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar, 13Galli A. Crabb D.W. Ceni E. Salzano R. Mello T. Svegliati-Baroni G. Ridolfi F. Trozzi L. Surrenti C. Casini A. Gastroenterology. 2002; 122: 1924-1940Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar). PPARγ level and activity are reduced in activated HSC, and the treatment of HSC with synthetic ligands for PPARγ such as thiazolidinediones effectively suppresses fibrogenic activity of HSC in vitro (11Miyahara T. Schrum L. Rippe R. Xiong S. Yee Jr., H.F. Motomura K. Anania F.A. Willson T.M. Tsukamoto H. J. Biol. Chem. 2000; 275: 35715-35722Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar, 12Marra F. Efsen E. Romanelli R.G. Caligiuri A. Pastacaldi S. Batignani G. Bonacchi A. Caporale R. Laffi G. Pinzani M. Gentilini P. Gastroenterology. 2000; 119: 466-478Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar, 13Galli A. Crabb D.W. Ceni E. Salzano R. Mello T. Svegliati-Baroni G. Ridolfi F. Trozzi L. Surrenti C. Casini A. Gastroenterology. 2002; 122: 1924-1940Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar) and in vivo in experimental animals (13Galli A. Crabb D.W. Ceni E. Salzano R. Mello T. Svegliati-Baroni G. Ridolfi F. Trozzi L. Surrenti C. Casini A. Gastroenterology. 2002; 122: 1924-1940Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar). However, these ligands are known to have PPARγ-independent effects (14Chawla A. Barak Y. Nagy L. Liao D. Tontonoz P. Evans R.M. Nat. Med. 2001; 7: 48-52Crossref PubMed Scopus (953) Google Scholar), and it was yet to be tested whether PPARγ per se had a direct effect to suppress activation of HSC. To address this question, our laboratory has recently expressed PPARγ1 by an adenoviral vector in culture-activated HSC. This manipulation reversed their phenotype to that of quiescent HSC with reduced expression of activation markers such as TGFβ1 or α1(I) procollagen and restored the ability to accumulate retinyl esters (15Hazra S. Xiong S. Wang J. Rippe R.A. Krishna V. Chatterjee K. Tsukamoto H. J. Biol. Chem. 2004; 279: 11392-11401Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar). More importantly, the fact that PPARγ is required for the maintenance of differentiated HSC highlights an analogy between differentiation of adipocytes and that of HSC (Fig. 1). PPARγ is considered as a master transcriptional regulator for adipogenesis, and along with other putative transcription factors such as C/EBPα, β, and δ and SREBP-1, it induces adipocyte-specific genes to promote adipocytic differentiation as demonstrated in preadipocytes such as 3T3L1 cells exposed to the adipocyte differentiation mixture (16MacDougald O.A. Lane M.D. Annu. Rev. Biochem. 1995; 64: 345-373Crossref PubMed Scopus (926) Google Scholar, 17Morrison R.F. Farmer S.R. J. Nutr. 2000; 130: 3116S-3121SCrossref PubMed Google Scholar). If these cells are treated with mediators such as cytokines (tumor necrosis factor α and leptin) or growth factors (platelet-derived growth factor, epidermal growth factor/TGFα, and TGFβ) that suppress the activity of PPARγ and adipogenic transcriptional regulation, adipocyte differentiation is inhibited and preadipocyte differentiation ensues (18Zhang B. Berger J. Hu E. Szalkowski D. White-Carrington S. Spiegelman B.M. Moller D.E. Mol. Endocrinol. 1996; 10: 1457-1466Crossref PubMed Scopus (306) Google Scholar, 19Camp H.S. Tafuri S.R. J. Biol. Chem. 1997; 272: 10811-10816Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, 20Spiegelman B.M. Flier J.S. Cell. 1996; 87: 377-389Abstract Full Text Full Text PDF PubMed Scopus (1150) Google Scholar) (Fig. 1). Interestingly, these are the same mediators that are also implicated in activation/transdifferentiation of HSC (21Pinzani M. Marra F. Semin. Liver Dis. 2001; 21: 397-416Crossref PubMed Scopus (402) Google Scholar) (Fig. 1). In fact, our recent work demonstrates that PPARγ activity is inhibited in HSC in a manner similar to that previously observed in adipocytes by the treatment with tumor necrosis factor α (22Sung C.K. She H. Xiong S. Tsukamoto H. Am. J. Physiol. 2004; 286: G722-G729Crossref PubMed Scopus (64) Google Scholar) that is known to cause early activation of HSC (21Pinzani M. Marra F. Semin. Liver Dis. 2001; 21: 397-416Crossref PubMed Scopus (402) Google Scholar). Indeed, HSC was once called “fat-storing cells” because of their lipid content (23Ito T. Nemoto M. Okajima. Folia Anat. Jpn. 1952; 24: 243-258Crossref PubMed Scopus (125) Google Scholar), and they do store neutral lipids besides retinyl esters (24Yamada M. Blaner W.S. Soprano D.R. Dixon Hepatology. 