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Principal Investigator: GRACE L GUO
Organization: VA NEW JERSEY HEALTH CARE SYSTEM
Fiscal Year: 2024
Funding agency: Veterans Affairs
PROJECT SUMMARY
The prevalence of cirrhosis and decompensated liver disease has doubled, whereas the prevalence of
hepatocellular carcinoma (HCC) has increased 10-fold in the veteran population. Worldwide, HCC has
emerged as a major cause of cancer-related death. There is an urgent need to further understand HCC
pathogenesis and discover new biomarkers that could accurately predict HCC development in patients with
chronic liver diseases, so that we can provide better and more effective strategies for HCC prevention and/or
treatment in veteran population. Bile acids (BAs) are well known to be cytotoxic due to their detergent-like
properties and overt BAs promote HCC development. In humans, increased levels of secondary BAs,
especially deoxycholic acid, is associated with the development of HCC in veteran patients with cirrhosis. BA
homeostasis is tightly regulated by farnexoid X receptor (FXR). FXR expression and function are reduced in
patients with HCC, and FXR knockout (KO) mice develop spontaneous HCC. FXR suppresses BA levels
mainly by fibroblast growth factor 15 (FGF15; FGF19 in humans) mediated gut liver crosstalk and by promoting
BA enterohepatic circulation. FGF15/19 emerges to be critical endocrine hormones to suppress BA synthesis,
promote liver regeneration and regulate energy homeostasis. Long-term overexpression of FGF15 in vivo
(Fgf15 transgenic-Tg mice) results in reduced growth hormone (GH) signaling in the liver and GH signaling is
involved in cell proliferation and HCC formation. In this proposal, we will determine the mechanisms by which
long-term FGF15 overexpression protects the liver from HCC development in FXR KO mice. Using a novel
mouse model we generated, Fgf15 Tg mice, and the newly generated FXR KO/Fgf15 Tg mice, we provided
preliminary data showing that FGF15 overexpression completely protected FXR KO mice from developing
spontaneous HCC. In addition, overexpression of FGF15 led to a marked reduction in BA levels and GH
signaling. Based on these compelling preliminary data, we generate a novel hypothesis: overexpression of
FGF15 prevents HCC development through two interactive mechanisms: suppression of BA levels and
reduction of GH signaling to reduce cell injury and cell proliferation. This novel hypothesis will be tested in two
independent but related specific aims. Aim 1. Determine to what extent reduction of BAs is the mechanism for
suppressing HCC development in cholestasis mouse models. Aim 2. Determine the extent of GH signal
blockage, and to what extent the reduced GH signal in the Fgf15 Tg mice prevents HCC development. This
proposal is highly innovative because we will provide a profound understanding of the molecular mechanisms
by which endocrine FGF15 collectively suppresses BA levels and GH signaling, which can markedly prevent
HCC development during cholestasis. It is also very technically innovative due to the unique and novel animal
models we have generated for in vivo studies. Furthermore, we will provide profound understanding of the
mechanisms of BA homeostasis, liver growth and HCC development. This study will be highly human relevant
because humans and rodents share similar BA pathways in liver disease development. We believe that this
study will help to provide scientific basis for prevention, early diagnosis, and treatment of human HCC
development in cirrhotic veteran patients in the future.
Terms: <Alcoholic Liver Diseases><Animal Model><Animal Models and Related Studies><Animals><Apoptosis><Apoptosis Pathway><Automobile Driving><Autoregulation><Bile Acid Biosynthesis><Bile Acid Biosynthesis Pathway><Bile Acids><Bile Duct Obstruction><Biliary Stasis><Biological Markers><Cancer Cause><Cancer Etiology><Cell Communication and Signaling><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cellular Proliferation><Cellular injury><Cessation of life><Cholalic Acids><Cholestasis><Cholic Acids><Cirrhosis><DNA Synthesis Factor><Data><Death><Deoxycholic Acid><Desoxycholic Acid><Detergents><Development><Dihydroxycholanoic Acid><Early Diagnosis><Endocrine><Endocrine Gland Secretion><Endothelial Cell Growth Factor><Entero-Hepatic Circulation><Enterohepatic Circulation><Event><FGF><FGF19><FGF19 gene><Fibroblast Growth Factor><Fibroblast Growth Factor Gene Family><Fibroblast Growth Regulatory Factor><Fibroblast growth factor 19><Future><Generalized Growth><Goals><Growth><Growth Hormone><Growth Hormone 1><Health Benefit><Hepatic Disorder><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatoma><Homeostasis><Hormones><Human><Injury to Liver><Intestinal><Intestines><Intracellular Communication and Signaling><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Liver><Liver Cells Carcinoma><Liver Regeneration><Liver diseases><Mediating><Medical><Mice><Mice Mammals><Modern Man><Molecular><Murine><Mus><NAFLD><Null Mouse><Pathogenesis><Pathology><Pathway interactions><Patients><Physiological Homeostasis><Physiology><Pituitary Growth Hormone><Prevalence><Prevention><Primary carcinoma of the liver cells><Programmed Cell Death><Property><Receptor Protein><Research><Rodent><Rodentia><Rodents Mammals><Role><Signal Transduction><Signal Transduction Systems><Signaling><Somatotropin><TG gene><Testing><Therapeutic Hormone><Time><Tissue Growth><Transgenic Mice><Transgenic Organisms><Tumor Promotion><Tumor Suppressor Proteins><Veterans><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol related liver disease><alcohol-associated liver disease><alcohol-induced hepatic dysfunction><alcohol-induced liver disease><alcohol-induced liver dysfunction><alcohol-mediated liver dysfunction><alcohol-mediated liver injury><alcohol-related liver disease><alcoholic liver injury><bile acid anabolism><bile acid biosynthetic process><bile acid formation><bile acid synthesis><bile obstruction><bile occlusion><bio-markers><biologic marker><biological signal transduction><biomarker><bowel><cell damage><cell injury><cellular damage><cholestatic diseases><cholestatic disorder><cholestatic liver disease><cholestatic liver disorder><cholestatic syndromes><chronic hepatic disease><chronic hepatic disorder><chronic liver disease><chronic liver disorder><cirrhotic><cytotoxic><damage to cells><developmental><diagnostic biomarker><diagnostic marker><driving><drug induced hepatotoxicity><drug induced liver disease><drug induced liver injury><early detection><effective therapy><effective treatment><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol liver disease><ethanol-induced hepatic dysfunction><ethanol-induced liver disease><ethanol-induced liver dysfunction><ethanol-mediated liver dysfunction><ethanol-mediated liver injury><hepatic body system><hepatic damage><hepatic disease><hepatic injury><hepatic organ system><hepatopathy><hormonal signals><hormone signals><in vivo><injury to cells><innovate><innovation><innovative><liver carcinoma><liver damage><liver disorder><liver injury><military veteran><model of animal><mouse model><murine model><non-alcohol fatty liver disease><non-alcoholic fatty liver disease><non-alcoholic liver disease><nonalcoholic fatty liver disease><novel><ontogeny><overexpress><overexpression><pathway><patient population><prevent><preventing><receptor><receptor expression><receptor function><social role><somatotropic hormone><transgenic><tumor suppressor><veteran population>