Advancing Understanding of Mechanisms of Liver Disease Raymond Chung, MD
Overview
Raymond Chung, MD, Chief of AMC Medicine Div. of Gastroenterology, Hepatology & Endoscopy at Mass General Brigham, leads an NIH-funded Center for Human Immunology U19 Program, a consortium of eight projects centered on understanding the basis for the persistence of hepatitis C virus, hepatitis B virus, and HIV, infections with remarkable tendencies to become chronic.
His laboratory successfully uncovered strategies employed by both hepatitis C virus to ensure its persistence in the liver, and the basis by which the infection causes liver scarring and cancer.
Dr. Chung also led the Mass General site of the NIH Hepatitis B Research Network, which is committed to long term study of optimal antiviral treatment strategies to prevent cirrhosis and liver cancer in persons chronically infected with this hepatitis virus.
Our current laboratory projects include:
- Understanding how and why HIV cooperates with fatty liver to cause more accelerated and severe liver disease than those persons with fatty liver alone; specifically, we are evaluating HIV’s cooperative effects on monocyte/macrophage activation through the Hippo pathway
- Development and refinement of proteomic biomarkers to identify those persons with more severe, progressive forms of fatty liver
- Defining how modulation of the gut bacteria and bile salt pool attenuates fatty liver inflammation and fibrosis via the gut-liver axis
- Exploration of how chronic HCV infection induces lasting epigenetic and functional suppression of immune responses even following cure of infection.
- Investigation of how HIV co-infection amplifies HBV-induced liver fibrosis by driving metabolic reprogramming in hepatic cells
- Investigation of the role of pyruvate production and reactive oxygen species generation in HBV-related liver fibrosis
- Investigation of precision-cut liver slices (PCLS) as a novel ex vivo human liver model to evaluate HIV-induced liver damage.
- A randomized controlled trial to investigate the chemopreventive effects of statins (atorvastatin) on liver cancer development in patients at high risk
- Target trial emulations to evaluate the chemopreventive effects of statins on liver fibrosis progression and liver cancer development
- Target trial emulations to evaluate the chemopreventive effects of GLP-1 agonists on liver fibrosis progression and liver cancer development
- Target trial emulations to evaluate the chemopreventive effects of SGLT-2 inhibitors on liver fibrosis progression and liver cancer development
- Assessment of radiomic markers to predict hepatic decompensation in persons with compensated cirrhosis
Research Projects
YAP signaling in the pathogenesis of NAFLD in people living with HIV
Since the introduction of effective combination antiretroviral therapy (cART), HIV infection has been converted from a fatal disease into a chronic condition. Liver disease has emerged as the second leading cause of non- AIDS related death in persons living with HIV (PLWH). Nonalcoholic fatty liver disease (NAFLD) is the leading form of chronic liver disease in the U.S., afflicting approximately 30% of adults. PLWH have a high prevalence of NAFLD with rates as high as 53%, associated with not only higher frequency of the inflammatory non-alcoholic steatohepatitis (NASH) but also accelerated liver fibrosis progression. Moreover, in NAFLD/HIV, there is a disproportionate burden of progressive NASH and fibrosis compared with HIV(-) NAFLD. While recent studies have replicated the accelerated fibrosis progression seen in PLWH/NAFLD, the precise mechanisms remain poorly defined. We and others have led the field in demonstrating that HIV itself induces a profibrogenic program in the liver via several pathways. The Hippo signaling pathway controls cell proliferation and fibrogenesis through YAP transcriptional co-activators that regulate more than 400 genes through binding to TEAD, SMAD1/2/3 and other sites. Our recent work has shown increases in YAP-related gene expression among NAFLD patients with fibrosis and in mouse NASH models. We also observed a significant