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INFORMATION FOR

Wajahat Mehal

PhD, MD, BA
Professor of Medicine (Digestive Diseases); Director of Yale Weight Loss Program; Director of Yale Fatty Liver Disease Program

Contact Information

Wajahat Mehal, PhD, MD, BA

Mailing Address

  • Yale School of Medicine

    Department of Medicine (Digestive Diseases), P.O. Box 208019

    New Haven, CT 06520-8019

    United States

Research Summary

Sterile Inflammation: Inflammation occurs in response to tissue injury even in the absence of signals from pathogens. There are numerous examples of this, from soft tissue swelling after trauma to the inflammatory infiltrate after a myocardial infarction. In the liver a number of clinically important conditions have a significant sterile inflammatory component. These include drug induced liver injury, alcoholic, and non-alcoholic liver disease. We have recently identified a two signals pathway consisting of activation of TLR9 by DNA from apoptotic self cells, and also activation of the inflammasome pathway. In addition we have found that the cheap and safe anti-inflammatory drug aspirin can inhibit the TLR9 mediated pathway. We are expanding these findings to test their general applicability to a wide range of liver diseases and also to further identify the role of up-stream activating steps including nuclear DNA, and metabolites of the uric acid pathway.

Specialized Terms: Non-alcoholic hepatitis, Sterile inflammation; Liver fibrosis; Liver immunology

Extensive Research Description

Sterile Inflammation: Inflammation occurs in response to tissue injury even in the absence of signals from pathogens. There are numerous examples of this, from soft tissue swelling after trauma to the inflammatory infiltrate after a myocardial infarction. In the liver a number of clinically important conditions have a significant sterile inflammatory component. These include drug induced liver injury, alcoholic, and non-alcoholic liver disease. We have recently identified a two signals pathway consisting of activation of TLR9 by DNA from apoptotic self cells, and also activation of the inflammasome pathway. In addition we have found that the cheap and safe anti-inflammatory drug aspirin can inhibit the TLR9 mediated pathway. We are expanding these findings to test their general applicability to a wide range of liver diseases and also to further identify the role of up-stream activating steps including nuclear DNA, and metabolites of the uric acid pathway.

Liver Fibrosis: The hepatic stellate cell (HSC) is recognized as central to the development of liver fibrosis. We explored the paradigm that signals from dying cells result in HSC activation, and demonstrated that adenosine, which accumulates in conditions of tissue injury and inflammation, results in HSC activation. Interestingly in addition to up-regulating pro-fibrotic genes, adenosine also inhibits cytosolic calcium fluxes resulting in loss of HSC chemotaxis and contractility. We are currently examining other functional consequences of adenosine on HSC.

Liver Immunology: Antigens presented in the liver generate a suboptimal immune response often resulting in their chronic persistence (immune tolerance). This occurs clinically with tolerance to food antigens, to allo-antigens after transplantation, and to viral antigens during chronic infection with hepatitis viruses B and C. Despite these long-standing observations, it was recently realized that the healthy liver contains a large number of T cells (between 4-8 x 106 per gram of tissue). In this population conventional CD8+ T cells, and NK-T cells are over-represented, have an activated phenotype, and are undergoing cell cycle. We are interested in defining the interactions that occur between the healthy liver and the immune system during immune homeostasis, acute viral infections, and presentation of allo-antigens. We have shown that the healthy liver retains activated CD8+ T cells flowing through it. This retention is mediated mostly by hepatic ICAM-1 on Kupffer cells, and a proportion of the retained CD8+ T cells are undergoing apoptosis in the liver. Current work is focusing on the fate of activated CD8+ T cells when specific peptide is present in the liver, and also the ability of the liver to prime naive CD8+ T cells.

Coauthors

Research Interests

Digestive System Diseases; Fibrosis; Hepatitis; Inflammation; Liver; Weight Loss; Weight Reduction Programs

