Research Project 4
Project Narative
Obesity and non-alcoholic fatty liver (NAFL) are prevalent in many impoverished communities, contributes to health disparities, and increases the risk in these individuals developing toxicant-associated steatohepatitis (TASH) if exposed to environmental toxicants such as those found at NPL-Superfund sites. Since Hispanic and Native Americans are genetically predisposed to develop NAFL as a result of polymorphisms in the PNPLA3 gene, we propose to investigate the contribution of reactive oxygen species towards promoting TASH when the PNPLA3 gene with human polymorphic alleles are combined in mice expressing the inducible human CYP2E1 gene. The contribution of intestinal microbiota on increased susceptibility of toxicants generating TASH will be pursued, and the mechanisms of these responses will be examined in “human livers in the dish” (exVive3D™ Liver) following exposure to Superfund toxicants to examine if this novel culture system can be exploited to investigate TASH.
Summary of Project
Environmental exposures to industrial chemicals, such as carbon tetrachloride (CCl4) causes toxicant-induced steatohepatitis (TASH) characterized by fatty liver, inflammation, and fibrosis. Although susceptibility to occupational and environmental TASH may be modified by genetic predisposition (SNPs) and nutritional factors, our central hypothesis are that obesity and non-alcoholic fatty liver (NAFL) increase the severity of TASH by (1) Inducing the activity of cytochrome P450 2E1, (2) Increasing the generation of reactive oxygen species (ROS) by activating NADPH oxidases (NOXs), and (3) Inducing dysbiosis of the gut microbiome and increased intestinal permeability. The goal is to determine the mechanism by which obesity and CCl4 synergistically facilitate progression of TASH to liver cirrhosis, and develop new approaches to identifying toxicants that induce TASH. The following specific aims have been developed: (AIM1) To study the effect of “fast food diet” (FFD)-induced obesity and NAFL on CCl4-induced TASH. We propose to use improved diet-induced and genetic mouse models, including mice expressing human CYP2E1 gene and knock-in PNPLA3 mice (expressing the human SNP associated with NAFL). Since hCYP2E1 mice are more susceptible to toxicants, we anticipate that production of Nox1 and Nox4, release of pro-inflammatory cytokines by activated Kupffer cells, and development of liver fibrosis will closely recapitulate the pathology observed in patients with NASH/TASH. The specific role of NOX 1 and 4 in this TASH model will be assessed by pharmacological inhibition. (AIM2) To investigate the role of dysbiosis in transgenic mice subjected to fecal microbiota transplantation (FMT) from patients with NASH or matched normal controls from a well phenotyped cohort. We propose that the microbiome from NASH patients will render mice more sensitive to CCl4, while the transfer of “healthy” microbiota will decrease liver fibrosis in these mice. We will then do a therapeutic intervention by FMT of normal flora into a mouse with liver fibrosis to assess reversal of TASH. (AIM3) To translate our findings in mice to humans, we will utilize a “human liver in a dish” (exVive3D™ Livers, Organovo), a 3D culture composed of 4 primary hepatic cell types that maintains architectural and functional features of the human liver for greater than 40 days. These cultures will be subjected to Superfund toxicants and then assessed for TASH. The effects of potential drugs, such as Nox inhibitors, will be assessed in these 3D culture models of TASH. Overall, we will develop a high through-put system for ex vivo drug screening by measuring hepatotoxicity of Superfund toxicants and effectiveness of therapeutic interventions.
Publications
Haas ME, Pirruccello JP, Friedman SN, Wang M, Emdin CA, Ajmera VH, Simon TG, Homburger JR, Guo X, Budoff M, Corey KE, Zhou AY, Philippakis A, Ellinor PT, Loomba R, Batra P, Khera AV. Machine learning enables new insights into genetic contributions to liver fat accumulation. Cell Genom. 2021 Dec 8;1(3):100066. doi:10.1016/j.xgen.2021.100066. PMID: 34957434; PMCID: PMC8699145.
Danis N, Weeks SR, Kim A, Baghdadi A, Ghadimi M, Kamel IR, Saberi B, Woreta T, Garonzik-Wang J, Philosophe B, Gurakar A, Loomba R. Noninvasive Risk Stratification for Nonalcoholic Fatty Liver Disease Among Living Liver Donor Candidates: A Proposed Algorithm. Liver Transpl. 2021 Nov 9. doi:10.1002/lt.26365. Epub ahead of print. PMID: 34753223.
Tamaki N, Kurosaki M, Yasui Y, Mori N, Tsuji K, Hasebe C, Joko K, Akahane T, Furuta K, Kobashi H, Kimura H, Yagisawa H, Marusawa H, Kondo M, Kojima Y, Yoshida H, Uchida Y, Tada T, Nakamura S, Yasuda S, Toyoda H, Loomba R, Izumi N. Hepatocellular Carcinoma Risk Assessment for Patients With Advanced Fibrosis After Eradication of Hepatitis C Virus. Hepatol Commun. 2022 Mar;6(3):461-472. doi: 10.1002/hep4.1833. Epub 2021 Oct 22. PMID: 34676692.
