The 1sT NTU-UsC JoiNT symposiUm oN FroNTiers iN Liver Disease researChby JUN XU

Fall 2011The Center is supported by grants

from the National Institute on Alcohol Abuse and Alcoholism:

P50 AA011999 and R24 AA012885.

InsIde thIs Issue

1 6th ISALPD/C

1 First NTU-USC Joint Symposium

2 Spotlight on Douglas E. Feldman

2 Center Retreat

2 Lee Summer Student Fellowship Program

3 2011 Publications by Center Members

4 New Grants by Center Members

COntaCtshide tsukamoto Director htsukamo@usc.edu 323-442-5107

Rosy Macias Administrative Manager rmacias@usc.edu 323-442-3109

Wendy alvarez Administrative Assistant wendyalv@usc.edu 323-442-3121

Fax: 323-442-3126 www.usc.edu/alpd

the sOutheRn CalIFORnIa ReseaRCh Center for ALPD and Cirrhosis (the Center) proudly co-sponsored

its first NTU-USC Joint Symposium, held at National Taiwan University (NTU) in the beautiful city of Taipei on July 9, 2011. This symposium is a continuation of the global outreach mission that the Center has committed to promote world-wide basic and translational research on health issues related to alcohol abuse. Prior to this Joint Symposium, our Center has successfully organized or co-sponsored several international symposia in the United States, Japan, Spain, and Egypt.The NTU-USC Joint Symposium is highly supported by NTU College of Medicine. Professor Ding-Shinn Chen, the Distinguished Chair Professor of Medicine at NTU and who was elected to the US National Academy of Sciences as a foreign associate in 2005, came to give the opening remarks that emphasized the significance of scientific collaboration at global levels. Professor Hide Tsukamoto, the Center’s director then introduced the history, mission, and goals of our research Center, followed by his state-of-art lecture on epigenetic regulation of hepatic stellate cells in liver fibrosis, regeneration, and cancer. During the whole day event, eight cutting-edge researchers were presented by investigators from the US, Taiwan, and Hong Kong, including Jun Xu (USC, synergistic

TODAY the sOutheRn CalIFORnIa ReseaRChCenteR FOR alPd and CIRRhOsIs

6Th isaLpD/Cthe sOutheRn CalIFORnIa ReseaRCh CenteR for ALPD and Cirrhosis was a proud co-sponsor and co-organizer for the 6th International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis held in Fukuoka, Japan on October 20 and 21. It was showcased as a special event for the Japan Digestive Disease Week (JDDW) which attracted nearly 20,000 participants. Dr. Kenneth Warren, Acting Director of the NIAAA/NIH delivered an opening lecture, followed by special tribute made in memory of the late Professor Hiromasa Ishii by Profs. Helmut K. Seitz and Nobuhiro Sato. The symposium had 22 invited speakers and moderators from 13 nations and 56 selected poster presentations for the themes ranging from stem cells, cell death regulation, therapeutic targets, and global health. Total number of attendees exceeded 300 over the 2-day period. The level of science discussed was exceptionally high as praised by many who attended the symposium, and this was attributable to outstanding lectures by prominent scientists such as Michael Karin, Antonello Pietrangelo, Arun Sanyal, and others. Poster sessions involved active participation of leading investigators as the moderators who have made the experiences by young scientists quite enlightening and memorable. Many of the foreign invitees and participants also made contributions to the Japan Recovery Funds, and nearly four thousand dollars raised were donated via the Japan Red Cross. The copy of the abstract book is available at our web site (usc.edu/alpd). The 7th symposium will be held in Beijing as a satellite symposium for the 2012 ISBRA meeting in Sapporo, Japan, on September 6 and 7, 2012 under the leadership of Drs. Fu-sheng Wang and Bin Gao. w

[COntInued On Page 4]

spoTLiGhT oN DoUGLas e. FeLDmaN, ph.D.dOuglas (dOug) FeldMan is currently a CIRM Postdoctoral Scholar in Dr. Keigo Machida’s laboratory in the Department of Molecular Microbiology & Immunology at Keck School of Medicine of USC. He graduated from Harvard University, Magna cum laude, in A.B. Biochemical Sciences and obtained his Ph.D. in Molecular and Cellular Biology from Stanford University. Doug started his postdoctoral research in the Center’s training program two years ago under the direction of Dr. Machida, Ph.D. whose research includes molecular virology of hepatitis C virus infection and molecular mechanisms of oncogenesis.