Selected Publications

  • S1358 Nonalcoholic Fatty Liver Disease Outcomes in Patients With Comorbid Psychiatric Disorders Improved by Integrated Medical Weight Management and Hepatology Clinic CareIlagan-Ying Y, Ilagan-Ying Y, Cotter R, Bollinger B, Mehal W, Do A. S1358 Nonalcoholic Fatty Liver Disease Outcomes in Patients With Comorbid Psychiatric Disorders Improved by Integrated Medical Weight Management and Hepatology Clinic Care The American Journal Of Gastroenterology 2022, 117: e975-e976. DOI: 10.14309/01.ajg.0000862072.84358.84.
  • S1345 Weight Loss Outcomes With and Without Diabetes in Patients With NAFLD in a Specialty Fatty Liver Disease ProgramIlagan-Ying Y, Ilagan-Ying Y, Valido K, Chehayeb R, Bollinger B, Mehal W, Do A. S1345 Weight Loss Outcomes With and Without Diabetes in Patients With NAFLD in a Specialty Fatty Liver Disease Program The American Journal Of Gastroenterology 2022, 117: e967-e968. DOI: 10.14309/01.ajg.0000862020.76034.41.
  • S1453 Weight Loss in Bariatric Surgery Patients Treated at a Novel Clinic Incorporating Obesity Medicine for Treatment of Nonalcoholic Fatty Liver DiseaseIlagan-Ying Y, Ilagan-Ying Y, Schwartz A, Park E, Bollinger B, Ying L, Ying L, Mehal W, Do A. S1453 Weight Loss in Bariatric Surgery Patients Treated at a Novel Clinic Incorporating Obesity Medicine for Treatment of Nonalcoholic Fatty Liver Disease The American Journal Of Gastroenterology 2022, 117: e1043-e1044. DOI: 10.14309/01.ajg.0000862452.53915.0f.
  • Nonalcoholic Fatty Liver Disease in the Post Liver Transplant PatientBatisti J, Mehal W. Nonalcoholic Fatty Liver Disease in the Post Liver Transplant Patient Current Transplantation Reports 2020, 7: 332-339. DOI: 10.1007/s40472-020-00303-0.
  • S1015 Bariatric Surgery Can Be Performed Safely at Yale-New Haven Hospital in Patients With CirrhosisMankash M, Yousaf M, Duffy A, Mehal W, Do A. S1015 Bariatric Surgery Can Be Performed Safely at Yale-New Haven Hospital in Patients With Cirrhosis The American Journal Of Gastroenterology 2020, 115: s518-s518. DOI: 10.14309/01.ajg.0000706108.48385.f8.
  • S1016 Tolerance and Safety of Meal Replacement Program in Nonalcoholic Steatohepatitis With Fibrosis and Cirrhosis: A Case SeriesMankash M, Kelly M, Mehal W, Do A. S1016 Tolerance and Safety of Meal Replacement Program in Nonalcoholic Steatohepatitis With Fibrosis and Cirrhosis: A Case Series The American Journal Of Gastroenterology 2020, 115: s518-s519. DOI: 10.14309/01.ajg.0000706112.69854.c1.
  • S1189 Incorporation of Obesity Medicine Into the Care of Patients With Nonalcoholic Fatty Liver Disease: 1-Year Interim ResultsMankash M, Kelly M, Duffy A, Mehal W, Do A. S1189 Incorporation of Obesity Medicine Into the Care of Patients With Nonalcoholic Fatty Liver Disease: 1-Year Interim Results The American Journal Of Gastroenterology 2020, 115: s595-s595. DOI: 10.14309/01.ajg.0000706804.10023.a3.
  • Medical Approach for Weight Loss in Nonalcoholic Fatty Liver DiseaseDo A, Ilagan-Ying Y, Mehal W. Medical Approach for Weight Loss in Nonalcoholic Fatty Liver Disease Current Hepatology Reports 2019, 18: 444-454. DOI: 10.1007/s11901-019-00498-6.
  • The impact of scoring system in the evaluation of Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)Yousaf M, Chaudhary F, Mehal W. The impact of scoring system in the evaluation of Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) Gastroenterology & Hepatology Open Access 2019, 10: 262-266. DOI: 10.15406/ghoa.2019.10.00392.
  • 1056 Incorporation of Obesity Management into the Care of Patients With Nonalcoholic Steatohepatitis: The Yale Fatty Liver Disease ModelMankash M, Kelly M, Dean J, Duffy A, Mehal W, Do A. 1056 Incorporation of Obesity Management into the Care of Patients With Nonalcoholic Steatohepatitis: The Yale Fatty Liver Disease Model The American Journal Of Gastroenterology 2019, 114: s599-s599. DOI: 10.14309/01.ajg.0000593756.22484.ae.
