Shelly Lu, MD
Disclosures: Nothing to disclose
OMB No. 0925-0046, Biographical Sketch Format Page

OMB No. 0925-0001 and 0925-0002 (Rev. 09/17 Approved Through 03/31/2020)

BIOGRAPHICAL SKETCH

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NAME:  Lu, Shelly Chi-Loo

eRA COMMONS USER NAME (credential, e.g., agency login):  shellylu

POSITION TITLE:  Professor of Medicine

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)

INSTITUTION AND LOCATION

DEGREE

(if applicable)

 

Completion Date

MM/YYYY

 

FIELD OF STUDY

 

UCLA, Los Angeles, California

BA

06/1978

Biology

UCLA, Los Angeles, California

MD

06/1982

Medicine

 

  1. Personal Statement

I am a physician scientist engaged in teaching, clinical work and basic research. I have been working in the fields of S-adenosylmethionine (SAMe) and glutathione (GSH) metabolism for 27 years and have received uninterrupted NIH funding since 1992. I currently have NIH-funded research programs that investigate molecular mechanisms of fatty liver, liver injury and cancer. Many of the research projects have translational applications, such as identifying biomarkers that can differentiate simple fatty liver from those with more severe form called nonalcoholic steatohepatitis and examining agents that are effective in the prevention and treatment for both liver and colon cancer. I have actively engaged in teaching at all levels, mentored over 50 pre-doctoral and post-doctoral trainees and over 20 junior faculty during my career and received recognition as an outstanding teacher and mentor. Many of my mentees are now faculty in many different institutions both in the United States and abroad. Thus, in addition to having a well-funded laboratory dedicated to the study of liver injury and cancer, I am recognized as an outstanding mentor.

1.              Lu SC, and Mato JM. S-adenosylmethionine in liver health, injury and cancer. Physiological Reviews 92:1515-1542, 2012. PMCID: PMC3698976.

2.              Lu SC. Glutathione synthesis. BBA-Gen 1830:3143-3153, 2013. PMCID: PMC3549305.

3.              Mato JM, Martínez-Chantar ML, and Lu SC.  Methionine metabolism and liver disease.  Ann Rev. Nutr. 28:273-293, 2008.

4.              Fan W, Yang H, Liu T, Wang J, Li TWH, Mavila N, Tang Y, Yang JW, Peng H, Annamalai A, Noureddin M, Krishnan A, Gores GJ, Martínez-Chantar ML, Mato JM, and Lu SC. Prohibitin 1 suppresses liver cancers tumorigenesis in mice and humans. Hepatology 65(4):1249-1266, 2017. PMCID: PMC5360526.

  1. Positions and Honors

Positions

7/82-6/85              Internship and residency Cedars-Sinai Medical Center, Los Angeles, CA

7/85-12/87               Fellowship.  UCLA, CA - Integrated Training Program in Gastroenterology

1/88-2/90              Director, Section of Hepatobiliary Disease and Medical Director of Biliary Lithotripsy,

              Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA

10/88-2/90              Assistant Professor of Medicine, University of California, Los Angeles, CA

2/90-6/96              Assistant Professor of Medicine, USC School of Medicine, Los Angeles, CA

3/95-7/14              Director, Cell Culture Core, USC Research Center for Liver Diseases

7/96-2/01              Associate Professor of Medicine with Tenure, USC School of Medicine, Los Angeles, CA

3/01-7/14              Professor of Medicine with Tenure, Keck School of Medicine USC, Los Angeles, CA

7/03 -7/14              Associate Director, USC Research Center for Liver Diseases

7/11 - 7/14              Associate Chief, Division of GI and Liver Diseases, Keck School of Medicine USC, LA, CA

3/16 – 2/17              Co-Director, Translational Oncology Program, Samuel Oschin Comprehensive Cancer Institute-Cedars Sinai

8/14 – present              Adjunct Professor of Medicine, Keck School of Medicine USC, Los Angeles, CA

8/14 - present              Director, Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, LA, CA             

1/15 - present              Professor of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA

1/15 – 6/18              Professor in Residence Step 6, UCLA, Los Angeles, CA

1/18 – present              Vice Chair of Basic Science and Translational Research, Department of Medicine, Cedars-Sinai Medical Center

7/18 - present              Professor in Residence Step 7, UCLA, Los Angeles, CA

Honors

1974-1978,                            Dean's Honors List every quarter for four years; 1978, graduated with highest honors in