7: PubMed Scopus Google Scholar). Upon activation, HSC lose lipid content and myofibroblastic with induced expression of type and also have a phenotype with expression of these adipocyte this expression to that of type and A. PubMed Scopus Google Scholar). This is also a of extracellular matrices expressed by quiescent HSC in the of the these proposed that the maintenance of the quiescent HSC phenotype transcriptional regulation similar not to that known for adipocyte To test this the present study the expression of putative adipogenic transcription factors in quiescent and culture-activated HSC, as as HSC. also tested the effects of the adipocyte differentiation mixture (isobutylmethylxanthine, dexamethazone, and activated HSC. SREBP-1c an adenoviral vector in activated HSC to expression and to effects HSC Our results that the expression of adipogenic transcription factors are in quiescent HSC, and their transdifferentiation to myofibroblastic cells. the treatment or ectopic expression of PPARγ or SREBP-1c expression of the adipogenic transcription factors and activated HSC to quiescent HSC. dexamethasone, and from was from PPARγ factor and from was from Hepatic Cell and from normal by in of the liver and as previously H. S. Blaner W.S. Am. J. Physiol. 1996; Google Scholar). The of the cells was by and and the was by In vitro activation of HSC was by HSC in with fetal a for or They treated with the adipogenic differentiation mixture isobutylmethylxanthine, dexamethasone, and insulin) and for or with vector for PPARγ1 was as (15Hazra S. Xiong S. Wang J. Rippe R.A. Krishna V. Chatterjee K. Tsukamoto H. J. Biol. Chem. 2004; 279: 11392-11401Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar, M. M. M. C. Chatterjee J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). vector for SREBP-1c Spiegelman B.M. 1996; 10: PubMed Scopus Google Scholar) was by M. Spiegelman of These of PPARγ1 or SREBP-1c in activated HSC for of their effects the HSC phenotype and expression of other adipogenic transcription These also expressed for of the and the vector was used as a HSC for by the vector with a of or (PPARγ) for the cellular to be of HSC positive the of and in or with phosphate-buffered and in The cells and with in in the with PBS, by a with lipid HSC with in in was with of and to the HSC. HSC and the lipid and and was by analysis for PPARγ, liver X receptor α α1(I) and (15Hazra S. Xiong S. Wang J. Rippe R.A. Krishna V. Chatterjee K. Tsukamoto H. J. Biol. Chem. 2004; 279: 11392-11401Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar), of total and by the was to the of a and to a for C/EBPα, ACC, FAS, and the was The of the and the used for are in I. of adipocyte-specific analysis was for and The used for these genes are as and and and used for in a new of and cell with and The protein a a and with by The by the expression was used for of genes in HSC for or was as and for the of The to a expression of genes to The expression level of a was by to a and with a HSC treated with or for and with acid for The cells with by the of and with and for the was Jr., M. E. Chatterjee S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), and the lipid by with acid exposed in a and with analysis expressed as the test was to the between the of and considered adipogenic transcription factors are expressed in quiescent HSC. HSC their quiescent phenotype with stellate and storage of vitamin A for They begin to be activated by in culture and activated by as by a cell with and vitamin A storage S.L. S. Blaner W.S. Am. J. Physiol. Google Scholar). the expression of transcription factors known to be in adipocyte differentiation in and HSC by or the transcription factors transcriptional and an nuclear of SREBP-1c in quiescent HSC as by and their expression in and cells (Fig. is known to be in a of preadipocytes adipogenic (16MacDougald O.A. Lane M.D. Annu. Rev. Biochem. 