Doug’s research involves tumor initiating stem cell-like cells (TISCs) which have been identified as rare subpopulations in multiple tumor types. Although research on TISCs promises great potential, their origins or the molecular basis for their potent tumor-initiation capacity, are still largely unknown. Doug has recently discovered that robust and selective expression of OB-R, the transmembrane receptor for the adipocyte-derived peptide hormone leptin, is a characteristic feature of TISCs isolated from liver tumors of alcohol-fed HCV Core transgenic mice, as well as of a broad array of embryonic and induced pluripotent stem cells. By employing gain- and loss-of-function strategies, he and his co-workers demonstrated that the hormone leptin serves as a key intermediary linking the accumulation of excess adipose tissue to activation obesity-induced oncogenesis. These findings may help to explain the increased incidence of tumors in overweight and obese individuals and may lead to the development of targeted therapies that disarm critical, tumor-promoting pathways in cancers such as hepatocellular carcinoma.Doug is such a dedicated scientist. His major extracurricular activities are reading journals and thinking about experiments! His wife is currently a resident in general surgery at UCLA Medical Center. w

2 www.usc.edu/alpd

CeNTer reTreaT by hiDe TsUkamoToPlannIng FOR the thIRd renewal of the center grant in the end of 2012, the Southern California Research Center for ALPD and Cirrhosis hosted its Center Retreat in La Jolla, California on July 15–16, 2011. Key center investigators attended this event, updated their progress, and discussed specific recommendations for their future collaborative research and programmatic developments. In essence, this retreat made us confirm that we indeed are a group of outstanding and unique expertise with tremendous potential for further growth. The center has also embraced and celebrated successful acquisition of competitive NIH grants by the center’s young investigators. Among enlightening discussions we had, the most noteworthy are integration of these young investigators into the center projects and infrastructure; new developmental cores such as the Metabolomic Core and a Human Liver Cell Isolation Core, and promotion of liver-pancreas collaborations on cancer and cancer stem cells, mitochondria, and stellate cell biology. Drs. Jun Xu and Paul Lee have already collaborated with several center investigators on metabolomic profiling, and this expertise and activity are the basis for a new development of the Metabolomic Core. This has led to discussions with Dr. Clay Wang of the USC School of Pharmacy and a potential three-way collaboration for the core for the center. The center has a critical mass of scientists on mitochondria of the liver (Neil Kaplowitz, Jose Fernandez-Checa, Derick Han) and pancreas (Anna Gukovskaya). Their collaboration for comparative and parallel analysis on alcohol’s effects on mitochondria in these two organs is considered to be very unique and novel. Dr. Keigo Machida is leading studies on cancer stem cells isolated from liver tumors, and this cutting-edge research may stimulate interactions with pancreatic cancer researchers such as Drs. Steve Pandol, Aurelia Lugea, and Mouad Edderkaoui. The same can be said for stellate cell biology in the liver and pancreas. Dr. Kinji Asahina’s cell lineage analysis expertise in hepatic stellate cells may be applied to determine the origin of pancreatic stellate cells. Some of these recommendations have already being implemented, stimulating new programmatic developments based on center-wide integrations of investigators. The retreat ended with a lovely dinner party at home of Drs. David Brenner and Tatiana Kisseleva. It was the elegant finishing touch after a very productive weekend. We thank David and Tatiana for the fantastic evening. w

In suMMeR 2011, the Southern California Research Center for ALPD and Cirrhosis offered eight Student Fellowship Awards under its Annual Lee Summer Student Fellowship Program. The highest number ever awarded in one year due to its large applicant pool! The Fellowship Program provided opportunity for the Master and undergraduate students to participate for at least ten weeks in research in the Center investigator’s laboratory and to give a presentation of their research at the center’s progress report meeting in August. They received an $800 Award and a Certificate after completion of the program. This year, the awards were presented to: Wei-lan Chang, (PROJeCt tItle: The effect of RIG-I on HCV RNA Replication) whose mentor was James Ou, Ph.D.; Pamela duarte (PROJeCt tItle: Inflammation and Fibrogenesis in Liver, Brain and Intestine after Intragastric Ethanol Feeding in Mice) whose mentor was Ekihiro Seki, Ph.D.; James gubbins (PROJeCt tItle: Canonical Wnt Signalling’s Relationship with Fibrosis in the PTen Deletion Liver Injury Model) whose mentor was Banyan Stiles, Ph.D.; Phillip hartman (PROJeCt tItle: The Role of Mucin 2 in Alcoholic Liver Disease) whose mentor was Bernd Schnabl, Ph.D.; deepak Jayakumar (PROJeCt tItle: Notch Dependent M1 Macrophage Activation and Nitrosative Stress in Steatohepatitis) whose mentor was Jun Xu, Ph.D., M.D.,; Yuri Kim (PROJeCt tItle: Hepatic Innate Immunity in Response to Therapeutic IFN That Govern HCV Replication) whose mentor was Takeshi Saito, M.D.; daniel sexton (PROJeCt tItle: Characterization and Refinement of Tissue Engineered Small Intestine, a Novel Preventative Treatment for TPN-Induced Liver Failure) whose mentor was Tracy Grikscheit, Ph.D.; and Corbin toodgood (PROJeCt tItle: The Regulation of Mitochondria Bioenergetics During Alcoholic Liver Disease in Mice) whose mentor was Derick Han, Ph.D. Congratulations to all the students! w