                            Biology and Summa Cum Laude, Phi Beta Kappa and Alpha Lambda Delta

2/95, 3/99, 10/00, 2/02, 7/06, 10/08, 6/09, 3/10, 3/19, 7/19, 4/20-Ad Hoc Reviewer, various NIH Study Sections             

4/15              Distinguished Editor, NIH Director’s New Innovator Award Second Stage Review Panel

7/97-6/00, 7/03-6/07, 7/13-6/17 - Regular Member, GMA2/HBPP/XNDA NIH Study Sections, respectively

2001 - 2003              Editorial board, American J. Physiol. GI liver Section

2001               Best attending of the Firm, Internal Medicine, LA County-USC Medical Center             

2002               American Society for Clinical Investigation (Young Turk)

2003 - 2006              Associate Editor, American J. Physiol. GI liver Section

4/04               USC Medical Faculty Assembly Recognition Award

2005              Western Society of Clinical Investigation’s Outstanding Investigator Award

2006                                                             Association of American Physicians (Old Turk)

July 2006 - Dec 2011              Associate Editor, Hepatology

Jan 2007 -              Editorial board, Experimental Biology and Medicine

May 2008              AGA Outstanding Women in Science

Jan 2011 - present              Co-Editor, Comprehensive Physiology: Liver Physiology             

July 2011 - 2016              Editorial board, Gastroenterology

Jan 2012              Mayo Soley Award – Lifetime Achievement in Science and Mentoring

May 2014              Best Attending in Gastroenterology, LAC-USC Medical Center

July 2016 - 2019              Senior Associate Editor, Gastroenterology

April 2017 – present              Women’s Guild Chair in Gastroenterology

Jan 2018 – present              Editorial board, Hepatology

  1. Contribution to Science

I am regarded as an expert on methionine adenosyltransferase (MAT) genes, GSH and SAMe. My lab developed liver-specific Phb1 KO mice. My most significant contributions to science are:

1.              First to establish a liver-specific prohibitin 1 (PHB1) knockout mouse model in order to study its role in liver function. One of the findings from Mat1a KO mice is downregulation of PHB1 from birth that persisted to development of steatohepatitis. In order to understand this, my laboratory took on the task of developing the liver-specific Phb1 knockout mouse model. This is the first tissue-specific Phb1 knockout available in the world as total deletion is embryonically lethal. We described severe liver injury, fibrosis and multi-focal HCC development at a young age in these mice. We have also found that although HCC may have developed in this model largely due to injury and repair, PHB1 exerts a direct effect on hepatocyte growth. Indeed, our recent works clearly established PHB1 as a tumor suppressor in HCC and cholangiocarcinoma, and identified multiple mechanisms by which PHB1 inhibits tumorigenesis.

a.              Ko K, Iglesias-Ara A, French BA, French SW, Ramani K, Tomasi ML, Lozano JJ, Oh P, He L, Stiles BL, Li TWH, Yang HP, Martínez-Chantar ML, Mato JM, and Lu SC. Liver-specific deletion of prohibitin 1 results in spontaneous liver injury, fibrosis and hepatocellular carcinoma in mice. Hepatology 52:2096-2108, 2010. PMCID: PMC3005187.

b.              Ramani K, Mavila N, Ko KS, Mato JM, and Lu SC.  Prohibitin 1 regulates the H19-Igf2 axis and proliferation in hepatocytes. J. Biol. Chem. 91(46):24148-24159, 2016. PMCID: PMC5104939.

c.              Liu T, Yang HP, Fan W, Tu J, Li TWH, Wang J, Shen H, Yang JW, Xiong T, Steggerda J, Liu Z, Noureddin M, Maldonado SS, Annamalai A, Seki E, Mato JM, and Lu SC. Mechanisms and therapeutic implications of MAFG dysregulation in cholestatic liver injury and cancers. Gastroenterology 155:557-571, 2018. PMCID: PMC6067975.

d.              Yang JW, Murray B, Barbier-Torres L, Liu T, Liu Z, Yang HP, Fan W, Wang JH, Li Y, Seki E, Mato JM, and Lu SC. The mitochondrial chaperone Prohibitin 1 negatively regulates interleukin-8 in human liver cancers. J. Biol. Chem. 294(6):1984-1996, 2019. PMCID: PMC6369293.