Kanwal F, Shubrook JH, Adams LA, Pfotenhauer K, Wai-Sun Wong V, Wright E, Abdelmalek MF, Harrison SA, Loomba R, Mantzoros CS, Bugianesi E, Eckel RH, Kaplan LM, El-Serag HB, Cusi K. Clinical Care Pathway for the Risk Stratification and Management of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2021 Nov;161(5):1657-1669. doi:10.1053/j.gastro.2021.07.049. Epub 2021 Sep 20. PMID: 34602251; PMCID: PMC8819923.
Tamaki N, Imajo K, Sharpton S, Jung J, Kawamura N, Yoneda M, Valasek MA, Behling C, Sirlin CB, Nakajima A, Loomba R. Magnetic resonance elastography plus Fibrosis-4 versus FibroScan-aspartate aminotransferase in detection of candidates for pharmacological treatment of NASH-related fibrosis. Hepatology. 2022 Mar;75(3):661-672. doi:10.1002/hep.32145. Epub 2021 Dec 15. PMID: 34496054.
Majzoub AM, Nayfeh T, Barnard A, Munaganuru N, Dave S, Singh S, Murad MH, Loomba R. Systematic review with network meta-analysis: comparative efficacy of pharmacologic therapies for fibrosis improvement and resolution of NASH. Aliment Pharmacol Ther. 2021 Oct;54(7):880-889. doi:10.1111/apt.16583. Epub 2021 Aug 25. PMID: 34435378;PMCID: PMC8711247.
Tamaki N, Higuchi M, Kurosaki M, Loomba R, Izumi N; MRCH Liver Study Group. Risk Difference of Liver-Related and Cardiovascular Events by Liver Fibrosis Status in Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol. 2021 Jul 16:S1542-3565(21)00752-7. doi:10.1016/j.cgh.2021.07.021. Epub ahead of print. PMID: 34280550; PMCID: PMC8761224.
Vilarinho S, Ajmera V, Zheng M, Loomba R. Emerging Role of Genomic Analysis in Clinical Evaluation of Lean Individuals With NAFLD. Hepatology. 2021 Oct;74(4):2241-2250. doi:10.1002/hep.32047. PMID: 34233030;PMCID: PMC8463418.
Park JG, Jung J, Loomba R. Letter: coronary atherosclerosis in patients with significant hepatic fibrosis in non-alcoholic fatty liver disease-a realm for non-invasive testing. Authors' reply. Aliment Pharmacol Ther. 2021 Jul;54(2):216. doi: 10.1111/apt.16462. PMID: 34170539.
Jiao N, Loomba R, Yang ZH, Wu D, Fang S, Bettencourt R, Lan P, Zhu R, Zhu L. Alterations in bile acid metabolizing gut microbiota and specific bile acid genes as a precision medicine to subclassify NAFLD. Physiol Genomics. 2021 Aug 1;53(8):336-348. doi:10.1152/physiolgenomics.00011.2021. Epub 2021 Jun 21. PMID: 34151600; PMCID: PMC8424563.
Ajmera V, Liu A, Bettencourt R, Dhar D, Richards L, Loomba R. The impact of genetic risk on liver fibrosis in non-alcoholic fatty liver disease as assessed by magnetic resonance elastography. Aliment Pharmacol Ther. 2021 Jul;54(1):68-77. doi:10.1111/apt.16392. Epub 2021 May 11. PMID: 33975381.
Tamaki N, Munaganuru N, Jung J, Yonan AQ, Loomba RR, Bettencourt R, Ajmera V, Valasek MA, Behling C, Sirlin CB, Loomba R. Clinical utility of 30% relative decline in MRI-PDFF in predicting fibrosis regression in non-alcoholic fatty liver disease. Gut. 2021 Apr 21:gutjnl-2021-324264. doi:10.1136/gutjnl-2021-324264. Epub ahead of print. PMID: 33883248; PMCID: PMC8594562.
Park JG, Jung J, Verma KK, Kang MK, Madamba E, Lopez S, Qas Yonan A, Liu A, Bettencourt R, Sirlin C, Loomba R. Liver stiffness by magnetic resonance elastography is associated with increased risk of cardiovascular disease in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2021 May;53(9):1030-1037. doi:10.1111/apt.16324. Epub 2021 Mar 25. PMID: 33764550; PMCID: PMC8514119.
Byra M, Han A, Boehringer AS, Zhang YN, O'Brien WD Jr, Erdman JW Jr, Loomba R, Sirlin CB, Andre M. Liver Fat Assessment in Multiview Sonography Using Transfer Learning With Convolutional Neural Networks. J Ultrasound Med. 2022 Jan;41(1):175-184. doi:10.1002/jum.15693. Epub 2021 Mar 10. PMID: 33749862.
Caussy C, Aubin A, Loomba R. The Relationship Between Type 2 Diabetes, NAFLD, and Cardiovascular Risk. Curr Diab Rep. 2021 Mar 19;21(5):15. doi:10.1007/s11892-021-01383-7. PMID: 33742318; PMCID: PMC8805985.