Lee sUmmer sTUDeNT FeLLowship proGram by rosy maCias

OB-Rb

oncogenesisSTAT3

OCT4/SOX2

leptinadipose tissue

OB-Rb

Lepr

tumor-initiating stem cell

www.usc.edu/alpd 3

1. Alexandre M, Pandol SJ, Gorelick FS, Thrower EC. The Emerging Role of Smoking in the Development of Pancreatitis. Pancreatology 2011;11:469–474. PMID 21986098

2. Angulo S, Morales A, Danese S, Llacuna L, Masamunt MC, Pultz N, Cifone MG, De Simone C, Delgado S, Vila J, Panés J, Donskey C, Fernández-Checa JC, Fiocchi C, Sans M. Probiotic sonicates selectively induce mucosal immune cells apoptosis through ceramide generation via neutral sphingomyelinase. PloS One 6:e16953, 2011. PMID 21408067

3. Asahina K, Zhou B, Pu WT, Tsukamoto H. Septum transversum-derived mesothelium gives rise to hepatic stellate cells and perivascular mesenchymal cells in developing mouse liver. Hepatology. 2011 Mar;53(3):983–95. PMID: 21294146

4. Bardag-Gorce F, French SW. Delta-aminolevulinic dehydrates is a proteasome interacting protein. Exp Mol Pathol 2011, 91: 485–489. PMID 21640720

5. Bardag-Gorce F, Oliva J, Lin A, Li J, French BA, French SW. Proteasome inhibitor up regulates liver antioxidative enzymes in rat model of alcoholic liver disease. Exp Molec Pathol 2011, 90: 123–30. PMID 21036165

6. Beaven SW, Wroblewski K, Wang J, Hong C, Bensinger S, Tsukamoto H, Tontonoz P. Liver X receptor signaling is a determinant of stellate cell activation and susceptibility to fibrotic liver disease. Gastroenterology. 2011 Mar;140(3):1052–62. PMID: 21134374

7. Biswas A, Senthilkumar SR, Said HM. Effect of chronic alcohol exposure on folate uptake by liver mitochondria. Am J Physiol Cell Physiol. 2011 Sep 28. PMID: 21956163

8. Bosch M, Marí M, Gross SP, Fernández-Checa JC, Pol A. Mitochondrial Cholesterol: A Connection Between Caveolin, Metabolism, and Disease.Traffic 12:1483–1489, 2011. PMID 21801290

9. Bosch M, Marí M, Herms A, Fernández A, Fajardo A, Kassan A, Giralt A, Colell A, Balgoma D, Barbero E, González-Moreno E, Matias N, Tebar F, Balsinde J, Camps M, Enrich C, Gross SP, García-Ruiz C, Pérez-Navarro E, Fernández-Checa JC, Pol A., Caveolin-1 deficiency causes cholesterol-dependent mitochondrial dysfunction and apoptotic susceptibility.Curr Biol 21, 681–686, 2011. PMID 21497090

10. Brenner DA, Seki E, Taura K, Kisseleva T, Deminicis S, Iwaisako K, Inokuchi S, Schnabl B, Oesterreicher CH, Paik YH, Miura K, Kodama Y. Non-alcoholic steatohepatitis-induced fibrosis: Toll-like receptors, reactive oxygen species and Jun N-terminal kinase. Hepatol Res. 2011 Jul;41(7):683–6. PubMed PMID: 21711427

11. Cano A, Buqué X, Martínez-Uña M, Aurrekoetxea I, Menor A, García-Rodriguez JL, Lu SC, Martínez-Chantar ML, Mato JM, Ochoa B, and Aspichueta P. Methionine adenosyltransferase 1A gene deletion disrupts hepatic VLDL assembly in mice. Hepatology (in press). PMC:NIHMS317499.