2.              First to establish the importance of MAT genes dysregulation in liver injury and cancer. MAT is a critical cellular enzyme as it catalyzes the formation of SAMe, the principal methyl donor. Two genes encode for MAT, MAT1A is expressed in normal differentiated liver and MAT2A is expressed in all extrahepatic tissues as well as in fetal liver. As the liver matures, MAT2A is replaced by MAT1A. We were the first to describe a switch from MAT1A to MAT2A expression in human HCC, which is pathogenetically important because MAT2A expression provides a growth advantage. In addition, MAT1A expression falls in the majority of cirrhotic livers. My laboratory developed the Mat1a knockout mouse model and showed that in the absence of Mat1a, mice are more prone to liver injury and developed steatohepatitis and HCC spontaneously. This model proves the importance of maintaining normal SAMe levels and MAT1A expression in the liver. Using this model we have elucidated many important signaling pathways that are abnormal when MAT1A is absent that have provided insight into how liver injury and cancer can occur because of SAMe deficiency. We also demonstrated MAT1A acts as a tumor suppressor in cholangiocarcinoma and uncovered a novel cross-talk with c-MYC. Peer-review publications that demonstrate our contribution to this field are:

a.              Cai J, Mao Z, Hwang J, and Lu SC. Differential expression of methionine adenosyltransferase genes influences the rate of growth of human hepatocellular carcinoma cells. Cancer Res 58:1444-1450, 1998. PMID: 9537246

b.              Tomasi ML, Iglesias Ara A, Yang H, Ramani K, Feo F, Pascale MR, Martínez-Chantar ML, Mato JM, and Lu SC. S-adenosylmethionine Regulates Apurinic/Apyrimidinic Endonuclease 1 Stability: Implication in Hepatocarcinogenesis. Gastroenterology 136:1025-1036, 2009. PMCID: PMC3600984.

c.              Yang HP, Cho ME, Li TWH, Peng H, Ko KS, Mato JM, and Lu SC. MiRNAs regulate methionine adenosyltransferase 1A expression in hepatocellular carcinoma. J. Clin. Invest. 123:285-298, 2013. PMCID: PMC3533284.

d.              Yang HP, Liu T, Wang J, Li TWH, Fan W, Peng H, Krishnan A, Gores GJ, Mato JM, and Lu SC. Deregulated methionine adenosyltransferase α1, c-Myc and Maf proteins interplay promotes cholangiocarcinoma growth in mice and humans. Hepatology 64(2):439-455, 2016. PMCID: PMC4956551.

3.  First to show MAT2B is up-regulated in liver and colon cancer and provide a growth advantage by multiple mechanisms. MAT2B’s only function was thought to encode for a regulatory subunit (β) that regulate MAT2A-encoded isoenzyme. We were the first to show that MAT2B encodes for two dominant splice variants V1 and V2 that differ only by 20 amino acids at the N-terminus. Both variants are induced in human liver cancer at the mRNA levels. Interestingly, MAT2B is only increased at the protein level in colon cancer. Overexpression of either variant induced growth of both liver and colon cancer cells and knockdown of V1 resulted in apoptosis. We have identified two novel mechanisms of how MAT2B enhance growth. One is the finding that both variants interact with HuR, an mRNA binding protein that stabilizes several cyclin mRNAs. Overexpression of either variant resulted in higher cytoplasmic HuR content, cyclin D1 expression and increased growth. Another highly novel finding is that both variants are part of a scaffold complex that interact and activate each step of the Ras-Raf-MEK-ERK signaling pathway. Since Ras signaling is often induced in multiple cancers, targeting this interaction may provide a novel therapeutic strategy. Peer-review publications that demonstrate our contribution to this field are:

a.              Yang HP, Iglesias Ara A, Magilnick N, Xia M, Ramani K, Chen H, Lee TD, Mato JM, and Lu SC. Expression pattern, regulation and function of methionine adenosyltransferase 2β alternative splicing variants in hepatoma cells. Gastroenterology 134:281-291, 2008. PMCID: PMC2409110.

b.              Xia M, Chen Y, Wang LC, Zandi E, Yang HP, Bemanian S, Martínez-Chantar ML, Mato JM, and Lu SC.  Novel function and intracellular localization of methionine adenosyltransferase 2β splicing variants. J. Biol. Chem. 285:20015-21, 2010. PMCID: PMC 2888413.

c.              Peng H, Dara L, Li TWH, Zheng Y, Yang HP, Tomasi ML, Tomasi I, Giordano P, Mato JM, and Lu SC. Methionine adenosyltransferase 2B-GIT1 interplay activates MEK1-ERK1/2 to induce growth in human liver

              and colon cancer. Hepatology 57:2299-2313, 2013. PMCID: PMC3642222.

d.              Peng H, Li TWH, Yang HP, Mato JM, and Lu SC. Methionine Adenosyltransferase 2B-GIT1 complex serves as a scaffold to regulate Ras/Raf/MEK1/2 activity in human liver and colon cancer cells. Am. J. Pathol. 185:1135-44, 2015. PMCID: PMC4380842.