Ruuskanen MO, Åberg F, Männistö V, Havulinna AS, Méric G, Liu Y, Loomba R, Vázquez-Baeza Y, Tripathi A, Valsta LM, Inouye M, Jousilahti P, Salomaa V, Jain M, Knight R, Lahti L, Niiranen TJ. Links between gut microbiome composition and fatty liver disease in a large population sample. Gut Microbes. 2021 Jan-Dec;13(1):1-22. doi:10.1080/19490976.2021.1888673. PMID: 33651661; PMCID: PMC7928040.
Ajmera V, Thompson WK, Smith DM, Malhotra A, Mehta RL, Tolia V, Yin J, Sriram K, Insel PA, Collier S, Richards L, Loomba R. RAMIC: Design of a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of ramipril in patients with COVID-19. Contemp Clin Trials. 2021 Apr;103:106330. doi:10.1016/j.cct.2021.106330. Epub 2021 Feb 22. PMID: 33631357; PMCID: PMC7899027.
Rosenthal SB, Liu X, Ganguly S, Dhar D, Pasillas MP, Ricciardelli E, Li RZ, Troutman TD, Kisseleva T, Glass CK, Brenner DA. Heterogeneity of HSCs in a Mouse Model of NASH. Hepatology. 2021 Aug;74(2):667-685. doi:10.1002/hep.31743. Epub 2021 Aug 10. PMID: 33550587; PMCID: PMC8346581.
Dhar D, Loomba R. Emerging Metabolic and Transcriptomic Signature of PNPLA3-Associated NASH. Hepatology. 2021 Apr;73(4):1248-1250. doi:10.1002/hep.31735. PMID: 33544416.
Tamaki N, Kurosaki M, Yasui Y, Mori N, Tsuji K, Hasebe C, Joko K, Akahane T, Furuta K, Kobashi H, Kimura H, Yagisawa H, Marusawa H, Kondo M, Kojima Y, Yoshida H, Uchida Y, Loomba R, Izumi N. Change in Fibrosis 4 Index as Predictor of High Risk of Incident Hepatocellular Carcinoma After Eradication of Hepatitis C Virus. Clin Infect Dis. 2021 Nov 2;73(9):e3349-e3354. doi:10.1093/cid/ciaa1307. PMID: 33544129; PMCID: PMC8824825.
Hagström H, Adams LA, Allen AM, Byrne CD, Chang Y, Grønbaek H, Ismail M, Jepsen P, Kanwal F, Kramer J, Lazarus JV, Long MT, Loomba R, Newsome PN, Rowe IA, Ryu S, Schattenberg JM, Serper M, Sheron N, Simon TG, Tapper EB, Wild S, Wong VW, Yilmaz Y, Zelber-Sagi S, Åberg F. Administrative Coding in Electronic Health Care Record-Based Research of NAFLD: An Expert Panel Consensus Statement. Hepatology. 2021 Jul;74(1):474-482. doi: 10.1002/hep.31726. Epub 2021 Jun 22. PMID: 33486773; PMCID: PMC8515502.
Cariou B, Byrne CD, Loomba R, Sanyal AJ. Nonalcoholic fatty liver disease as a metabolic disease in humans: A literature review. Diabetes Obes Metab. 2021 May;23(5):1069-1083. doi: 10.1111/dom.14322. Epub 2021 Feb 10. PMID: 33464677; PMCID: PMC8248154.
Ajmera V, Loomba R. Imaging biomarkers of NAFLD, NASH, and fibrosis. Mol Metab. 2021 Aug;50:101167. doi:10.1016/j.molmet.2021.101167. Epub 2021 Jan 15. PMID: 33460786; PMCID: PMC8324681.
Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2021 Apr;18(4):223-238. doi:10.1038/s41575-020-00381-6. Epub 2020 Dec 21. PMID: 33349658; PMCID: PMC8016738.
Sharpton SR, Schnabl B, Knight R, Loomba R. Current Concepts, Opportunities, and Challenges of Gut Microbiome-Based Personalized Medicine in Nonalcoholic Fatty Liver Disease. Cell Metab. 2021 Jan 5;33(1):21-32. doi:10.1016/j.cmet.2020.11.010. Epub 2020 Dec 8. PMID: 33296678; PMCID: PMC8414992.
Jung J, Loomba RR, Imajo K, Madamba E, Gandhi S, Bettencourt R, Singh S, Hernandez C, Valasek MA, Behling C, Richards L, Fowler K, Sirlin CB, Nakajima A, Loomba R. MRE combined with FIB-4 (MEFIB) index in detection of candidates for pharmacological treatment of NASH-related fibrosis. Gut. 2021 Oct;70(10):1946-1953. doi: 10.1136/gutjnl-2020-322976. Epub 2020 Nov 19. PMID: 33214165; PMCID: PMC8131405.