1995; 64: 345-373Crossref PubMed Scopus (926) Google Scholar, 17Morrison R.F. Farmer S.R. J. Nutr. 2000; 130: 3116S-3121SCrossref PubMed Google Scholar), SREBP-1c causes transcriptional of genes in fatty acid and J. 2002; PubMed Scopus Google Scholar). also has a transcriptional that as a regulator P. Cell. Full Text PDF PubMed Scopus Google Scholar). Indeed, our transcriptional protein in quiescent HSC with and level also in culture activation not (Fig. a not level of of in quiescent HSC not PPARγ, and to be by because of the of or of Thus, their expression by and the to (Fig. The of genes also in HSC and in and cells. In the PPARγ level was in HSC. the of these adipogenic transcription factors in or activated HSC, the expression of factor increased in and cells (Fig. the previously expression of this protein in activated HSC in vitro and in vivo Y. V. A. G. S.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the level of was also increased in and HSC (Fig. as previously K. K. E. A. L. V. F. A. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The of to the expression of adipogenic transcription factors is in of known effects fatty acid and S. J. H. Evans R.M. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar), and these results the or of HSC In fact, quiescent HSC are with lipids besides vitamin A (24Yamada M. Blaner W.S. Soprano D.R. Dixon Hepatology. 7: PubMed Scopus Google Scholar) as by and activated cells are of lipids (Fig. a analysis of from HSC demonstrated higher of expression in HSC of adipocyte-specific genes that are the positive of PPARγ and analysis also the expression of adipocyte-specific genes such as and in HSC as with cells (Fig. expression HSC culture of was by the level of HSC by that of HSC by a genes for PPARγ acid protein genes for acid and The of was by the level of HSC by that of HSC by a in a new PPARγ Our study demonstrated that ectopic expression of PPARγ by an adenoviral vector a phenotypic reversal from activated to quiescent HSC (15Hazra S. Xiong S. Wang J. Rippe R.A. Krishna V. Chatterjee K. Tsukamoto H. J. Biol. Chem. 2004; 279: 11392-11401Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar). to whether this reversal is with of other adipogenic transcription factors expression are reduced in in the protein of and and the of and increased in HSC as with cells These results that adipogenic transcriptional regulation is restored by PPARγ and the known G. J. Y. I. B. 2000; PubMed Scopus Google Scholar, T. H. M. N. T. H. Y. Y. K. J. K. T. S. S. N. Mol. Cell. Biol. 2001; 21: PubMed Scopus Google Scholar, R. L. Tontonoz P. Mol. Cell. Biol. 2001; 21: PubMed Scopus Google Scholar, W.S. J. H. T.M. Mol. Cell. Biol. 2004; 24: PubMed Scopus Google Scholar). and HSC be treated with an adipocyte differentiation mixture to to adipocytes of adipogenic transcription whether the treatment the same effects activated HSC and cause a phenotypic to quiescent HSC. The treatment for in of and δ and protein expression and PPARγ and expression of whether the treatment was or HSC (Fig. are for Conversely, the protein level was reduced by the treatment (Fig. The treatment a in their to that quiescent HSC with reduced (Fig. The treatment with also in increased lipid content in HSC as by (Fig. as by of was increased by the treatment in HSC (Fig. of lipids in HSC. the treatment reduced by and of and TGFβ1 by and (Fig. that these markers for myofibroblastic transdifferentiation are by with are by the level of an of in quiescent HSC and in activated HSC. as an is to the is to the by SREBP cleavage-activating protein of SREBP the for nuclear T. D. Y. R. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). to and SREBP activation T. D. Y. R. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). whether the level be to the for and that level is higher in activated HSC as with quiescent cells, is in not cells (Fig. the treatment level by the level in HSC (Fig. Thus, these results that increased expression of have reduced the in activated HSC. of and HSC tested the effects of expression HSC by an adenoviral expression with the vector induced as by analysis (Fig. This also in a in the level for PPARγ, a in C/EBPα, and a in (Fig. The of and FAS, target genes of SREBP-1, increased by and (Fig. HSC and PPARγ expression the used and to that the of the cells and of and reduced SREBP-1c (Fig. and increased in HSC (Fig. type and cell nuclear expression by analysis (Fig. in these cells. These results that activated HSC are and reversed to the