4.                            First to show SAMe and its metabolite methylthioadenosine (MTA) can selectively kill cancer cells by targeting multiple oncogenic pathways. In addition to demonstrating signaling pathways affected when hepatic SAMe level is deficient, we have also examined actions of pharmacologic SAMe. SAMe is highly unstable and gives rise to MTA spontaneously so many of the pharmacologic actions may be actually mediated by MTA, which inhibits methylation. We have shown both agents induce selectively apoptosis in liver and colon cancer cells but by different mechanisms. We have also shown both agents can reduce tumor load in a colitis-induced colon cancer model by targeting many key oncogenic pathways, inhibit beta-catenin activation regardless of whether the cancer cell express wild type or mutant Wnt/beta-catenin, and more recently inhibit colon cancer metasis to the liver. This paves the way to consider these molecules in both chemoprevention and adjunct treatment of liver and colon cancers. Peer-review publications that demonstrate our contribution to this field are:

a.              Yang HP, Sadda MR, Li M, Zeng Y, Chen LX, Bae WJ, Ou, XP, Runnegar MT, Mato JM, and Lu SC. S-Adenosylmethionine and its metabolite induce apoptosis in HepG2 cells: role of protein phosphatase 1 and Bcl-xSHepatology 40:221-231, 2004. PMID: 15239106.

b.              Lu SC, Ramani K, Ou XP, Lin M, Yu V, Ko K, Park R, Bottiglieri T, Tsukamoto H, Kanel G, French S, Mato JM, Moat R, and Grant E.  S-adenosylmethionine in the chemoprevention and treatment of hepatocellular carcinoma in a rat model.  Hepatology 50:462-471, 2009. PMCID: PMC2754739.

c.              Li TWH, Yang HP, Peng H, Xia M, Mato JM, and Lu SC. Effects of S-adenosylmethionine and methylthioadenosine on inflammation-induced colon cancer in mice. Carcinogenesis 33:427-435, 2012. PMCID: PMC3279046.

d.              Tomasi ML, Cossu C, Spissu Y, Floris A, Ryoo M, Iglesias-Ara A, Wang Q, Pandol SJ, Bhowmick NA, Seki E, Posadas EM, and Lu SC. S-adenosylmethionine and methylthioadenosine inhibit cancer metastasis by targeting microRNA 34a/b-methionine adenosyltransferase 2A/2B axis. Oncotarget 8:78851-78869, 2017. PMCID: PMC5668003.

5.                             First to demonstrate the importance of dysregulated GSH synthesis in liver injury. GSH is vital in defense against oxidative stress and over the past 27 years my laboratory has shown how the GSH synthetic enzymes are regulated transcriptionally and post-transcriptionally. My laboratory is the first to show that the rate-limiting enzyme glutamate-cysteine ligase catalytic subunit is phosphorylated by various kinases and this leads to inactivation of the enzyme. We also described dysregulation of GSH synthesis under several pathological conditions of the liver including cholestatic liver injury, fibrosis and endotoxemia. We have uncovered many novel mechanisms providing druggable targets to treat these pathological conditions. Peer-review publications that demonstrate our contribution to this field are:

a.              Yang HP, Ko K, Xia M, Li TWH, Oh P, Li J, and Lu SC. Induction of avian musculoaponeurotic fibrosarcoma proteins by toxic bile acid inhibits expression of GSH synthetic enzymes and contributes to cholestatic liver injury in mice. Hepatology 51:1291-1301, 2010. PMCID: PMC2908963.

b.              Ramani K, Tomasi ML, Yang HP, Ko K, and Lu SC. Mechanism and significance of changes in glutamate-cysteine ligase expression during hepatic fibrogenesis. J. Biol. Chem. 287:36341-36355, 2012. PMCID: PMC3476301.

c.              Tomasi ML, Ryoo M, Yang HP, Iglesia Ara A, Ko K, and Lu SC. Molecular mechanisms of lipopolysaccharide-mediated inhibition of glutathione synthesis in mice. Free Radical Biology & Medicine 68:148-158, 2014. PMCID: PMC3943979.

d.              Yang HP, Li TWH, Zhou Y, Peng H, Liu T, Zandi E, Martínez-Chantar ML, Mato JM, and Lu SC. Activation of a novel c-Myc-miR27-Prohibitin 1 circuitry in cholestatic liver injury inhibits GSH synthesis in mice. Antioxidant & Redox Signaling 22:259-274, 2015. PMCID: PMC4283066.