Loomba R. MRI-Proton Density Fat Fraction Treatment Response Criteria in Nonalcoholic Steatohepatitis. Hepatology. 2021 Mar;73(3):881-883. doi:10.1002/hep.31624. PMID: 33179266; PMCID: PMC8221026.
Long MT, Zhang X, Xu H, Liu CT, Corey KE, Chung RT, Loomba R, Benjamin EJ. Hepatic Fibrosis Associates With Multiple Cardiometabolic Disease Risk Factors: The Framingham Heart Study. Hepatology. 2021 Feb;73(2):548-559. doi:10.1002/hep.31608. Epub 2021 Feb 6. PMID: 33125745; PMCID: PMC8515503.
Ajmera VH, Cachay ER, Ramers CB, Bassirian S, Singh S, Bettencourt R, Richards L, Hamilton G, Middleton M, Fowler K, Sirlin C, Loomba R. Optimal Threshold of Controlled Attenuation Parameter for Detection of HIV-Associated NAFLD With Magnetic Resonance Imaging as the Reference Standard. Clin Infect Dis. 2021 Jun 15;72(12):2124-2131. doi:10.1093/cid/ciaa429. PMID: 32975278; PMCID: PMC8204791.
Stine JG, Munaganuru N, Barnard A, Wang JL, Kaulback K, Argo CK, Singh S, Fowler KJ, Sirlin CB, Loomba R. Change in MRI-PDFF and Histologic Response in Patients With Nonalcoholic Steatohepatitis: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol. 2021 Nov;19(11):2274-2283.e5. doi:10.1016/j.cgh.2020.08.061. Epub 2020 Aug 31. PMID: 32882428; PMCID: PMC7914285.
Loomba R, Ling L, Dinh DM, DePaoli AM, Lieu HD, Harrison SA, Sanyal AJ. The Commensal Microbe Veillonella as a Marker for Response to an FGF19 Analog in NASH. Hepatology. 2021 Jan;73(1):126-143. doi:10.1002/hep.31523. Epub 2020 Dec 11. PMID: 32794259; PMCID: PMC7898628.
Zhao P, Sun X, Chaggan C, Liao Z, In Wong K, He F, Singh S, Loomba, R, Karin M, Witztum JL, Saltiel AR. (2020) An AMPK-caspase-6 axis controls liver damage in nonalcoholic steatohepatitis. Science. Feb 7; 367(6478):652-660.
doi: 10.1126/science.aay0542
Dhar, D., Baglieri, J., Kisseleva, T. and Brenner, D.A. (2020) Mechanisms of liver fibrosis and its role in cancer. Exp Biol Med (Maywood). Jan 10:1535370219898141. doi: 10.1177/1535370219898141
Ma HY, Yamamoto G, Xu J, Liu X, Karin D, Kim JY, Alexandrov LB, Koyama Y, Nishio T, Benner C, Heinz S, Rosenthal SB, Liang S, Sun M, Karin G, Zhao P, Brodt P, Mckillop IH, Quehenberger O, Dennis E, Saltiel A, Tsukamoto H, Gao B, Karin M, Brenner DA, Kisseleva T. (2019) IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease. J Hepatol. Dec 31.
doi: 10.1016/j.jhep.2019.12.016
Sun, X., Seidman, J.S., Zhao, P., Troutman, T.D., Spann, N.J., Que, X., Zhou, F., Liao, Z., Pasillas, M., Yang, X., Magida, J.A., Kisseleva, T., Brenner, D.A.,Downes, M., Evans, R.M., Saltiel, A.R., Tsimikas, S., Glass, C.K., Witztum, J.L. (2020) Neutralization of Oxidized Phospholipids Ameliorates Non-alcoholic Steatohepatitis. Cell Metab. Jan 7;31(1):189-206.e8.
doi: 10.1016/j.cmet.2019.10.014
Loomba, R., Adams, L.A. (2019) The 20% Rule of NASH Progression: The Natural History of Advanced Fibrosis and Cirrhosis Caused by NASH. Hepatology. Dec;70(6):1885-1888. doi: 10.1002/hep.30946
Pai, R.K., Kleiner, D.E., Hart, J., Adeyi, O.A., Clouston, A.D., Behling, C.A., Jain, D., Kakar, S., Brahmania, M., Burgart, L., Batts, K.P., Valasek, M.A., Torbenson, M.S., Guindi, M., Wang, H.L., Ajmera, V., Adams, L.A., Parker, C.E., Feagan, B.G., Loomba, R., Jairath, V. (2019) Standardising the interpretation of liver biopsies in non-alcoholic fatty liver disease clinical trials. Aliment Pharmacol Ther. 50(10):1100-1111. doi: 10.1111/apt.15503. (https://onlinelibrary.wiley.com/doi/full/10.1111/apt.15503) Epub 2019 Oct 3.
