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Xiao-Ming Yin, M.D., Ph.D.

Education

  • 1995-1998 Residency in Clinical Pathology, Department of Pathology, Washington University School of Medicine, St. Louis, MO
  • 1991-1995 Postdoctoral Fellow and Research Associate: Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO
  • 1986-1991 PhD in Immunology, University of Texas Southwestern Medical Center, Dallas, TX
  • 1983-1985 MS in Immunology, Fudan University Shanghai Medical School, Shanghai, China
  • 1978-1982 MD, Fudan University Shanghai Medical School, Shanghai, China

Biography

Appointment and Position

1997-1998 Instructor, Department of Medicine, Washington University School of Medicine, St. Louis, MO

1998-2010 Assistant, Associate, Full Professor, Associated Director, Division of Molecular Diagnostics, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA

2010-2020 Louis Y. Mazzini Professor of Pathology, Vice Chair for Clinical Pathology, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN

2010-2020 Director, Indiana University Health Pathology Laboratory, Indianapolis, IN

2020-Present  Professor and Chair, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA

 

Research

Current Research Interests

Determination of the homeostatic role of autophagy in the liver

Autophagy function is important for the normal hepatic physiology and structure.  Deletion of key autophagy genes leads to hepatomegaly, liver injury, inflammation, fibrosis and liver cancer.  The mechanism by which autophagy deficiency leads to these pathophysiological changes are not clear.  We have elucidated a key step in liver tumor development, in which HMGB1 secreted by the autophagy-deficient hepatocytes is instrumental. HMGB1 is also required for the ductular reaction, i.e., the expansion of hepatic progenitor cells, which is implicated in liver repair and regeneration. Representative publications are shown below.

 

  1. Yin, X.-M. W-X. Ding and W. Gao.  Autophagy in the liver. Hepatology 47:1773-1785, 2008.
  2. Khambu, B., N. Huda, X. Chen, Y. Li, G. Dai, Z. Dong, W-X Zong, S. Waguri, U.A. Kohler, S. Werner, T.D. Oury, and X.-M. Yin. HMGB1 promotes ductular reaction and tumorigenesis in autophagy deficient livers.  J. Clin. Invest.  128(6): 2419-2435, 2018.
  3. Khambu, B., S. Yan, N. Huda, G. Liu and X.-M. Yin. Homeostatic role of autophagy in hepatocytes. Seminar in Liver Research.  38:308-319, 2018.
  4. Khambu, B., T. Li, S. Yan, C. Yu, X. Chen, M. Goheen, Y. Li, J. Lin, O.W. Cummings, Y. A. Lee, S. Friedman, Z. Dong, G-S. Feng, S. Wu and X.-M. Yin.  Hepatic autophagy deficiency compromises FXR functionality and causes cholestatic injury.  Hepatology, 69:2196-2213, 2019.

 

Determination of the role of autophagy in alcohol and non-alcohol fatty liver diseases (AFLD and NAFLFD)

Autophagy is intimately associated with metabolism and in fact is an integrated component of catabolic process.  Being the largest metabolic organ in the body, liver has a potent activity of autophagy at the basal physiological level, which can be further enhanced in pathological conditions.  We find that alcohol drinking can stimulate hepatic autophagy, which is required to alleviate alcohol-induced liver injury.  Autophagy achieves this function by selective autophagy against damaged mitochondria and accumulated lipid droplets.  We have extended our finding to non-alcoholic fatty liver diseases and furthermore indicate that pharmacological promotion of autophagy can be an effective way to reduce liver injury and metabolic syndrome in AFLD and NAFLD.  The significance of these studies is the revelation of another survival mechanism against AFLD and NAFLD, which may be explored for therapeutic intervention.  Some of the representative publications are shown below.

 

  1. Ding, W.-X., M. Li, X. Chen, H-M. Ni, W. Gao, B. Lu, D. B. Stolz, D. L. Clemens and X.-M. Yin.  Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice.  Gastroenterology, 139: 1740-52. 2010.
  2. Lin, C.-W., H. Zhang, M. Li, X. Xiong, Xi Chen, X. Chen, C. X. Dong, and X.-M. Yin. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice.  J. Hepatology, 58: 993-999, 2013.
  3. Wang, L., J. Zhou, S. Yan, G. Lei, C-H. Lee, and X.-Ming Yin.  Ethanol-triggered lipophagy requires SQSTM1 in AML12 cells.  Science Reports, 7(1):12307, 2017.
  4. Zhang, H., B. Khambu, S. Yan, F. Ma, Y. Li, X. Chen, J. A. Martina, R. Puertollano, Y. Li, N. Chalasani, X.-M. Yin.  Oscillating TFEB signaling regulates hepatic steatosis and liver injury.  Autophagy, 14:1779-1795, 2018.