  • Reduction in Serum Cholesterol in Subjects Consuming the Fermented Soy Beverage Q-CAN® Plus (P06-118-19)Mehal W, Dioletis E, Paiva R, Secor E, Weiss T, Fields M, Ouyang X, Ali A. Reduction in Serum Cholesterol in Subjects Consuming the Fermented Soy Beverage Q-CAN® Plus (P06-118-19) Current Developments In Nutrition 2019, 3 PMCID: PMC6576748, DOI: 10.1093/cdn/nzz031.p06-118-19.
  • Hematology Safety Data for the Fermented Soy Beverage Q-CAN® Plus (P12-033-19)Mehal W, Suyavaran A, Dioletis E, Paiva R, Secor E, Weiss T, Fields M, Ouyang X, Ali A. Hematology Safety Data for the Fermented Soy Beverage Q-CAN® Plus (P12-033-19) Current Developments In Nutrition 2019, 3 PMCID: PMC6574472, DOI: 10.1093/cdn/nzz035.p12-033-19.
  • Reduction in Serum Levels of Inflammatory Cytokines in Subjects Consuming the Fermented Soy Beverage Q-CAN® Plus (P19-010-19)Mehal W, Suyavaran A, Dioletis E, Paiva R, Weiss T, Fields M, Ouyang X. Reduction in Serum Levels of Inflammatory Cytokines in Subjects Consuming the Fermented Soy Beverage Q-CAN® Plus (P19-010-19) Current Developments In Nutrition 2019, 3 PMCID: PMC6579392, DOI: 10.1093/cdn/nzz049.p19-010-19.
  • Isoflavone Stability Quality Control Assessment of Q-CAN® Plus, a Novel Fermented Soy Beverage (P12-034-19)Mehal W, Secor E, Weiss T, Fields M, Leapman M, Ali A. Isoflavone Stability Quality Control Assessment of Q-CAN® Plus, a Novel Fermented Soy Beverage (P12-034-19) Current Developments In Nutrition 2019, 3 PMCID: PMC6574992, DOI: 10.1093/cdn/nzz035.p12-034-19.
  • The Fermented Soy Beverage Q-CAN® Plus Induces Changes in the Oral and Intestinal Microbiome (P20-018-19)Mehal W, Dioletis E, Paiva R, Secor E, Weiss T, Fields M, Ali A. The Fermented Soy Beverage Q-CAN® Plus Induces Changes in the Oral and Intestinal Microbiome (P20-018-19) Current Developments In Nutrition 2019, 3 PMCID: PMC6574065, DOI: 10.1093/cdn/nzz040.p20-018-19.
  • 894 - Digoxin Protects from Alcoholic Hepatitis and Inhibits TGF-B Induced Fibrotic ResponseOuyang X, Mehal W. 894 - Digoxin Protects from Alcoholic Hepatitis and Inhibits TGF-B Induced Fibrotic Response Gastroenterology 2018, 154: s-1109. DOI: 10.1016/s0016-5085(18)33689-8.
  • Role of sterile inflammation in fatty liver diseasesChen Y, Yousaf M, Mehal W. Role of sterile inflammation in fatty liver diseases Liver Research 2018, 2: 21-29. DOI: 10.1016/j.livres.2018.02.003.
  • Ammonia Mediated Brain-oedema and Immune Dysfunction is Mediated by Toll-like Receptor (TLR) 9Vijay G, Hu C, Peng J, Martinez I, Hoque R, Zhang X, Ma Y, Mehal W, Shawcross D, Wen L. Ammonia Mediated Brain-oedema and Immune Dysfunction is Mediated by Toll-like Receptor (TLR) 9 Journal Of Clinical And Experimental Hepatology 2017, 7: s2-s3. DOI: 10.1016/j.jceh.2017.01.004.
  • THU-418 Ammonia-Induced Brain Oedema and Immune Dysfunction is Mediated by Toll-Like Receptor 9 (TLR9)Vijay G, Hu C, Peng J, Martinez I, Hoque R, Zhang X, Ma Y, Mehal W, Shawcross D, Wen L. THU-418 Ammonia-Induced Brain Oedema and Immune Dysfunction is Mediated by Toll-Like Receptor 9 (TLR9) Journal Of Hepatology 2016, 64: s314. DOI: 10.1016/s0168-8278(16)00420-7.
  • Aspartate a New Treatment Modality in the Treatment of Acute Liver Failure and Actiminophen-Induced ToxicityFarooq A, Farooq A, Mehal W. Aspartate a New Treatment Modality in the Treatment of Acute Liver Failure and Actiminophen-Induced Toxicity The American Journal Of Gastroenterology 2015, 110: s895. DOI: 10.14309/00000434-201510001-02147.
  • 237 Humans and Mice With NASH Have Increased Plasma Levels of TLR9 Ligand, and a TLR7/9 Bifunctional Antagonist Reduces NASH in MiceGarcia-Martinez I, Santoro N, Chen Y, Ouyang X, Caprio S, Coffman R, Candia A, Mehal W. 237 Humans and Mice With NASH Have Increased Plasma Levels of TLR9 Ligand, and a TLR7/9 Bifunctional Antagonist Reduces NASH in Mice Gastroenterology 2015, 148: s-974. DOI: 10.1016/s0016-5085(15)33328-x.