Ajmera VH, Liu A, Singh S, Yachoa G, Ramey M, Bhargava M, Zamani A, Lopez S, Mangla N, Bettencourt R, Rizo E, Valasek M, Behling C, Richards L, Sirlin C, Loomba R. (2019) Clinical utility of an increase in magnetic resonance elastography in predicting fibrosis progression in NAFLD. Hepatology. Sep 25. doi: 10.1002/hep.30974
Wang, L., Mazagova, M., Pan, C., Yang, S., Brandl, K., Liu, J., Reilly, S.M., Wang, Y., Miao, Z., Loomba, R., Lu, N., Guo, Q., Liu, J., Yu, R.T., Downes, M., Evans, R.M., Brenner, D.A., Saltiel, A.R., Beutler, B., Schnabl, B. (2019) YIPF6 controls sorting of FGF21 into COPII vesicles and promotes obesity. Proc Natl Acad Sci U S A. 116(30):15184-15193. doi: 10.1073/pnas.1904360116. (https://www.pnas.org/content/116/30/15184) Epub 2019 Jul 9.
Mouzaki, M., Loomba, R. (2019) Insights into the evolving role of the gut microbiome in nonalcoholic fatty liver disease: rationale and prospects for therapeutic intervention. Therap Adv Gastroenterol. 12:1756284819858470. doi: 10.1177/1756284819858470. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591661/) eCollection 2019. Review.
Mangla, N., Ajmera, V.H., Caussy, C., Sirlin, C., Brouha, S., Bajwa-Dulai, S., Madamba, E., Bettencourt, R., Richards, L., Loomba, R. (2019) Liver Stiffness Severity is Associated With Increased Cardiovascular Risk in Patients With Type 2 Diabetes. Clinical gastroenterology and hepatology. May 14. doi: 10.1016/j.cgh.2019.05.003
Baglieri J, Brenner DA, Kisseleva T. (2019) The Role of Fibrosis and Liver-Associated Fibroblasts in the Pathogenesis of Hepatocellular Carcinoma. Int J Mol Sci. Apr 7; 20(7). pii: E1723. Review. doi: 10.3390/ijms20071723
Mills, P.J., Caussy, C., Loomba, R. (2019) Glyphosate Excretion is Associated With Steatohepatitis and Advanced Liver Fibrosis in Patients With Fatty Liver Disease. Clin Gastroenterol Hepatol. pii: S1542-3565(19)30361-1. doi: 10.1016/j.cgh.2019.03.045. (https://www.sciencedirect.com/science/article/abs/pii/S1542356519303611?...) [Epub ahead of print]
Caussy, C., Tripathi, A., Humphrey, G., Bassirian, S., Singh, S., Faulkner, C., Bettencourt, R., Rizo, E., Richards, L., Xu, Z.Z., Downes, M.R., Evans, R.M., Brenner, D.A., Sirlin, C.B., Knight, R., Loomba, R. (2019) A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease. Nat Commun. Mar 29; 10(1):1406. doi: 10.1038/s41467-019-09455-9
Caussy, C., Bhargava, M., Villesen, I.F., Gudmann, N.S., Leeming, D.J., Karsdal, M.A., Faulkner, C., Bao, D., Liu ,A., Lo, M.T., Bettencourt, R., Bassirian, S., Richards, L., Brenner, D.A., Chen, C.H., Sirlin, C.B., Loomba, R. (2019) Collagen Formation Assessed by N-Terminal Propeptide of Type 3 Procollagen Is a Heritable Trait and Is Associated With Liver Fibrosis Assessed by Magnetic Resonance Elastography. Hepatology. 70(1):127-141. doi: 10.1002/hep.30610. (https://doi.org/10.1002/hep.30610) Epub 2019 Apr 29.
Castera, L., Friedrich-Rust, M., Loomba, R. (2019) Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 156(5):1264-1281.e4. doi: 10.1053/j.gastro.2018.12.036. Epub 2019 Jan 18. Review.
Liang, S., Ma, H.Y., Zhong, Z., Dhar, D., Liu, X., Xu, J., Koyama, Y., Nishio, T., Karin, D., Karin, G., Mccubbin, R., Zhang, C., Hu, R., Yang, G., Chen, L., Ganguly, S., Lan, T., Karin, M., Kisseleva, T., Brenner, D.A. (2018) NADPH Oxidase 1 in Liver Macrophages Promotes Inflammation and Tumor Development in Mice. Gastroenterology. 156(4):1156-1172.e6. doi: 10.1053/j.gastro.2018.11.019. Epub 2018 Nov 13.
Kim, J.Y., Garcia-Carbonell, R., Yamachika, S., Zhao, P., Dhar, D., Loomba, R., Kaufman, R.J., Saltiel, A.R., Karin, M. (2018) ER Stress Drives Lipogenesis and Steatohepatitis via Caspase-2 Activation of S1P. Cell. 175(1):133-145.e15. doi: 10.1016/j.cell.2018.08.020. Epub 2018 Sep 13.
Zhong, Z., Liang, S., Sanchez-Lopez, E., He, F., Shalapour, S., Lin, X.J., Wong, J., Ding, S., Seki, E., Schnabl, B., Hevener, A.L., Greenberg, H.B., Kisseleva, T., Karin, M. (2018) New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature. 560(7717):198-203. doi: 10.1038/s41586-018-0372-z. Epub 2018 Jul 25.