 

Development of small molecules for manipulation of autophagy and for cancer therapy

To explore the mechanism of autophagy and potential applications based on manipulation of autophagy, we have established high throughput screening assays based on cellular responses (high content) or chemical reactions (target based).  For the formal, cells expression GFP-LC3 were subjected to a library of 200,000 compounds to find out those cause autophagy alterations.  For the latter, we focused on Atg4, the only protease in the entire autophagy machinery, which is required for autophagy.  There are four Atg4 homologues and at least 8 homologue substrates in the mammalian cells.  We have characterized the enzymatic properties of the enzymes for most of the substrates.  The screening assays have generated multiple potential targets that are being characterized.  However, the usefulness of inhibition of Atg4 in selective typed of cancer has now been demonstrated in collaborative researches.  Some of the representative publications are shown below.

 

  1. Li, M., Y. Hou, J. Wang, X. Chen, Z.M. Shao and X.-M. Yin.  Kinetics comparisons of mammalian Atg4 homologues indicate selective preferences toward diverse Atg8 substrates.  J. Bio. Chem. 286:7327-7338, 2011.
  2. Li, M., Xi Chen, Q.-Z. Ye, A. Vogt and X.-M. Yin.  A High-throughput FRET-based Assay for Determination of Atg4 Activity.  Autophagy, 8:401-412, 2012.
  3. Akin, S., K. Wang, P. Habibzadegah-Tari, B. Law, D. Ostrov, M. Li, X.-M. Yin, J.-S. Kim, N. Horenstein, W.A Dunn, Jr.  A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors.  Autophagy, 10 (11): 2021-35, 2014.
  4. Li, M., Z. Yang, L.L. Vollmer, Y. Gao, Y. Fu, C. Liu, Xiaoyun Chen, P. Liu, A. Vogt, X.-M. Yin.  AMDE-1 Is a Dual Function Chemical for Autophagy Activation and Inhibition.  PLoS One 10 (3): e0122083, April 20, 2015.
  5. Huang, T., C.K. Kim, A.A. Alvarez, R.P. Pangeni, X. Wan, X. Song, T. Shi, Y. Yang, N. Sastry, C.M. Horbinski, S. Lu, R. Stupp, J. A. Kessler, R. Nishikawa, I. Nakano, E.P. Sulman, X. Lu, C.D. James, X-M. Yin, B Hu, and S-Y. Cheng.  MST4 phosphorylation of ATG4B regulates autophagic activity, tumorigenicity, and radioresistance in glioblastoma.  Cancer Cell, 32: 840-855.e8, 2017.

 

Determination of the multiple functions and molecular effects of Bid

As a pro-death Bcl-2 family molecule, Bid promotes mitochondrial release of cytochrome c.  My laboratory also found that Bid can induce the release of other mitochondrial inter-membrane proteins (Kim et al, JBC, 2000), including SMAC, whose significance has been mentioned above.  We further find that Bid has multiple effects on mitochondria, including causing mitochondrial permeability transition, mitochondrial cristae reorganization and ROS generation under TNFα or anti-Fas stimulation.  Bid interacts with mitochondrial cardiolipin for promoting these effects, which is different from its role in promoting mitochondrial release of cytochrome c and SMAC, for which its interaction with Bax via the BH3 domain is required.  What is most interesting is that we find that Bid possesses an entirely different function under non-apoptosis condition.  Bid can promote cell proliferation under growth stimulation condition.  This is achieved through its control of ER release of calcium.  This pro-proliferation explains the paradoxical finding of Bid’s ability to promote hepatic carcinogenesis.  Most recently in collaboration we also found that Bid can promote inflammasome activation through its effect at the mitochondria.  The significance of these findings is that Bid can have other functions than apoptosis regulation, and that Bid can have multiple molecular targets to exert its activity.  Some of the representative publications are shown below.

 

  1. Li, B., H.-M. Ni, X. Chen, D. DiFrancesca and X.-M. Yin.  Deletion of Bid impedes cell proliferation and hepatic carcinogenesis.  American J. Path. 166:1523-1532, 2005.
  2. Ni, H-M, C. J. Baty, N. Li, W-X. Ding, W. Gao, M. Li, X. Chen, J. Ma, G. K. Michalopoulos and X.-M. Yin.  Bid regulates murine hepatocyte proliferation by controlling ER calcium homeostasis.  Hepatology, 52: 338-348, 2010.
  3. Leibowitz, B., W. Qiu, M.E. Buchanan, F. Zou, P. Vernon; M.P. Moyer, X.-M. Yin, R.E. Schoen, J. Yu and L. Zhang.  BID mediates selective killing of APC-deficient cells in intestinal tumor suppression by nonsteroidal anti-inflammatory drugs.  Proc. Natl. Acad. Sci, 111:16520-16525, 2014.
  4. Bronner, D.N., B.H. Abuaita, X. Chen, K.A. Fitzgerald, G. Nuñez, Y. He, X.M. Yin, M.X. O'Riordan. Endoplasmic reticulum Stress activates the inflammasome via NLRP3- and caspase-2-driven mitochondrial damage.  Immunity. 43:451-462, 2015.
  5. Yu, C., S. Yan, B. Khambu, Xiaoyun Chen, Z. Dong, J. Luo, G. K. Michalopoulus, S. Wu, and X.-M. Yin.  Gene expression analysis indicates divergent mechanisms in DEN-induced carcinogenesis in wild type and Bid-deficient livers.  PLoS ONE 11(5): e0155211, 2016.