  • Su1058 Low Dose Digoxin Protects From NASH and Alcoholic Hepatitis in Mice by Inhibiting Inflammasome Activity and Mitochondrial ROS ProductionOuyang X, Zhang J, Feng D, Cai S, Protiva P, Garcia-Martinez I, Wang F, Gao B, Mehal W. Su1058 Low Dose Digoxin Protects From NASH and Alcoholic Hepatitis in Mice by Inhibiting Inflammasome Activity and Mitochondrial ROS Production Gastroenterology 2015, 148: s-1052. DOI: 10.1016/s0016-5085(15)33588-5.
  • Food Reactivity on the ALCAT Leukocyte Activation Test Is Associated with Upregulation of CD11b on T CellsGhani A, Mehal W, Ali A. Food Reactivity on the ALCAT Leukocyte Activation Test Is Associated with Upregulation of CD11b on T Cells Journal Of Alternative And Complementary Medicine 2014, 20: a35-a36. DOI: 10.1089/acm.2014.5089.abstract.
  • The Immunopathogenesis of CirrhosisGao B, Friedman S, Mehal W. The Immunopathogenesis of Cirrhosis 2013, 413-424. DOI: 10.1007/978-3-319-02096-9_28.
  • M1674 Caspase-1 and TLR-7,9 Signaling are Required for Cerulein PancreatitisSohail M, Husain S, Hoque R, Malik A, Shah A, Mehal W. M1674 Caspase-1 and TLR-7,9 Signaling are Required for Cerulein Pancreatitis Gastroenterology 2010, 138: s-827. DOI: 10.1016/s0016-5085(10)63811-5.
  • 239 P2X7 Receptor Activation up-Stream of the NLRP3 Inflammasome is Required for APAP Hepatotoxicity in MiceSohail M, Malik A, Hoque R, Mehal W. 239 P2X7 Receptor Activation up-Stream of the NLRP3 Inflammasome is Required for APAP Hepatotoxicity in Mice Gastroenterology 2010, 138: s-781. DOI: 10.1016/s0016-5085(10)63599-8.
  • T1773 Adenosine Inhibits Hepatocyte Growth Factor Induced Chemotaxis in Mesenchymal Stem CellsMohamadnejad M, Sohail M, Swenson E, Mehal W. T1773 Adenosine Inhibits Hepatocyte Growth Factor Induced Chemotaxis in Mesenchymal Stem Cells Gastroenterology 2008, 134: a-819. DOI: 10.1016/s0016-5085(08)63829-9.
  • 467 Aspirin Blocks Acetaminophen Induced Hepatotoxicity and Mortality in Mice - Dependent On the ASC/Caspase-1 InflammasomeImaeda A, Sutterwala F, Watanabe A, Mahmood S, Sohail M, Flavell R, Mehal W. 467 Aspirin Blocks Acetaminophen Induced Hepatotoxicity and Mortality in Mice - Dependent On the ASC/Caspase-1 Inflammasome Gastroenterology 2008, 134: a-767. DOI: 10.1016/s0016-5085(08)63581-7.
  • 56 Aacetaminophen Hepatotoxicity Is Dependent On TLR9 and Can Be Reduced By a TLR9 AntagonistMahmood S, Watanabe A, Sohail M, Flavell R, Mehal W. 56 Aacetaminophen Hepatotoxicity Is Dependent On TLR9 and Can Be Reduced By a TLR9 Antagonist Gastroenterology 2008, 134: a-752. DOI: 10.1016/s0016-5085(08)63514-3.
  • M1578 Adenosine Induces Loss of Actin Stress Fibers and Inhibits Contraction in Hepatic Stellate Cells Via Rho InhibitionSohail M, Watanabe A, Mahmood S, Hashmi A, Hakim W, Mehal W. M1578 Adenosine Induces Loss of Actin Stress Fibers and Inhibits Contraction in Hepatic Stellate Cells Via Rho Inhibition Gastroenterology 2008, 134: a-797. DOI: 10.1016/s0016-5085(08)63725-7.
  • The Role of Inflammation and Immunity in the Pathogenesis of Liver FibrosisMehal W, Friedman S. The Role of Inflammation and Immunity in the Pathogenesis of Liver Fibrosis 2007, 111-121. DOI: 10.1007/978-1-59745-518-3_10.
  • The Clinician's Guide to Liver DiseaseMehal W. The Clinician's Guide to Liver Disease Journal Of Clinical Gastroenterology 2006, 40: 564. DOI: 10.1097/00004836-200607000-00027.
  • 213 Leptin protects stellate cells, but not hepatocytes, from CD95 mediated apoptosisQamar A, Sheikh S, Inayat I, Mehal W. 213 Leptin protects stellate cells, but not hepatocytes, from CD95 mediated apoptosis Hepatology 2003, 38: 259. DOI: 10.1016/s0270-9139(03)80256-2.
  • ReplyTheise N, Krause D, Mehal W, Illei P. Reply Hepatology 2000, 32: 1181. DOI: 10.1016/s0270-9139(00)80044-0.

Clinical Trials

ConditionsStudy Title
Hepatitis; Diseases of the Digestive System - LiverDigoxin In Alcohol Associated Hepatitis
Immune SystemInhibition of Sterile Inflammation by Digoxin