Brenner, D.A. (2018) Of Mice and Men and Nonalcoholic Steatohepatits. Hepatology. 68(6):2059-2061. doi: 10.1002/hep.30186. Epub 2018 Nov 13. No abstract available.
Tripathi, A., Debelius, J., Brenner, D.A., Karin, M., Loomba, R., Schnabl, B., Knight, R. (2018) The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol. 15(12):785. doi: 10.1038/s41575-018-0031-8.
Ajmera, V., Park, C.C., Caussy, C., Singh, S., Hernandez, C., Bettencourt, R., Hooker, J., Sy, E., Behling, C., Xu, R., Middleton, M.S., Valasek, M.A., Faulkner, C., Rizo, E., Richards, L., Sirlin, C.B., Loomba, R. (2018) Magnetic Resonance Imaging Proton Density Fat Fraction Associates With Progression of Fibrosis in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 155(2):307-310.e2. doi: 10.1053/j.gastro.2018.04.014. Epub 2018 Apr 13.
Caussy, C., Hsu, C., Lo, M.T., Liu, A., Bettencourt, R., Ajmera, V.H., Bassirian, S., Hooker, J., Sy, E., Richards, L., Schork, N., Schnabl, B., Brenner, D.A., Sirlin, C.B., Chen, C.H., Loomba, R.; Genetics of NAFLD in Twins Consortium. (2018) Link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD. Hepatology. doi: 10.1002/hep.29892.
Desai, A.P., Mohan, P., Roubal, A.M., Bettencourt, R., Loomba, R. (2018) Geographic Variability in Liver Disease-Related Mortality Rates in the United States. Am J Med. 131(7):728-734. doi: 10.1016/j.amjmed.2018.01.047. Epub 2018 Feb 26.
Xu J., Ma H.Y., Liang S., Sun M., Karin G., Koyama Y., Hu R., Quehenberger O., Davidson N.O., Dennis E.A., Kisseleva T., Brenner D.A. (2017) The role of human cytochrome P450 2E1 in liver inflammation and fibrosis. Hepatol Commun. 1(10):1043-1057. doi: 10.1002/hep4.1115. eCollection 2017 Dec.
Hartmann P., Hochrath K., Horvath A., Chen P., Seebauer C.T., Llorente C., Wang L., Alnouti Y., Fouts D.E., Stärkel P., Loomba R., Coulter S., Liddle C., Yu R.T., Ling L., Rossi S.J., DePaoli A.M., Downes M., Evans R.M., Brenner D.A., Schnabl B. (2017) Modulation of the intestinal bile acid-FXR-FGF15 axis improves alcoholic liver disease in mice. Hepatology. doi: 10.1002/hep.29676.
Shalapour, S., Lin, X.J., Bastian, I.N., Brain, J., Burt, A.D., Aksenov, A.A., Vrbanac, A.F., Li, W., Perkins, A., Matsutani, T., Zhong, Z., Dhar, D., Navas-Molina, J.A., Xu, J., Loomba, R., Downes, M., Yu, R.T., Evans, R.M., Dorrestein, P.C., Knight, R., Benner, C., Anstee, Q.M., Karin, M. (2017). Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature. 551, 340-345. doi: 10.1038/nature24302.
Tapper, E.B., Loomba, R. (2018) Nonalcoholic fatty liver disease, metabolic syndrome, and the fight that will define clinical practice for a generation of hepatologists. Hepatology. 67(5):1657-1659. doi: 10.1002/hep.29722. Epub 2018 Apr 1.
Brouha, S.S., Nguyen, P., Bettencourt, R., Sirlin, C.B., Loomba, R. (2018) Increased severity of liver fat content and liver fibrosis in non-alcoholic fatty liver disease correlate with epicardial fat volume in type 2 diabetes: A prospective study. Eur Radiol. 28(4):1345-1355. doi: 10.1007/s00330-017-5075-6. Epub 2017 Oct 20.
Song IJ, Yang YM, Inokuchi-Shimizu S, Roh YS, Yang L, Seki E. (2018) The contribution of toll-like receptor signaling to the development of liver fibrosis and cancer in hepatocyte-specific TAK1-deleted mice. Int J Cancer. 142(1):81-91. doi: 10.1002/ijc.31029. Epub 2017 Sep 23.
Caussy C., Soni M., Cui J., Bettencourt R., Schork N., Chen C.H., Ikhwan M.A., Bassirian S., Cepin S., Gonzalez M.P., Mendler M., Kono Y., Vodkin I., Mekeel K., Haldorson J., Hemming A., Andrews B., Salotti J., Richards L., Brenner D.A., Sirlin C.B., Loomba R., Familial NAFLD Cirrhosis Research Consortium. (2017) Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis. J Clin Invest. 127(7):2697-2704. doi: 10.1172/JCI93465. Epub 2017 Jun 19.