 

Research Funding (last 5 years)

Grant Name                  1R21 AA021450-01A1

Grant Title:                    Mechanism and role of selective autophagy in ethanol-induced liver injury

Role in Project:             Principal Investigator

Year (Inclusive):            June 15, 2014-May 31, 2016 (no cost extension to May 31, 2017)

Source:                           NIAAA, NIH

 

Grant Name                  1R01 AA021751-01A1

Grant Title:                    The dynamics and mechanisms of autophagy in ethanol-induced liver pathogenesis

Role in Project:             Principal Investigator

Year (Inclusive):            Aug 15, 2013-July 31, 2019 (with no cost extension)

Source:                           NIAAA, NIH

 

Grant Name                  1R01 DK116605-01

Grant Title:                    The role of HMGB1 in autophagy-deficiency induced liver pathology

Role in Project:             Principal Investigator

Year (Inclusive):            July 26, 2018-May 31, 2022

Source:                           NIDDK, NIH

 

Publications

(Last 5 years)

Articles

  1. Li, M., Z. Yang, L.L. Vollmer, Y. Gao, Y. Fu, C. Liu, Xiaoyun Chen, P. Liu, A. Vogt, X.-M. Yin.  AMDE-1 Is a Dual Function Chemical for Autophagy Activation and Inhibition.  PLoS One 10 (3): e0122083, April 20, 2015 (doi: 10.1371/journal.pone.0122083).
  2. Bronner, D.N., B.H. Abuaita, X. Chen, K.A. Fitzgerald, G. Nuñez, Y. He, X.M. Yin, M.X. O'Riordan. Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage.  Immunity. 43:451-462, 2015
  3. Livingston, M.J., H.-F. Ding, S. Huang, J. A. Hill, X.-M. Yin and Z. Dong. Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction.  Autophagy 12(6):976-98, 2016 (doi: 10.1080/15548627.2016.1166317)
  4. Yu, C., S. Yan, B. Khambu, Xiaoyun Chen, Z. Dong, J. Luo, G. K. Michalopoulus, S. Wu, and X.-M. Yin.  Gene expression analysis indicates divergent mechanisms in DEN-induced carcinogenesis in wild type and Bid-deficient livers.  PLoS ONE 11(5): e0155211, 2016. Doi: 10.1371/journal.pone.0155211
  5. Gao, Y., Y. Liu, X. Cai, Z. Yang, Xiaoyun Chen, Y. Fu, Y. Lin, W. Wen, S. Li, X. Liu, H. Huang, A. Vogt, P. Liu, X.-M. Yin* and M. Li*.  Golgi-associated LC3 lipidation requires V-ATPase in non-canonical autophagy.  (*co-corresponding).  Cell Death Dis.;7(8):e2330, 2016. (doi: 10.1038/cddis.2016.236)
  6. Kwon, J.J. J.A. Willy, R.C. Wek, M. Korc, X.-M. Yin and J. Kota. Novel role of miR-29 in pancreatic cancer autophagy and its therapeutic potential.  Oncotarget. 7(44): 71635-71650, 2016 (doi: 10.18632/oncotarget.11928)
  7. Wang, Y., Y. Zhang, L. Chen, Q. Liang, X.-M. Yin, L. Miao, B.-H. Kang and D. Xue. Kinetics and specificity of paternal mitochondrial elimination in Caenorhabitis elegans.  Nature Commun. 7:12569. 2016 (doi: 10.1038/ncomms12569).
  8. Zhang, D., J. Pan, X. Xiang, Y. Liu, G. Dong, M.J. Livingston, J-K. Chen, X.-M. Yin and Z. Dong. Protein kinase Cδ suppresses autophagy to induce kidney cell apoptosis in cisplatin nephrotoxicity.  J. Am Soc Nephrol.  28:1131-1144, 2017 (published online on Oct 31, 2016, (doi: 10.1681/ASN.2016030337)
  9. Wang, L., J. Zhou, S. Yan, G. Lei, C-H. Lee, and X.-Ming Yin.  Ethanol-triggered lipophagy requires SQSTM1 in AML12 cells.  Science Reports, 7(1):12307. doi: 10.1038/s41598-017-12485-2.Sept 26, 2017
  10. Tang, C., H. Han, M. Yan, S. Zhu, J. Liu, Z. Liu, L. He, J. Tan, Y. Liu, H. Liu, L. Sun, S. Duan, Y. Peng, F. Liu, X-M. Yin, Z. Zhang and Z. Dong.  PINK1-PRKN/PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury.  Autophagy.  Published on Nov 26, 2017. https://doi.org/10.1080/15548627.2017.1405880
  11. Huang, T., C.K. Kim, A.A. Alvarez, R.P. Pangeni, X. Wan, X. Song, T. Shi, Y. Yang, N. Sastry, C.M. Horbinski, S. Lu, R. Stupp, J. A. Kessler, R. Nishikawa, I. Nakano, E.P. Sulman, X. Lu, C.D. James, X-M. Yin, B Hu, and S-Y. Cheng.  MST4 phosphorylation of ATG4B regulates autophagic activity, tumorigenicity, and radioresistance in glioblastoma.  Cancer Cell, 32: 840-855.e8, 2017. Doi: 10.1016/j.ccell.2017.11.005