12. Chau BN, Brenner DA. What goes up must come down: the emerging role of microRNA in fibrosis. Hepatology. 2011 Jan;53(1):4–6. PubMed PMID: 21254156.

13. Chen L, Charrier AL, Leask A, French SW, Brigstock DR. Ethanol-stimulated differentiated functions of human or mouse hepatic stellate cells are mediated by connective tissue growth factor. J Hepatol 2011; 55:399–406. PMID 21156189

14. Dara L, Ji C, Kaplowitz N. The contribution of endoplasmic reticulum stress to liver diseases. Hepatology 53:1752–63, 2011. PMID 21384408

15. DeLeve LD, Jaeschke H, Kalra VK, Asahina K, Brenner DA, Tsukamoto H. 15th International Symposium on Cells of the Hepatic Sinusoid, 2010. Liver Int. 2011 Jul;31(6):762–72. PubMed PMID: 21645207

16. Dong MH, Bettencourt R, Brenner DA, Barrett-Connor E, Loomba R. Serum Levels of Alanine Aminotransferase Decrease with Age in Longitudinal Analysis. Clin Gastroenterol Hepatol. 2011 Oct 20. PubMed PMID: 22020064

17. Feldman DE, Chen C, Punj V, Tsukamoto H, Machida H. Pluripotency Factor-Mediated Expression of the Leptin Receptor OB-R Links Obesity to Oncogenesis Through Tumor-Initiating Stem Cells. Proc Natl Acad Sci (revision submitted).

18. Fernandez-Domınguez I, Echevarria-Uraga JJ, Gomez N, Luka Z, Wagner C, Lu SC, Mato JM, Martınez-Chantar ML, Rodrıguez-Cuesta J, High-frequency ultrasound imaging for longitudinal evaluation of non-alcoholic fatty liver disease progression in mice, Ultrasound Med. Biol. 37:1161–1169, 2011. PMC:PMCID3118979

19. French SW, Bardag-Gorce F, French BA, Li J, Oliva J. The role of inmate immunity in the pathogenesis of preneoplasia in drug-induced chronic hepatitis based on a mouse model. Exp Molec Pathol 2011, July 28: 91(3)653–659. PMID 21820428

20. French BA, Oliva J, Bardag-Gorce F, French SW. The immunoproteasome in steatohepatitis: Its role in Mallory-Denk body formation. Exp Mol Pathol (Epub before print) 2011, 90: 252–6. PMID 21256843

21. Gao B, Seki E, Brenner DA, Friedman S, Cohen JI, Nagy L, Szabo G, Zakhari S. Innate immunity in alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol. 2011 Apr;300(4):G516-25. Epub 2011 Jan 20. Review. PubMed PMID: 21252049.

22. Gonalez E, van Liempd S, Conde-Vancels J, Gutierrez-de Juan V, Perez-Cormenzana M, Mayo R, Berisa A, Alonso C, Marquez CA, Barr J, Lu SC, Mato JM, and Falcon-Perez JM. Serum UPLC-MS/MS metabolic profiling in an experimental model for acute-liver injury reveals potential biomarkers for hepatotoxicity. Metabolomics (in press). PMC Journal-In Process.

23. Gukovskaya AS, Gukovsky I. Which way to die: the regulation of acinar cell death in pancreatitis by mitochondria, calcium, and reactive oxygen species. Gastroenterology. 2011 Ju140(7):1876–80. PMID 21524653

24. Gukovsky I, Gukovskaya AS Impaired autophagy underlies key pathological responses of acute pancreatitis Autophagy. 2010 6(3):428–9. PMID 20215882

25. Gukovsky I, Pandol SJ, Gukovskaya AS. Organellar dysfunction in the pathogenesis of pancreatitis. Antioxid Redox Signal 2011;15:2699–710. PMID 21834686

26. Hegyi P, Pandol S, Venglovecz V, Rakonczay Z, Jr. The acinar-ductal tango in the pathogenesis of acute pancreatitis. Gut 2011;60:544–52. PMID 20876773

27. Inokuchi S, Tsukamoto H, Park EJ, Liu Z-X, Brenner DA, Seki E. Toll-like receptor 4 mediates alcohol-induced steatohepatitis through bone marrow-derived and endogenous liver cells in mice. Alcohol Clin Exp Res 2011. 35(8):1509–18. PMID: 21463341

28. Ji C, Kaplowitz N, Lau MY, Kao E, Petrovic LM, Lee AS. Liver-specific loss of glucose-regulated protein 78 perturbs the unfolded protein response and exacerbates a spectrum of liver diseases in mice. Hepatology Jul;54(1):229–39. PMID 21503947

29. Kisseleva T, Brenner DA. Anti-fibrogenic strategies and the regression of fibrosis. Best Pract Res Clin Gastroenterol. 2011 Apr;25(2):305–17. Review. PubMed PMID: 21497747

30. Kisseleva T, Brenner DA. Is it the end of the line for the EMT? Hepatology. 2011 May;53(5):1433–5. PubMed PMID: 21433040.