Vollmann E.H., Cao L., Amatucci A., Reynolds T., Hamann S., Dalkilic-Liddle I., Cameron T.O., Hossbach M., Kauffman K.J., Mir F.F., Anderson D.G., Novobrantseva T., Koteliansky V., Kisseleva T., Brenner D., Duffield J., Burkly L.C. (2017) Identification of Novel Fibrosis Modifiers by In Vivo siRNA Silencing. Mol Ther Nucleic Acids. 7:314-323. doi: 10.1016/j.omtn.2017.04.014. Epub 2017 Apr 20.
Reinders M.E., Wardi G., Bettencourt R., Bouland D., Bazick J., Mendler M., Vodkin I., Kalmaz D., Savides T., Brenner D., Sell R.E., Loomba R. (2017) Increased Risk of Death, in the Hospital and Outside the Intensive Care Unit, for Patients With Cirrhosis After Cardiac Arrest. Clin Gastroenterol Hepatol. 15(11):1808-1810. doi: 10.1016/j.cgh.2017.05.044. Epub 2017 Jun 7.
Kim R.G., Loomba R., Prokop L.J., Singh S. (2017) Statin Use and Risk of Cirrhosis and Related Complications in Patients With Chronic Liver Diseases: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 15(10):1521-1530.e8. doi: 10.1016/j.cgh.2017.04.039. Epub 2017 May 4.
Loomba R., Seguritan V., Li W., Long T., Klitgord N., Bhatt A., Dulai P.S., Caussy C., Bettencourt R., Highlander S.K., Jones M.B., Sirlin C.B., Schnabl B., Brinkac L., Schork N., Chen C.H., Brenner D.A., Biggs W., Yooseph S., Venter J.C., Nelson K.E. (2017) Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metab. 25(5):1054-1062.e5. doi: 10.1016/j.cmet.2017.04.001.
Koyama Y., Wang P., Liang S., Iwaisako K., Liu X., Xu J., Zhang M., Sun M., Cong M., Karin D., Taura K., Benner C., Heinz S., Bera T., Brenner D.A., Kisseleva T. (2017) Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis. J Clin Invest. 127(4):1254-1270. doi: 10.1172/JCI88845. Epub 2017 Mar 13.
Dulai P.S., Singh S., Patel J., Soni M., Prokop L.J., Younossi Z., Sebastiani G., Ekstedt M., Hagstrom H., Nasr P., Stal P., Wong V.W., Kechagias S., Hultcrantz R., Loomba R. (2017) Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology. 65(5):1557-1565. doi: 10.1002/hep.29085. Epub 2017 Mar 31.
Lin S.C., Heba E., Bettencourt R., Lin G.Y., Valasek M.A., Lunde O., Hamilton G., Sirlin C.B., Loomba R. (2017) Assessment of treatment response in non-alcoholic steatohepatitis using advanced magnetic resonance imaging. Aliment Pharmacol Ther. 45(6):844-854. doi: 10.1111/apt.13951. Epub 2017 Jan 24.
Koyama Y., Brenner D.A. (2017) Liver inflammation and fibrosis. J Clin Invest. 127:55-64. doi: 10.1172/JCI88881.
Park C.C., Nguyen P., Hernandez C., Bettencourt R., Ramirez K., Fortney L., Hooker J., Sy E., Savides M.T., Alquiraish M.H., Valasek M.A., Rizo E., Richards L., Brenner D., Sirlin C.B., Loomba R. (2017) Magnetic Resonance Elastography vs Transient Elastography in Detection of Fibrosis and Noninvasive Measurement of Steatosis in Patients With Biopsy-Proven Nonalcoholic Fatty Liver Disease. Gastroenterology. 152:598-607. doi: 10.1053/j.gastro.2016.10.026.
Koyama Y., Xu J., Liu X., Brenner D.A. (2016) New Developments on the Treatment of Liver Fibrosis. Dig Dis. 34:589-96. doi: 10.1159/000445269.
Wang P., Koyama Y., Liu X., Xu J., Ma H.Y., Liang S., Kim I.H., Brenner D.A., Kisseleva T. (2016) Promising Therapy Candidates for Liver Fibrosis. Front Physiol. 7:47. doi: 10.3389/fphys.2016.00047.
Liang S., Kisseleva T., Brenner D.A. (2017) The Role of NADPH Oxidases (NOXs) in Liver Fibrosis and the Activation of Myofibroblasts. Front Physiol. 7:17. doi: 10.3389/fphys.2016.00017. eCollection 2016.
Brenner, D. A., Paik, Y. H., Schnabl, B. (2015) Role of Gut Microbiota in Liver Disease. J Clin Gastroenterol. 49 Suppl 1:S25-7. doi: 10.1097/MCG.0000000000000391.
Lan, T., Kisseleva, T., Brenner, D.A. (2015) Deficiency of NOX1 or NOX4 Prevents Liver Inflammation and Fibrosis in Mice through Inhibition of Hepatic Stellate Cell Activation. PLoS One. 10(7):e0129743. doi: 10.1371/journal.pone.0129743.