quiescent cells by the ectopic expression of The present study demonstrates higher expression of a panel of putative adipogenic transcription factors in quiescent HSC and their depletion in culture-activated HSC. HSC also express adipocyte of which are the of adipogenic transcription factors such as PPARγ and These results are in with our hypothesis that adipogenic transcriptional regulation is required for the maintenance of the quiescent HSC To further test the for adipogenic transcriptional They are the treatment with the adipocyte differentiation mixture and ectopic expression of PPARγ or of which are known to adipocyte differentiation (16MacDougald O.A. Lane M.D. Annu. Rev. Biochem. 1995; 64: 345-373Crossref PubMed Scopus (926) Google Scholar, 17Morrison R.F. Farmer S.R. J. Nutr. 2000; 130: 3116S-3121SCrossref PubMed Google Scholar, M. M. M. C. Chatterjee J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, Spiegelman B.M. 1996; 10: PubMed Scopus Google Scholar). These activated HSC in of adipogenic transcription factors and a cellular phenotypic reversal to quiescent HSC. PPARγ or SREBP-1c is expressed it induces the expression of other key adipogenic These findings their known in adipocyte differentiation G. J. Y. I. B. 2000; PubMed Scopus Google Scholar, T. H. M. N. T. H. Y. Y. K. J. K. T. S. S. N. Mol. Cell. Biol. 2001; 21: PubMed Scopus Google Scholar, R. L. Tontonoz P. Mol. Cell. Biol. 2001; 21: PubMed Scopus Google Scholar, W.S. J. H. T.M. Mol. Cell. Biol. 2004; 24: PubMed Scopus Google Scholar) in the of HSC and potential importance in HSC quiescence. The findings from the present study also an that the regulation demonstrated for HSC transdifferentiation be similar to that known for differentiation or transdifferentiation mesenchymal cells. PPARγ differentiation of mesenchymal cells adipocytes T. S. S. M. N. Y. Y. Y. K. T. H. J. 2004; PubMed Scopus Google Scholar). preadipocytes treated with protein and acid J. L. R. J. Cell Biol. 2002; PubMed Scopus Google Scholar). They also smooth cells the A. S. C. G. Cell 2004; PubMed Scopus Google Scholar) or the smooth muscle protein K. Y. J. Cell. Biochem. 2000; PubMed Scopus Google Scholar), is Thus, the in these or differentiated mesenchymal cells also HSC The level of in is in quiescent HSC, and the of this factor in activated HSC induces a reversal of the cell phenotype to quiescent HSC. The level of with the expression of genes in fatty acid and as demonstrated in quiescent HSC and cells (Fig. and with of as in the HSC (Fig. Indeed, quiescent HSC (24Yamada M. Blaner W.S. Soprano D.R. Dixon Hepatology. 7: PubMed Scopus Google Scholar) that serve as a of fatty for of and storage of vitamin A. of the SREBP-1c by in to sterol level by SREBP to for and of the of J. 2002; PubMed Scopus Google Scholar). is also activated in a manner by in to a S. A. 1996; PubMed Scopus Google Scholar) or by tumor necrosis factor α treatment Jr., M. E. Chatterjee S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). was as a regulator of This T. D. Y. R. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar) and D. S. A. 2002; PubMed Scopus Google Scholar), both of which to by SREBP in and is considered as a key to suppress in adipocyte and to differentiation of preadipocytes J. K. S. A. 2003; PubMed Scopus Google Scholar). analysis for in the present demonstrates increased expression of in culture-activated HSC with treatment reduces expression (Fig. This between the level of the and regulation of expression as a potential for the in quiescent and activated HSC. for expression and analysis of expression to be to this in HSC also causes of PPARγ (Fig. and ectopic PPARγ expression HSC quiescence (15Hazra S. Xiong S. Wang J. Rippe R.A. Krishna V. Chatterjee K. Tsukamoto H. J. Biol. Chem. 2004; 279: 11392-11401Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar), it is that the effects by SREBP-1c are in by This hypothesis is by the known of these adipogenic transcription factors in adipocyte the of other adipogenic transcription factors be These and their pivotal in adipocyte differentiation are their in HSC is the present of of these transcription factors not the understanding of the molecular for HSC differentiation also to novel molecular targets for the treatment of cirrhosis. Spiegelman of for the of the SREBP-1c adenoviral