31. Kisseleva T, von Köckritz-Blickwede M, Reichart D, McGillvray SM, Wingender G, Kronenberg M, Glass CK, Nizet V, Brenner DA. Fibrocyte-like cells recruited to the spleen support innate and adaptive immune responses to acute injury or infection. J Mol Med (Berl). 2011 Oct;89(10):997–1013. PubMed PMID: 21499735

32. Kwong AM, Tippin BL, Materi AM, Buslon VS, French SW, Lin HJ. High dietary niacin may increase prostaglandin formation but does not increase tumor formation in ApcMin/+ mice. Nutr Cancer. 2011:63(6): 950–9. PMID 21774590

33. Li J, Li XM, Caudell M, Maysheva O, Bardag-Gorce F, Oliva J, French BA, Gorce E, Morgan K, Kathirvel E, Morgan T, French SW. Betaine feeding prevents the blood alcohol cycle in rats fed alcohol continuously for 1 month using the rat intragastric tube feeding model. Exp Mol Pathol 2011 91: 540–547. PMID 21708146

34. Llacuna L, Fernández A, Montfort CV, Matías N, Martínez L, Caballero F, Rimola A, Elena M, Morales A, Fernández-Checa JC, García-Ruiz C. Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia-reperfusion injury. J Hepatol 54:1002–10, 2011. PMID 21145825

35. Loftus N, Barnes A, Ashton S, Michopoulos F, Theodoridis G, Wilson I, Ji C, Kaplowitz N. Metabonomic investigation of liver profiles of nonpolar metabolites obtained from alcohol-dosed rats and mice using high mass accuracy MSn analysis. J Proteome Res. 2011 Feb 4;10(2):705–13. PMID: 21028815

36. Lugea A, Gong J, Nguyen J, Nieto J, French SW, Pandol SJ. Cholinergic mediation of alcohol-induced experimental pancreatitis. Alcohol Clin Exp Res 2010;34:1768–81. PMID 20626730

37. Lugea A, Tischler D, Nguyen J, Gong J, Gukovsky I, French SW, Gorelick FS, Pandol SJ. Adaptive Unfolded Protein Response Attenuates Alcohol-induced Pancreatic Damage. Gastroenterology 2011, 140:987–997. PMID: 21111739

38. Lugea A, Waldron R, French SW, Pandol SJ. Drinking and driving pancreatitis: links between endoplasmic reticulum stress and autophagy. Autophagy 2011; 7:783–5. PMID: 21460613

39. Machida K, Chen C-L, Liu J-C, Kashiwabara C, Feldman D, Sher S, French SW, Mishra L, Hyeongnam JJ, Tsukamoto H. TLR4-NANOG stemness pathway in tumor stem cells confers resistance to TGF-b-mediated tumor suppression through YAP1 and IGF2BP3-AKT-mTOR. Cancer Cell (submitted).

40. Mato JM, and Lu SC. The hepatocarcinogenic effect of methionine and choline deficient diets: an adaptation to the Warburg effect? Alcoholism: Clin. and Exp Res 35:811–814, 2011. PMC:PMCID3083460

41. Mato JM, Lu SC. Where are we in the search for noninvasive nonalcoholic steatohepatitis biomarkers? Hepatology (AE Commentary) 54:1115–1117, 2011. PMC Journal-In Process.

42. Mato JM, Martínez-Chantar ML, and Lu SC. How MAT and GNMT keep fatty liver and cancer at bay. Int. J. Biochem. Cell Biol. (in press) PMC Journal-In Process.

43. Mareninova OA, Mukherjee R, Odinokova IV, Huang W, Chvanov M, Booth D, Cane M, Awais M, Criddle DN, Alexei Tepikin A, Petersen OH, Pandol SJ, Gukovsky I, Molkentin JD, Gukovskaya AS, Sutton R. Inhibition of the mitochondrial permeability transition pore prevents pathological digestive enzyme activation and necrosis in acute pancreatitis. Submitted for publication. – PMID not found

44. Miura K, Seki E, Ohnishi H, Brenner DA. Role of toll-like receptors and their downstream molecules in the development of nonalcoholic Fatty liver disease. Gastroenterol Res Pract. 2010;2010:362847. PMID: 21274430; PMCID: PMC3026974.