Koyama, Y., Brenner, D. A. (2015) New therapies for hepatic fibrosis. Clin Res Hepatol Gastroenterol. 39 Suppl 1, S75-9. doi: 10.1016/j.clinre.2015.06.011.
Seki, E., Brenner, D. A. (2015) Recent advancement of molecular mechanisms of liver fibrosis. J Hepatobiliary Pancreat Sci. 22(7):512-8. doi: 10.1002/jhbp.245
Kim, I. H., Kisseleva, T., Brenner, D. A. (2015) Aging and liver disease. Curr Opin Gastroenterol. 31(3):184-91. doi: 10.1097/MOG.0000000000000176.
Fang, S., Suh, J. M., Reilly, S. M., Yu, E., Osborn, O., Lackey, D., Yoshihara, E., Perino, A., Jacinto, S., Lukasheva, Y., Atkins, A. R., Khvat, A., Schnabl, B., Yu, R. T., Brenner, D. A., Coulter, S., Liddle, C., Schoonjans, K., Olefsky, J. M., Saltiel, A. R., Downes, M., Evans, R. M. (2015) Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. 21(2):159-65. doi: 10.1038/nm.3760.
Mazagova, M., Wang, L., Anfora, A. T., Wissmueller, M., Lesley, S. A., Miyamoto, Y., Eckmann, L., Dhungana, S., Pathmasiri, W., Sumner, S., Westwater, C., Brenner, D. A., Schnabl, B. (2015) Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J. 29(3):1043-55. doi: 10.1096/fj.14-259515.
Lopez-Sanchez, I., Dunkel, Y., Roh, Y. S., Mittal, Y., De Minicis, S., Muranyi, A., Singh, S., Shanmugam, K., Aroonsakool, N., Murray, F., Ho, S. B., Seki, E., Brenner, D. A., Ghosh, P. (2014) GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis. Nat Commun. 5:4451. doi: 10.1038/ncomms5451.
Inokuchi-Shimizu, S., Park, E. J., Roh, Y. S., Yang, L., Zhang, B., Song, J., Liang, S., Pimienta, M., Taniguchi, K., Wu, X., Asahina, K., Lagakos, W., Mackey, M. R., Akira, S., Ellisman, M. H., Sears, D. D., Olefsky, J. M., Karin, M., Brenner, D. A., Seki, E. (2014) ETAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. J Clin Invest. 124(8), 3566-78. doi: 10.1172/JCI74068.
Liu, C., Chen, X., Yang, L., Kisseleva, T., Brenner, D. A., Seki, E. (2014) Transcriptional Repression of the Transforming Growth Factor β (TGF-β) Pseudoreceptor BMP and Activin Membrane-bound Inhibitor (BAMBI) by Nuclear Factor κB (NF-κB) p50 Enhances TGF-β Signaling in Hepatic Stellate Cells. J Biol Chem. 289(10):7082-91. doi: 10.1074/jbc.M113.543769.
Schnabl, B., Brenner, D. A. (2014) Interactions between the intestinal microbiome and liver diseases. Gastroenterology. 146(6):1513-24. doi: 10.1053/j.gastro.2014.01.020.
Paik, Y. H., Kim, J., Aoyama, T., De Minicis, S., Bataller, R., Brenner, D. A. (2014) Role of NADPH Oxidases in Liver Fibrosis. Antioxid Redox Signal. 20(17):2854-72. doi: 10.1089/ars.2013.5619.
Madsen, D. H., Leonard, D., Masedunskas, A., Moyer, A., Jürgensen, H. J., Peters, D. E., Amornphimoltham, P., Selvaraj, A., Yamada, S. S., Brenner, D. A., Burgdorf, S., Engelholm, L. H., Behrendt, N., Holmbeck, K., Weigert, R., Bugge, T. H. (2013) M2-like macrophages are responsible for collagen degradation through a mannose receptor-mediated pathway J Cell Biol. 202(6):951-66. doi: 10.1083/jcb.201301081.
Seki, E., Brenner, D. A., Karin, M. (2012) A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches. Gastroenterology. 143(2), 307-20. doi: 10.1053/j.gastro.2012.06.004.
Österreicher, C.H., Penz-Österreicher, M., Grivennikov, S. I., Guma, M., Koltsova, E. K., Datz, C., Sasik, R., Hardiman, G., Karin, M., Brenner, D. A., (2011) Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver. Proc Natl Acad Sci USA. 108(1), 308-13. doi: 10.1073/pnas.1017547108.
Main Contact Information
Project Leaders
-
Dr. David A. Brenner
Dean, UCSD School of Medicine; Vice Chancellor for Health Sciences - Dr. Rohit Loomba
Professor, Division of Gastroenterology, Department of Medicine, UCSD School of Medicine
Superfund Project Members
- Tatiana Kisseleva, Researcher
- Jacopo Baglieri, Post-Doctoral Scholar
- Karin Diggle, Lab Manager
Contact
UCSD Superfund Research Center
University of California, San Diego
Pharmacology Department
9500 Gilman Drive, Mail Code 0722
La Jolla, CA 92093-0722
Supporting Partners
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