  12. Liu, J., M. Livingston, G. Dong, C. Tang, Y. Su, G. Wu, X-M. Yin and Z. Dong.  Histone deacetylase inhibitors protect against cisplatin-induced acute kidney injury by activating autophagy in proximal tubular cells.  Cell Death Dis. 9(3): 322, 2018.  Doi: 10.1038/s41419-018-0374-7
  13. Khambu, B., N. Huda, X. Chen, Y. Li, G. Dai, Z. Dong, W-X Zong, S. Waguri, U.A. Kohler, S. Werner, T.D. Oury, X.-M. Yin. HMGB1 promotes ductular reaction and tumorigenesis in autophagy deficient livers.  J. Clin. Invest.  128(6): 2419-2435, 2018 (doi: 10.1172/JCI91814. Epub 2018 May 7). (Correction: J Clin Invest. 129(5):2163. 2019; doi: 10.1172/JCI129234. Epub 2019 May 1) PMID: 31042163
  14. Sethunath, D., S. Morusu, M. Tuceryan, O.W. Cummings, H. Zhang, X-M. Yin, S. Vanderbeck, N. Chalasani, S. Gawrieh.  Automated assessment of steatosis in murine fatty liver.  PLOS One, 13(5):e0197242, 2018 (doi: 10.1371/journal.pone.0197242). 
  15. Zhang, H., S. Yan, B. Khambu, F. Ma, Y. Li, X. Chen, J. A. Martina, R. Puertollano, Y. Li, N. Chalasani, X.-M. Yin.  Dynamic MTORC1-TFEB feedback signaling regulates hepatic autophagy, steatosis and liver injury in ling-term nutrient oversupply.  Autophagy, 14:10, 1779-1795, 2018 (doi: 10.1080/15548627.2018.1490850). PMID: 30044707
  16. Liao, Y., M. Li, X. Chen, Y. Jiang, X-M. Yin.  Interaction of TBC1D9B with mammalian ATG8 homologues regulates autophagic flux.  Scientific Reports. 8: 13496, 2018 (doi: 10.1038/s41598-018-32003-2). PMID: 30202024
  17. Fu Y, L. Hong, J. Xu, G. Zhong, Q. Gu, Q. Gu, Y. Guan, X. Zheng, Q. Dai, X. Luo, C. Liu, Z. Huang, X.-M. Yin, P. Liu, M. Li. Discovery of a small molecule targeting autophagy via ATG4B inhibition and cell death of colorectal cancer cells in vitro and in vivo. Autophagy. 2018 Sep 3. doi: 10.1080/15548627.2018.1517073. [Epub ahead of print]  PMID: 30176161
  18. Lee, Y-M, L. A Noon, K. Akat, M. Ybanez, T.-F. Lee, M.-L. Berres, N. Fujiwara, N. Goossens, H.-I. Chou, F. Parvin-Nejad, B. Khambu, E. Kramer, R. Gordon, C. Pfleger, D. Germain, G. John, K. Campbell, Z. Yue, X.-M. Yin, A. M. Cuervo, M. Czaja, M. Fiel, Y. Hoshida, and S. Friedman. Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap.  Nature Commun. 9(1): 4962, 2018, PMID: 30470740
  19. Khambu, B., T. Li, S. Yan, C. Yu, X. Chen, M. Goheen, Y. Li, J. Lin, O.W. Cummings, Y. A. Lee, S. Friedman, Z. Dong, G-S. Feng, S. Wu and X.-M. Yin.  Hepatic autophagy deficiency compromises FXR functionality and causes cholestatic injury.  Hepatology, 69: 2196-2213, 2019, PMID: 30520052
  20. Liu Y, X. Luo, H. Shan, Y. Fu, Q. Gu X. Zheng, Q. Dai, F. Xia F, Z. Zheng, P. Liu, X.-M Yin, L. Hong, M. Li. Niclosamide Triggers Non-Canonical LC3 Lipidation.  Cells. 2019 Mar 15; 8(3). pii: E248. doi: 10.3390/cells8030248. PMID: 30875964
  21. Cho, S-G, X. Xiao, S. Wang, H. Gao, R. Rafikov, S. Black, S. Huang, H-F Ding, Y. Yoon, R. A. Kirken, X-M. Yin, H-G. Wang, Z. Dong. Bif-1 interacts with prohibitin-2 to regulate mitochondrial inner membrane during cell stress and apoptosis. J. Amer. Soc. Neph.  30: 1174-1191, 2019. PMID: 31126972
  22. Yan, S., J Zhou, X. Chen, Z. Dong and X.-M. Yin.  Diverse Consequences in liver injury in mice with different autophagy functional status treated with alcohol.  Am. J. Pathol. 189: 1744-1762, 2019  PMID: 31199920
  23. Livingston M. J., J. Wang, J. Zhou, G. Wu, I.G. Ganley, J. A. Jill, X-M. Yin, Z. Dong.  Clearance of damaged mitochondria via mitophagy is important to the protective effect of ischemic preconditioning in kidney.  Autophagy, 15: 2142-2162, 2019. PMID: 31066324
  24. Tang, C., H. Han, Z. Liu, Y. Liu, L. Yin, J. Cai, L. He. Y. Liu, G. Chen, Z. Zhang. X-M. Yin, and Z. Dong. Activation of BNIP3-mediated mitophagy protects against renal ischemia-reperfusion injury. Cell Death Dis. 10: 677, 2019,  PMID: 31515472
  25.  Zheng, X., Z. Yang, Q. Gu, F. Xia, Y. Fu, P. Liu, X-M. Yin, M. Li.  The protease activity of human ATG4B is regulated by reversible oxidative modification.  Autophagy. 2020 Jan 3: 1-13, doi: 1080/15548627.2019.1709763. PMID: 31880198