45. Garcia-Ruiz C, Marí M, Colell A, Morales A, Fernandez-Checa JC. Metabolic Therapy: Lessons from Liver Diseases. Curr Pharm Sci 2011 Sep 20. PMID 21933146

46. Oliva J, Bardag-Gorce F, Li J, French BA, French SW. S-adenosylmethionine prevents the up regulation of Toll Signalling caused by chronic ethanol feeding in rats. Exp Mol Pathol 90: 239–243, 2011. PMID 21276439

47. Oliva J, Bardag-Gorce F, Tillman B, French SW. Protective effect of quercetin, EGCG, catechin and betaine against oxidative stress induced by ethanol in vitro. Exp Mol Pathol 2011 90: 295–299. PMID 21352821

48. Osawa Y, Seki E, Kodama Y, Suetsugu A, Miura K, Adachi M, Ito H, Shiratori Y, Banno Y, Olefsky JM, Nagaki M, Moriwaki H, Brenner DA, Seishima M. Acid sphingomyelinase regulates glucose and lipid metabolism in hepatocytes through AKT activation and AMP-activated protein kinase suppression. FASEB J. 2011 Apr;25(4):1133–44. PMID: 21163859

49. Österreicher CH, Penz-Österreicher M, Grivennikov SI, Guma M, Koltsova EK, Datz C, Sasik R, Hardiman G, Karin M, Brenner DA. Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver. Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):308–13. PMID: 21173249

50. Paik YH, Iwaisako K, Seki E, Inokuchi S, Schnabl B, Osterreicher CH, Kisseleva T, Brenner DA. The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91(phox) mediate hepatic fibrosis in mice. Hepatology. 2011 May;53(5):1730–41. PMID: 21384410

51. Pandol SJ, Gorekick FS, Gerloff A, Lugea A. Alcohol abuse, endoplasmic reticulum stress and pancreatitis. Dig Dis. 2010;28(6):776–82. PMID:21525762; PMCID: PMC3094583

52. Pandol SJ, Gorekick FS, Lugea A. Environmental and genetic stressors and the unfolded protein response in exocrine pancreatic function - a hypothesis. Front Physiol, 2011; 2:8. PMID:21483727

53. Pandol SJ, Lugea A, Mareninova OA, Smoot D, Gorelick FS, Gukovskaya AS, Gukovsky I. Investigating the Pathobiology of Alcoholic Pancreatitis. Alcohol Clin Exp Res. 2011; 35:830–837. PMID: 21284675

54. Parsons CJ, Stefanovic B, Seki E, Aoyama T, Latour AM, Marzluff WF, Rippe RA, Brenner DA. Mutation of the 5’-untranslated region stem-loop structure inhibits α1(I) collagen expression in vivo. J Biol Chem. 2011 Mar 11;286(10):8609–19. PMID: 21193410

55. Ramani K, Mato JM, and Lu SC. Role of methionine adenosyltransferase genes in hepatocarcinogenesis. Cancers 3:1480–1497, 2011. PMC Journal-In Process.

56. Said HM, Mee L, Sekar VT, Ashokkumar B, Pandol SJ. Mechanism and regulation of folate uptake by pancreatic acinar cells: effect of chronic alcohol consumption. Am J Physiol Gastrointest Liver Physiol 2010;298:G985-93. PMID 20360131

57. Schmitz JC, Protiva P, Gattu AK, Utsumi T, Iwakiri Y, Neto A, Quinn M, Cornwell ML, Fitchev P, Lugea A, Crawford SE, Chung C. Pigment Epithelium-Derived Factor (PEDF) Regulates Early Pancreatic Fibrotic Responses and Suppresses the Pro-Fibrotic Cytokine Thrombospondin-1 (TSP-1). Am J Pathol 2011 (in press). PMID: 21964188

58. Scholten D, Reichart D, Paik YH, Lindert J, Bhattacharya J, Glass CK, Brenner DA, Kisseleva T. Migration of fibrocytes in fibrogenic liver injury. Am J Pathol. 2011 Jul;179(1):189–98. PMID: 21703401

59. Sinha-Hakim, Sinha-Hakim AP, Shen R, Kim H, French SW, Vazavi ND, Crum A, Rajavashisth TB, Norris KC. A novel cystine based antioxidant attenuates oxidative stress and hepatic steatosis in diet-induced obese mice. Exp Mol Pathol 2011 91: 419–28. PMID 21570964

