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Novel Determinants for Progression of Non-Alcoholic Fatty Liver Disease to Hepatocellular Carcinoma and Other Health Outcomes

非酒精性脂肪肝进展为肝细胞癌和其他健康结果的新决定因素

基本信息

批准号：
10295383
负责人：
Jaideep Behari
金额：
$ 63.48万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-07 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10295383
关键词：
Adult Affect Alcohols Animal Model Antigens Bile Acids Biological Factors Cessation of life Characteristics Cirrhosis Clostridium Deoxycholic Acid Development Diabetes Mellitus Enrollment Ensure Environmental Risk Factor Exposure to Family Fatty Liver Fibrosis Genes Glucose Glycols Goals Growth and Development function Health Hepatic Homeostasis Human Immune Immune Tolerance Immune response Immunologic Surveillance Immunomodulators Incidence Individual Infection Inflammation Inflammatory Interleukin-12 Interleukins Intestines Klebsiella pneumoniae Lipids Liver Liver Fibrosis Liver diseases Liver neoplasms Longitudinal cohort study Malignant Neoplasms Messenger RNA Metabolic Metabolic Diseases Metabolic dysfunction Metabolic syndrome Metabolism Mus Obesity Organ Outcome Participant Patient-Focused Outcomes Patients Physiological Portal vein structure Prevalence Prevention strategy Primary carcinoma of the liver cells Property Prospective cohort Public Health Research Risk Risk Factors Role Serum Signaling Molecule T cell response T-Lymphocyte The Cancer Genome Atlas Tissues Toxic Environmental Substances Triglycerides United States cancer type cytokine effective therapy elastography experimental study follow-up genotoxicity gut bacteria gut dysbiosis gut microbiota high risk high risk population interleukin-23 liver injury liver transplantation member microbial non-alcoholic fatty liver non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel overexpression prospective receptor response treatment strategy tumor tumor-immune system interactions

项目摘要

ABSTRACT The incidence rate of hepatocellular carcinoma in the United States has been increasing in the past several decades. Non-alcoholic fatty liver disease has become the most important risk factor for hepatocellular carcinoma. About 25 percent of adults in the United Stated have non-alcoholic fatty liver disease, which includes a spectrum of liver diseases from simple steatosis, non-alcoholic steatohepatitis to fibrosis and cirrhosis. Liver fibrosis has been recognized as the key determinant of the risk of long-term health outcome for patients with non-alcoholic fatty liver disease, which will soon be the most common indication for liver transplantation in the United States. Currently there is no effective treatment or prevention strategy for non-alcoholic fatty liver disease. It is an urgently unmet need to identify novel biological and environmental factors that drive the progression of non-alcoholic fatty liver disease to the development of hepatocellular carcinoma and end-stage liver disease that increasingly require liver transplantation, a significant public health burden in the United States. The liver is an organ that is constantly exposed to a wide range of immunomodulators, environmental toxins, and gut microbial metabolites through the portal vein. To ensure upkeep of immune tolerance to self and foreign antigens, the liver has a unique immunotolerance mechanism. Heightened immunotolerance or immune permissive microenvironment may create a setting with compromised immunosurveillance that promotes the tumor development and growth in the liver. The gut microbiota can produce large quantities of metabolites such as secondary bile acids that have genotoxic and tumor-promoting effect. The gut dysbiosis due to obesity and other metabolic diseases, which are underlying conditions for non-alcoholic fatty liver, alters the metabolism, synthesis, and transport of bile acids, resulting in the change of bile acid pool size and characteristics. The altered bile acids profile can elicit inflammation and cause liver injury, leading to fibrosis and cirrhosis, and eventually hepatocellular carcinoma. We propose prospectively enroll at least 1000 patients with non-alcoholic fatty liver disease with advanced fibrosis assessed by transient elastography at baseline and once every 6 months. All study participants will be longitudinally followed up for the occurrence of hepatocellular carcinoma and end-stage liver disease for up to five years. The specific aims are to determine if immunosuppressive cytokines, altered bile acid profiles, and the gut dysbiosis have significant impact on the risk of developing hepatocellular carcinoma and end-stage liver disease. The findings, if prove our hypotheses, will provide much needed scientific evidence for the development of effective strategy for management and surveillance for patients with non-alcoholic fatty liver disease with a goal to lower its progression to hepatocellular carcinoma and other end-stage liver disease.

摘要