 

Review

  1. L. Wang, B. Khambu, H. Zhang and X-M. Yin.  Autophagy in alcoholic liver disease, self-eating triggered by drinking.  Clinics and Research in Hepatology and Gastroenterology, 2015 Sep;39 Suppl 1:S2-6. doi: 10.1016/j.clinre.2015.05.023
  2. Klionsky, D, ……….X.-M. Yin et al.  Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).  Autophagy 12(1):1-222, 2016
  3. Li, M., Y. Fu, Z. Yang, and X.-M. Yin.  Analysis of the ATG4 cysteine proteases.  Methods in Enzymology, 587:207-225, 2017
  4. Khambu, B, L. Wang, H. Zhang, and X.-M. Yin, The activation and function of autophagy in alcoholic liver disease.  Current Molecular Pharmacology (special issue on “New Insights on Mechanisms of Alcohol-induced Fatty Liver”), 10(3): 165-171, 2017. (doi: 10.2174/1874467208666150817112654)
  5. Yan, S., N. Huda, B. Khambu and X-M. Yin. Relevance of autophagy to fatty liver diseases and potential therapeutic applications.  Amino Acids.  49: 1965-1979, 2017 (doi: 10.1007/s00726-017-2429-y)
  6. Khambu, B., S. Yan, N. Huda, G. Liu and X.-M. Yin. Homeostatic role of autophagy in hepatocytes. Seminar in Liver Research.  38:308-319, 2018. PMID: 30357768
  7. Khambu, B., S. Yan, N. Huda, G. Liu and X.-M. Yin. Autophagy in nonalcoholic fatty liver disease and alcoholic liver disease.  Liver Research.  2: 112-119, 2018
  8. Huda, N., S. Yan, B. Khambu, H. Zou and X-M. Yin.  Analysis of autophagy in fatty liver diseases.  Methods in Molecular Biology 1880: 481-489, 2019 (ed. By O. Florey and N. Ktistakis).  (PMID: 30610716)
  9. Fu, Y., Z. Huang, L. Hong, J.H. Lu, D. Feng, X-M. Yin, M. Li.  Targeting ATG4 in cancer therapy.  Cancers (Basel), 2019 May 10;11(5). pii: E649. doi: 10.3390/cancers11050649, PMID: 31083460
  10. Huda, N. G. Liu, H. Hong, S. Yan, B. Khambu and X.-M. Yin. Hepatic senescence, the good and the bad.  World Journal of Gastroenterology. 25: 5069-5081, 2019. doi: 10.3748/wjg.v25.i34.5069. PMID: 31558857, PMID: 31558857
  11. Yan, S., B. Khambu, H. Hong, G. Liu, N. Huda and X-M. Yin. Autophagy, metabolism, and alcohol-related liver disease: Novel modulators and functions. International Journal of Molecular Sciences. 20: E5029, doi: 10.3390/ijms20205029, PMID: 31614437
  12. Khambu, B., S. Yan, N. Huda, and X-M. Yin. Role of High-Mobility Group Box-1 in liver pathogenesis.  International Journal of Molecular Sciences. 20: E5314, 2019, doi: 10.3390/ijms20215514, PMID: 31731454

 