reduction in fibrosis-related parameters in hepatocyte-specific YAP knockout mice fed a NASH diet. We have also shown that HIV induces YAP activation in hepatocytes and macrophages via the LPA/PI3K and AKT pathways. Therefore, HIV and NAFLD likely cooperate at the level of YAP activation to contribute to fibrogenesis and liver damage. Hepatic and monocyte- derived macrophages, dysregulated by HIV infection and polarized during liver injury, are likely to contribute to NAFLD and HIV-related liver disease. Studies have observed increased macrophage content in the livers of PLWH and others have linked YAP activation to macrophage infiltration. However, comprehensive studies of the in vitro and in vivo effects of YAP activation among the key cell types (hepatocytes, macrophages, and HSCs) that drive fibrogenesis in PLWH are lacking. We hypothesize that HIV and NAFLD exert independent and additive effects on YAP activation in both macrophage and hepatocyte populations that in turn accelerate hepatic fibrosis progression through their action on HSCs. In this proposal, using novel coculture assays, ex vivo liver tissue, and a humanized mouse model and combining the efforts of liver pathogenesis and HIV virology/pathogenesis experts, we will: (1) define the contribution of YAP signaling to macrophage polarization, hepatocyte and hepatic stellate cell (HSC) activation in HIV/NAFLD.; (2) assess the effect of cART regimens on macrophage, hepatocyte and HSC phenotypes and YAP activation in models of HIV/NAFLD.; and (3) determine the effects of YAP inhibition on fibrogenesis in HIV/NAFLD. A detailed understanding of the upstream and downstream regulators of YAP in NAFLD/HIV is likely to uncover novel antifibrotic strategies for NAFLD that could block this highly prevalent progressive liver disease in PLWH. .
Cooperative mechanisms of HIV-enhanced liver fibrogenesis in HBV Coinfection
HIV infects about 40 million people worldwide, among whom approximately 10% harbor chronic hepatitis B virus (HBV) co-infection. The progression of chronic HBV to cirrhosis, end-stage liver disease, or hepatocellular carcinoma is accelerated in HIV coinfection compared to chronic HBV monoinfection. Nucleos(t)ide analogues (NAs) including entecavir and tenofovir are currently approved for the treatment of chronic HBV infection. In HIV coinfection, despite HBV suppression with NAs, there is still evidence for more severe liver injury and fibrosis compared with NA-suppressed HBV monoinfection. However, the mechanisms by which HIV increases HBV replication and HBV-induced liver fibrosis are not well characterized. One of the major obstacles in HIV-HBV coinfection study has been the lack of a robust animal or co-culture model. We have extensive experience in the study of HIV-induced liver fibrosis in HCV-HIV coinfection and have parlayed this experience into relevant models for HIV-HBV co-infection. Using HIV/HBV mono-culture and novel transwell and spheroid co-culture models (up to 3 lines) developed in our laboratory, we have found that HIV increases HBV replication, HBV cccDNA levels, and enhances HBV-induced fibrosis-related gene expression in HBV HepAD38, HBV- infected NTCP-HepG2 and LX2 HSC cells. We have found that HBV and HIV infection each induce cytokine disturbances that could contribute to fibrosis. Separately, we have found that HIV enhances pyruvate production, which in turn promotes hepatic fibrosis. We hypothesize that HIV cooperatively promotes HBV-related liver fibrosis through (1) alterations in profibrogenic cytokine secretion and (2) changes in pyruvate status. To evaluate these hypotheses, we will use in vitro mono-culture, and transwell and spheroid co-culture models and verify these findings in liver and blood from in vivo humanized mice HIV/HBV coinfection models. These Aims are feasible, mechanistically grounded, and highly likely to yield results that will lead to clarification of HIV-HBV-host interactions. They are also likely to yield an array of new targets for the development of treatments designed to enhance HBV functional cure and preventing HIV-accelerated HBV liver disease progression.