60. Tarrats N, Moles A, Morales A, García-Ruiz C, Fernández-Checa JC, Marí M. Critical role of tumor necrosis factor receptor 1, but not 2, in hepatic stellate cell proliferation, extracellular matrix remodeling, and liver fibrogenesis. Hepatology 54:319–27, 2011. PMID 21523796

61. Than TA, Lou H, Ji C, Win S, Kaplowitz N. Role of cAMP-responsive element-binding protein (CREB)-regulated transcription coactivator 3 (CRTC3) in the initiation of mitochondrial biogenesis and stress response in liver cells. J Biol Chem. 2011 Jun 24;286(25):22047–54. PMID: 21536665

62. Thrower EC, Yuan J, Usmani A, Liu Y, Jones C, Minervini SN, Alexandre M, Pandol SJ, Guha S. A novel protein kinase D inhibitor attenuates early events of experimental pancreatitis in isolated rat acini. Am J Physiol Gastrointest Liver Physiol 2011;300:G120-9. PMID 20947701

63. Tomasi ML, Li TWH, Li M, Mato JM, and Lu SC. Inhibition of methionine adenosyltransferase 1A transcription by coding region methylation. J. Cell Physiol. (in press) PMC:NIHMS301666.

64. Tsukamoto H, Morphogens and hepatic stellate cell fate regulation in chronic liver disease. J Gastroenterol Hepatol, (submitted)

65. Tsukamoto H, Zhu NL, Asahina K, Mann DA, Mann J. Epigenetic cell fate regulation of hepatic stellate cells. Hepatol Res 2011 Jul;41(7):675–82. PMID: 21504520

66. Ueno A, Lazaro R, Higashiyama R, and Tsukamoto H. Mouse intragastric infusion (iG) Model. Nature Protocols (revision submitted).

67. Varely-Rey M, Beraza N, Lu SC, Mato JM, and Martínez-Chantar ML. Role of AMPK in the control of hepatocyte priming and proliferation during liver regeneration. Exp. Biol. Med. 236:402–408, 2011. PMC Journal-In Process.

68. Xu J, Lai KK, Verlinsky A, Lugea A, French SW, Cooper MP, Ji C, Tsukamoto H. Synergistic steatohepatitis by moderate obesity and alcohol in mice despite increased adiponectin and p-AMPK. J Hepatol. 2011 Sep;55(3):673–82. Epub 2011 Jan 21. PubMed PMID: 21256905; PubMed Central PMCID: PMC3094601.

69. Yamaji S, Droggiti A, Lu SC, Martínez-Chantar ML, Warner A, Varela-Rey M. S-Adenosylmethionine regulates connexins sub-types expressed by hepatocytes. Eur J Cell Biol 90:312–322, 2011. PMC:PMCID3042521

70. Yan AW, Fouts DE, Brandl J, Stärkel P, Torralba M, Schott E, Tsukamoto H, Nelson KE, Brenner DA, Schnabl B. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology. 2011 Jan;53(1):96–105. Epub 2010 Dec 10. PubMed PMID: 21254165; PubMed Central PMCID: PMC3059122.

71. Yang HP, Li TWH, Peng J, Mato JM, and Lu SC. Insulin-like growth factor 1 activates methionine adenosyltransferase 2A transcription by multiple pathways in human colon cancer cells. Biochem J. 436:506–516, 2011. PMC Journal-In Process.

72. Yang M, Chiang Y-M, Qin L, Asahina K, Higashiyama R, Mann J, Mann D, Wang C, Tsukamoto H. Rosmarinic acid exerts anti-fibrotic effects via epigenetic de-repression of Ppar-gamma in hepatic stellate cells. Hepatology in press.

73. Ye R, Mareninova OA, Barron E, Wang M, Hinton DR, Pandol SJ, Lee AS. Grp78 heterozygosity regulates chaperone balance in exocrine pancreas with differential response to cerulein-induced acute pancreatitis. Am J Pathol 2010;177:2827–36. PMID 20971738

74. Yuan J, Liu Y, Tan T, Guha S, Gukovsky I, Gukovskaya A, Pandol SJ. Protein Kinase D Regulates Cell Death Pathways in Acute Pancreatitis: a Target for Therapy. (submitted)

75. Zhang AS, Anderson SA, Wang J, Yang F, DeMaster K, Ahmad R, Pizzi CP, Eisenstein RS, Tsukamoto H, and Enns CA. Suppression of hepatic hepcidin expression in response to acute iron deprivation is correlated with an increase of matripatase-2 protein in the liver. Blood 2011 Feb 3;117(5):1687–99. PMID 21115976/PMCID: PMC3056593