Comments and Book Chapters

  1. Zhang, H., B. Khambu, and X.-M. Yin.  Chapter 11. Autophagy.  In “Signaling Pathways in Liver Diseases” (3rd edition, by J. F. Dufour and P.A. Clavien), Wiley, 2015
  2. Khambu, B., H. Zhang, and X.-M. Yin.  Chapter 9, Role of autophagy and mitophagy in liver disease.  In “Mitochondria in Liver Disease” (ed. By D. Han and N. Kaplowitz, a book of “Oxidative Stress and Disease” series), CRC Press, 2015
  3. Khambu, B; N. Huda, J. Zhou, S. Yan, and X.-M. Yin. Chapter 8, Autophagy in liver homeostasis.  In “Cell Death in Liver Injury” (ed. by W.-X. Ding and X-M. Yin, a book of the “Cell death in Biology and Disease” series. Springer, 2017)
  4. Yin, X.-M.  Autophagy in liver diseases: a matter of what to remove and whether to keep.  Liver Research. 2:109-111, 2018

 

Research

Current Research Interests

Determination of the homeostatic role of autophagy in the liver

Autophagy function is important for the normal hepatic physiology and structure.  Deletion of key autophagy genes leads to hepatomegaly, liver injury, inflammation, fibrosis and liver cancer.  The mechanism by which autophagy deficiency leads to these pathophysiological changes are not clear.  We have elucidated a key step in liver tumor development, in which HMGB1 secreted by the autophagy-deficient hepatocytes is instrumental. HMGB1 is also required for the ductular reaction, i.e., the expansion of hepatic progenitor cells, which is implicated in liver repair and regeneration. Representative publications are shown below.

 

  1. Yin, X.-M. W-X. Ding and W. Gao.  Autophagy in the liver. Hepatology 47:1773-1785, 2008.
  2. Khambu, B., N. Huda, X. Chen, Y. Li, G. Dai, Z. Dong, W-X Zong, S. Waguri, U.A. Kohler, S. Werner, T.D. Oury, and X.-M. Yin. HMGB1 promotes ductular reaction and tumorigenesis in autophagy deficient livers.  J. Clin. Invest.  128(6): 2419-2435, 2018.
  3. Khambu, B., S. Yan, N. Huda, G. Liu and X.-M. Yin. Homeostatic role of autophagy in hepatocytes. Seminar in Liver Research.  38:308-319, 2018.
  4. Khambu, B., T. Li, S. Yan, C. Yu, X. Chen, M. Goheen, Y. Li, J. Lin, O.W. Cummings, Y. A. Lee, S. Friedman, Z. Dong, G-S. Feng, S. Wu and X.-M. Yin.  Hepatic autophagy deficiency compromises FXR functionality and causes cholestatic injury.  Hepatology, 69:2196-2213, 2019.

 

Determination of the role of autophagy in alcohol and non-alcohol fatty liver diseases (AFLD and NAFLFD)

Autophagy is intimately associated with metabolism and in fact is an integrated component of catabolic process.  Being the largest metabolic organ in the body, liver has a potent activity of autophagy at the basal physiological level, which can be further enhanced in pathological conditions.  We find that alcohol drinking can stimulate hepatic autophagy, which is required to alleviate alcohol-induced liver injury.  Autophagy achieves this function by selective autophagy against damaged mitochondria and accumulated lipid droplets.  We have extended our finding to non-alcoholic fatty liver diseases and furthermore indicate that pharmacological promotion of autophagy can be an effective way to reduce liver injury and metabolic syndrome in AFLD and NAFLD.  The significance of these studies is the revelation of another survival mechanism against AFLD and NAFLD, which may be explored for therapeutic intervention.  Some of the representative publications are shown below.

 

  1. Ding, W.-X., M. Li, X. Chen, H-M. Ni, W. Gao, B. Lu, D. B. Stolz, D. L. Clemens and X.-M. Yin.  Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice.  Gastroenterology, 139: 1740-52. 2010.
  2. Lin, C.-W., H. Zhang, M. Li, X. Xiong, Xi Chen, X. Chen, C. X. Dong, and X.-M. Yin. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice.  J. Hepatology, 58: 993-999, 2013.
  3. Wang, L., J. Zhou, S. Yan, G. Lei, C-H. Lee, and X.-Ming Yin.  Ethanol-triggered lipophagy requires SQSTM1 in AML12 cells.  Science Reports, 7(1):12307, 2017.
  4. Zhang, H., B. Khambu, S. Yan, F. Ma, Y. Li, X. Chen, J. A. Martina, R. Puertollano, Y. Li, N. Chalasani, X.-M. Yin.  Oscillating TFEB signaling regulates hepatic steatosis and liver injury.  Autophagy, 14:1779-1795, 2018.