Chemoprevention of hepatocellular carcinoma
Worldwide, hepatocellular carcinoma (HCC) represents the fifth most common cancer and the second-leading cause of cancer-related mortality. In the U.S., both the HCC incidence and mortality are increasing at an alarming pace. Despite these concerning trends, treatment options for HCC remain limited, and the prognosis is grim, with a 5-year survival rate of just 15%. Thus, identifying effective strategies to prevent the development of incident HCC represents a critical public health need. A growing body of preclinical and population-based observational data now demonstrate that lipophilic statins, and in particular atorvastatin, reduces hepatic inflammation, cellular proliferation and cancer cell invasion, and reduces the incidence of HCC, in part by acting on relevant pathways, including the Hippo-YAP signaling pathway. However, despite these promising data, well-designed randomized controlled trials (RCTs) of atorvastatin for HCC prevention have not yet been reported. Historically, the feasibility of an HCC prevention trial has been limited by large sample size and long lengths of follow-up required to assess target endpoints. Recently, however, our group has derived and validated a 186-gene expression Prognostic Liver Signature (PLS), that represents an accurate, reproducible and highly reliable surrogate biomarker for HCC risk in multiple international cohorts of all major viral and non-viral etiologies of cirrhosis. Further, we have demonstrated that therapeutic modulation of the PLS accurately recapitulates future risk of developing incident HCC tumors, both in vivo and in confirmatory human studies. Finally, we and others have demonstrated in human liver tissue samples that atorvastatin modulates the PLS in part by acting on the Hippo-YAP pathway. Thus, the PLS represents a novel and highly tractable surrogate biomarker endpoint for an RCT of atorvastatin for the reduction of incident HCC risk. In this proposal, we will conduct a phase II RCT in 60 patients with compensated cirrhosis, designed to test the efficacy, safety and tolerability of 48 weeks of atorvastatin for the reduction of HCC risk, defined by our validated PLS profile. All subjects will have a high-risk PLS defined at screening liver biopsy, and subjects will be randomly assigned to 1 of 2 study arms for the 48-week study period: atorvastatin 20mg/day or placebo, with appropriate monitoring for the 48-week period, followed by a repeat biopsy at week 48 to assess for improvement in the PLS profile. We will also confirm whether atorvastatin has adequately engaged its targets by evaluating pharmacokinetics/pharmacodynamics, pre/neoplastic markers, and alteration in the Hippo-YAP pathway. We hypothesize that PLS-based HCC risk level decreases in the atorvastatin arm at the end of 48-week treatment. If atorvastatin treatment is effective, safe and well-tolerated, it could become the first chemopreventive agent designed to prevent the development of HCC, guided by PLS, in the growing population of patients in the U.S. who are affected by cirrhosis and are at high risk for this devastating complication.
Research Team
Raymond Chung, MD
Chief, Division of Gastroenterology, Hepatology & Endoscopy, Mass General Brigham
Zhou Family Endowed Chair in Gastroenterology, Massachusetts General Hospital
Professor of Medicine, Harvard Medical School
Email: Chung.Raymond@mgh.harvard.edu
Olivia Mezzetti
Research Technician
Email: omezzetti@mgh.harvard.edu
Thien Trang Nguyen
Pre-Doctoral Fellow
Email: tnguyen162@mgh.harvard.edu
Shadi Salloum, MD-PhD
Instructor of Medicine
Email: ssalloum1@mgh.harvard.edu
Shadi Salloum is a research scientist focused on liver disease modeling and fibrosis. He develops and applies advanced in vitro systems, including organoids and co-culture models, to investigate cellular interactions and signaling pathways involved in liver injury. His work emphasizes translational approaches to better understand disease mechanisms and identify potential therapeutic targets.
Zeinab Heidariyan, PhD
Research Fellow
Email: zheidariyan@mgh.harvard.edu
Zeinab Heidariyan, PhD, is a Research Fellow at Massachusetts General Hospital and Harvard Medical School with expertise in stem cell biology, liver organoids, and regenerative medicine. Her work focuses on developing human stem cell–derived models to study liver disease and fibrosis. She applies a range of molecular and cellular approaches to investigate disease mechanisms and support the development of translational strategies for liver disorders.
Swas Tripathi
Research Technician
Email: satripathi@mgh.harvard.edu
I am a Research Technician II working under Shadi and Zeinab, focusing on liver fibrosis in HIV and MASLD. I recently completed my Master’s in Biotechnology at the University of Pennsylvania and am broadly interested in using molecular and immunology tools to understand how liver disease progresses.