76. Zhang Q, Zhong Q, Evans AG, Levy D, Zhong SP. Phosphorylation of histone H3 serine 28 modulates RNA polymerase III-dependent transcription. Oncogene 2011 Sept 15;30: 3943–3952. PMID:21460852/PMCID: PMC3134635

77. Zhong S, Machida K, Tsukamoto H, Johnson DL. Alcohol induces RNA polymerase III-dependent transcription through c-Jun and co-regulating TATA-biding protein (TBP) and Brf1 expression. J Biol Chem 2011, Jan 28;286(4):2393–401. PMID: 21106530/PMCID: PMC3024733

78. Zhu N-L, Asahina K, Wang J, Ueno A, Lazaro R, Miyaoka Y, Miyajima A, Tsukamoto H. Hepatic stellate cell-derived DLK1 in liver regeneration. J Biol Chem (revision submitted).

2011 pUbLiCaTioNs by CeNTer members

the southern California Research Center for alPd and CirrhosisKeck School of Medicine of theUniversity of Southern California1333 San Pablo Street, MMR 4th FloorLos Angeles, CA 90033-9141www.usc.edu/alpd

CoNGraTULaTioNs!!!New GraNT aCqUisiTioNs by CeNTer members (aNNUaL DireCT CosTs)1. Kinji Asahina, 1R01AA020753-01, 09/01/2011–07/31/2016, $212,5002. Kinji Asahina, Pilot Project, 5P30DK048522-17, 04/01/2011–03/31/2012,

$40,0003. Ilya Gukovsky and Olga A. Mareninova, R01AA019730-01A1,

02/01/2011–01/31/2016, $269,2304. Shelly Lu, 2R01DK05719-15, 09/20/2011–06/30/2015, $221,0355. Aurelia Lugea, 1R01AA019954-01A1, 08/01/2011–07/31/2016, $261,0006. Mouad Edderkaoui, 1K01AA019996-01, 03/01/2011–02/29/2016, $110,099 7. J.-H. James Ou, 1R01DK094652-01, 09/21/2011–08/31/2016, $217,5008. EekJoong Park, American Liver Foundation, 07/01/2011–06/30/2014,

$75,0009. EekJoong Park, UCSD/UCLA DERC Pilot and Feasibility Award,

05/01/2011–04/30/2012, $54,07510. Takeshi Saito, Pilot Project, 5P30DK048522-17, 04/01/2011–03/31/2012,

$50,00011. Takeshi Saito, BAXTER FDN AWARD FY12-SAITO, 07/01/2011–

06/30/2012, $100,00012. Bernd G. Schnabl, 1R01AA020703-01, 09/25/2011–06/30/2016, $250,00013. Ekihiro Seki, R01 DK085252, 02/15/2011–01/31/2016, $250,0014. Ekihiro Seki, ABMRF, 01/01/2011–12/31/2011, $43,478 15. Hidekazu Tsukamoto, 2R24AA012885-11, 06/01/2011–05/31/2016,

$260,81516. Hidekazu Tsukamoto, 1R13AA020691-01, 08/01/2011–07/31/2016,

$89,00017. Jun Xu, 1K01AA020524-01, 08/20/2011–07/31/2016, $102,854

4 www.usc.edu/alpd

steatohepatitis), Shwu-Bin Lin (NTU, biomarkers discovery for liver fibrosis), Kai-Wen Huang (NTU, translational liver research), Keigo Machida (USC, liver tumor-initiating stem-like cells), Jack Chun-ming Wong (UHK, miRNA and liver cancer), Hui-Lin Wu (NTU, viral hepatitis animal model), Steve Chen (Academia Sinica, autophagy against HCV), and Jun-Jen Liu (Taipei Medical University, liver cancer therapy through drug-induced ER-stress). Although the symposium was held on Saturday, more than 100 faculty and students attended this event. There were lively discussions following the presentations and at the end of symposium. We were particularly glad to have opportunities to establish potential collaborations with NTU’s investigators, such as translational research on hepatocellular carcinoma with Professor Ding-Shinn Chen’s group. Professor Hide Tsukamoto offered training opportunities to NTU students either by special request or through our Center’s Lee Summer Student Research Fellowship program. In September 2011, Ping-Yen Wang, a master student from NTU was trained in our Center on animal modeling and non-parenchymal liver cell isolation. We are expecting more scientific interaction between our Center and NTU. Lastly, we would like to thank Professor Shwu-Bin Lin for organizing this symposium, Professor Woei-Horng Fang for hosting the event, and S.P. Pharmaceutics for providing financial support. w

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