 

Development of small molecules for manipulation of autophagy and for cancer therapy

To explore the mechanism of autophagy and potential applications based on manipulation of autophagy, we have established high throughput screening assays based on cellular responses (high content) or chemical reactions (target based).  For the formal, cells expression GFP-LC3 were subjected to a library of 200,000 compounds to find out those cause autophagy alterations.  For the latter, we focused on Atg4, the only protease in the entire autophagy machinery, which is required for autophagy.  There are four Atg4 homologues and at least 8 homologue substrates in the mammalian cells.  We have characterized the enzymatic properties of the enzymes for most of the substrates.  The screening assays have generated multiple potential targets that are being characterized.  However, the usefulness of inhibition of Atg4 in selective typed of cancer has now been demonstrated in collaborative researches.  Some of the representative publications are shown below.

 

  1. Li, M., Y. Hou, J. Wang, X. Chen, Z.M. Shao and X.-M. Yin.  Kinetics comparisons of mammalian Atg4 homologues indicate selective preferences toward diverse Atg8 substrates.  J. Bio. Chem. 286:7327-7338, 2011.
  2. Li, M., Xi Chen, Q.-Z. Ye, A. Vogt and X.-M. Yin.  A High-throughput FRET-based Assay for Determination of Atg4 Activity.  Autophagy, 8:401-412, 2012.
  3. Akin, S., K. Wang, P. Habibzadegah-Tari, B. Law, D. Ostrov, M. Li, X.-M. Yin, J.-S. Kim, N. Horenstein, W.A Dunn, Jr.  A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors.  Autophagy, 10 (11): 2021-35, 2014.
  4. Li, M., Z. Yang, L.L. Vollmer, Y. Gao, Y. Fu, C. Liu, Xiaoyun Chen, P. Liu, A. Vogt, X.-M. Yin.  AMDE-1 Is a Dual Function Chemical for Autophagy Activation and Inhibition.  PLoS One 10 (3): e0122083, April 20, 2015.
  5. Huang, T., C.K. Kim, A.A. Alvarez, R.P. Pangeni, X. Wan, X. Song, T. Shi, Y. Yang, N. Sastry, C.M. Horbinski, S. Lu, R. Stupp, J. A. Kessler, R. Nishikawa, I. Nakano, E.P. Sulman, X. Lu, C.D. James, X-M. Yin, B Hu, and S-Y. Cheng.  MST4 phosphorylation of ATG4B regulates autophagic activity, tumorigenicity, and radioresistance in glioblastoma.  Cancer Cell, 32: 840-855.e8, 2017.

 

Determination of the multiple functions and molecular effects of Bid

As a pro-death Bcl-2 family molecule, Bid promotes mitochondrial release of cytochrome c.  My laboratory also found that Bid can induce the release of other mitochondrial inter-membrane proteins (Kim et al, JBC, 2000), including SMAC, whose significance has been mentioned above.  We further find that Bid has multiple effects on mitochondria, including causing mitochondrial permeability transition, mitochondrial cristae reorganization and ROS generation under TNFα or anti-Fas stimulation.  Bid interacts with mitochondrial cardiolipin for promoting these effects, which is different from its role in promoting mitochondrial release of cytochrome c and SMAC, for which its interaction with Bax via the BH3 domain is required.  What is most interesting is that we find that Bid possesses an entirely different function under non-apoptosis condition.  Bid can promote cell proliferation under growth stimulation condition.  This is achieved through its control of ER release of calcium.  This pro-proliferation explains the paradoxical finding of Bid’s ability to promote hepatic carcinogenesis.  Most recently in collaboration we also found that Bid can promote inflammasome activation through its effect at the mitochondria.  The significance of these findings is that Bid can have other functions than apoptosis regulation, and that Bid can have multiple molecular targets to exert its activity.  Some of the representative publications are shown below.

 

  1. Li, B., H.-M. Ni, X. Chen, D. DiFrancesca and X.-M. Yin.  Deletion of Bid impedes cell proliferation and hepatic carcinogenesis.  American J. Path. 166:1523-1532, 2005.
  2. Ni, H-M, C. J. Baty, N. Li, W-X. Ding, W. Gao, M. Li, X. Chen, J. Ma, G. K. Michalopoulos and X.-M. Yin.  Bid regulates murine hepatocyte proliferation by controlling ER calcium homeostasis.  Hepatology, 52: 338-348, 2010.
  3. Leibowitz, B., W. Qiu, M.E. Buchanan, F. Zou, P. Vernon; M.P. Moyer, X.-M. Yin, R.E. Schoen, J. Yu and L. Zhang.  BID mediates selective killing of APC-deficient cells in intestinal tumor suppression by nonsteroidal anti-inflammatory drugs.  Proc. Natl. Acad. Sci, 111:16520-16525, 2014.
  4. Bronner, D.N., B.H. Abuaita, X. Chen, K.A. Fitzgerald, G. Nuñez, Y. He, X.M. Yin, M.X. O'Riordan. Endoplasmic reticulum Stress activates the inflammasome via NLRP3- and caspase-2-driven mitochondrial damage.  Immunity. 43:451-462, 2015.
  5. Yu, C., S. Yan, B. Khambu, Xiaoyun Chen, Z. Dong, J. Luo, G. K. Michalopoulus, S. Wu, and X.-M. Yin.  Gene expression analysis indicates divergent mechanisms in DEN-induced carcinogenesis in wild type and Bid-deficient livers.  PLoS ONE 11(5): e0155211, 2016.