Complete List of Published Work in MyBibliography:

https://www.ncbi.nlm.nih.gov/pubmed/?term=lu%2C+shelly+c

  1. Additional Information: Research Support

Ongoing Research Support

1.              5R01 AT001576-16              Lu (PI)              9/20/02-6/30/20

              Role of SAMe in pathogenesis and treatment of non-alcoholic fatty liver disease

              The are 3 specific aims in this NIH proposal:

(1) Examine the influence of SAMe level on personalized NASH treatment, (2) examine the influence of SAMe level on progression from steatosis to NASH, and (3) examine the influence of SAMe level on serum lipid signature

Role: PI

2.              5R01 CA172086-05              Lu (PI)              1/10/14-12/31/20

              Prohibitin 1 in Liver Injury and Cancer

              There were 3 specific aims in this NIH proposal:

              (1) Examine the role of prohibitin 1 in liver injury, (2) examine how prohibitin 1 influences HCC development, and (3) determine if prohibitin 1 down-regulation contributes to mitochondrial dysfunction, liver injury and HCC formation in the Mat1a KO mice.

              Role: PI

3.              1R01 DK107288-04              Lu (PI)              7/1/15-6/30/20

              S-Adenosylmethionine in protein posttranslational modifications and HCC treatment

              There are 4 specific aims in this NIH proposal:

              (1) Define the effect of SAMe depletion on sumoylation machinery and protein PTMs, (2) examine how SAMe depletion affects activity of MAPKs, receptor tyrosine kinases (RTKs) and Tyr-phospho-proteome, (3) examine pharmacologic SAMe and MTA actions on protein PTMs, (4) examine effectiveness of SAMe/MTA or sorafenib alone or in combination in HCC treatment             

              Role: PI

4.              1R01 AA026759-02              Lu (PI)              5/15/18-3/31/23

              Methionine Adenosyltransferase α1 in Alcoholic Liver Disease

              There are 3 specific aims in this NIH proposal:

              (1) Examine how MATα1 targets the mitochondria and why its targeting is impaired in ALD, (2) examine how MATα1 regulates CYP2E1 protein expression, (3) examine the role of mitochondrial MATα1 and MATα1-regulated CYP2E1 in ALD             

              Role: PI

5.              1R21AA025841-02              Seki (PI)                            8/1/17-7/31/20 (NCE)

              Alcohol enhances colon cancer liver metastasis via cancer-associated fibroblasts

              Role: co-investigator

6.              1 U01 AA026817-01A1              Lu (MPI)               9/20/19-8/31/24

              S-adenosylmethionine treatment in alcoholic liver disease

This is a double blind randomized placebo-controlled clinical trial that assess the efficacy of S-adenosylmethionine in the treatment of alcoholic liver disease. 

7.              1 P01 CA233452-01A1              Lu (MPI)               1/1/21-12/31/24

              Determinants of liver metastasis

This is a program project that includes 3 Cores and 4 projects.  In addition to being the contact PI, Lu also is the PI of Project 4 (Targeting methionine adenosyltransferases in liver metastasis). 

Completed Research Support

1.              2R01 DK051719-19              Lu (PI)               4/1/97-6/30/17

              Regulation and functions of methionine adenosyltransferase genes in liver

              There are 4 specific aims in this NIH proposal:

(1) Examine regulation of MAT genes by miRNAs, (2) Elucidate the molecular mechanisms of MAT1A-regulated growth and angiogenesis, (3) Define regulation of MAT2B and molecular mechanisms of MAT2B variants-mediated growth and apoptosis, (4) Solve the crystal structures of MAT2B V1 and V2

2.              1R01DK092407-05              Lu (PI)              4/1/12 – 3/31/19              

Dysregulation of GSH Synthesis During Liver Injury and Fibrosis

There are 3 specific aims in this NIH proposal:

(1) Elucidate the molecular mechanism(s) of Nrf2 to MafG/c-Maf switch in nuclear binding to ARE during cholestatic liver injury, (2) Elucidate the mechanism(s) by which UDCA and SAMe prevent the fall in expression of GSH synthetic enzymes and the significance of preserving GSH during cholestasis, (3) Identify molecular mechanisms of LPS-induced inhibition of GSH synthetic enzymes.