 

Research Funding (last 5 years)

Grant Name                  1R21 AA021450-01A1

Grant Title:                    Mechanism and role of selective autophagy in ethanol-induced liver injury

Role in Project:             Principal Investigator

Year (Inclusive):            June 15, 2014-May 31, 2016 (no cost extension to May 31, 2017)

Source:                           NIAAA, NIH

 

Grant Name                  1R01 AA021751-01A1

Grant Title:                    The dynamics and mechanisms of autophagy in ethanol-induced liver pathogenesis

Role in Project:             Principal Investigator

Year (Inclusive):            Aug 15, 2013-July 31, 2019 (with no cost extension)

Source:                           NIAAA, NIH

 

Grant Name                  1R01 DK116605-01

Grant Title:                    The role of HMGB1 in autophagy-deficiency induced liver pathology

Role in Project:             Principal Investigator

Year (Inclusive):            July 26, 2018-May 31, 2022

Source:                           NIDDK, NIH

 

 

Honors & Awards

  • Awards, Honors and Memberships

     

    Major Academic Awards and Recognition

    1996 — Howard Temin Award (NCI, NIH)

    2010 — Louis Y. Mazzini Professorship in Pathology, Indiana University

    2010 — Distinguished Alumnus Lecture, Immunology Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX

    2011 — Marquis Who’s Who in America 2011 (65th Edition)

    2015 — Elected to the Pluto Society (American Association of University Pathologists)

    2016 — Fellow, American Association for the Study of Liver Diseases

    2017 — Outstanding Investigator Award from American Society for Investigative Pathology

    2018 — President, Indiana Association of Pathologists

    2018 — Fellow, College of American Pathologists

    2019 — President, Society of Chinese Bioscientists in America-Hepatology Division (aka Chinese American Liver Society)

    2021 — Fellow, Southern Society for Clinical investigation

     

    Current Professional Membership

    1999-Present — American Society for Investigative Pathology (ASIP)

    2002-Present — Association of Molecular Pathology (AMP)

    2002-Present — American Society of Biochemistry and Molecular Biology (ASBMB)

    2005-Present — American Association for the Study of Liver Diseases (AASLD)

    2014-Present — American Association for the Advancement of Science (AAAS)

    2015-Present — Pluto Society (American Association of University Pathologists)(Elected)

    2017-Present — Association of Pathology Chairs

    2018-Present — College of American Pathologists

     

    Review Services

    A. NIH Study Section Membership

    2003-2004 — Ad hoc member: NIH study Section: Cell Development and Function 3

    2005-2008 — Standing member: NIH study Section: Cellular Signaling and Dynamics (CSD)/Cellular Signaling and Regulatory Systems (CSRS).  CSRS starts in June 2007 to replace CSD.

    2009 — Ad hoc reviewer: NIH challenge grants.

    2012.6 — Ad hoc reviewer: NIH Study Section -CSRS

    2013.7 — Ad hoc reviewer: Special emphasis panel on P50 grants, NIAAA, NIH

    2013.10 — Ad hoc reviewer, Special emphasis panel (ZDK1 GRB-7 (J3)), NIDDK, NIH

    2014.11 — Ad hoc reviewer, Special panel on ancillary clinical studies in liver and kidney disease (ZDK1 GRB-J (J2)), NIDDK, NIH

    2015.11 — Ad hoc reviewer, Special panel on small R03 grants for new investigators (ZDK1 GRB-7 (J2)), NIDDK, NIH

    2016.7-2020.6 — Standing member: NIH AA-1 Study Section

     

    B. Editorial Board Services

    2003 — Executive Editor: Molecular Mechanisms of Liver Injury, Current Molecular Medicine. Vol. 3, issue 6, September, 2003.

    01/2007-12/2011 — Editorial Board of Hepatology (The official journal of AASLD)

    07/2007- 09/2012 — Editorial Board of Journal of Biological Chemistry (The official journal of ASBMB)

    2007-2009 — Editorial Board of World Journal of Gastroenterology

    2009-2015 — Senior Editorial Board of American Journal of Translational Research

    2009-Present — International Editorial Board of Hepatology Research

    2010-2014 — Editorial Board of Autophagy

    08/2011-Present — Editorial Board of American Journal of Pathology (The official journal of ASIP)

    08/2013-Present — Associate Editor, American Journal of Pathology (The official journal of ASIP)

    2018 — Guest Editor: for the special issue on Autophagy and the Liver, Liver Research, Vol 3, Sept. 2018.

    1/2019-Present — Associate Editor: Liver Research

    11/2019-Present — Editorial Board of Hepatology (The official journal of AASLD)