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Principal Investigator: Chelsea Thorsheim
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $51,974
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging public health risk. Approximately 35% of
Americans have NAFLD, and if left untreated, NAFLD can progress to non-alcoholic steatohepatitis (NASH),
cirrhosis, and hepatocellular carcinoma. Although obesity and Type II diabetes have emerged as risk factors,
disease pathogenesis is poorly understood. Accordingly, there are no FDA-approved pharmacotherapies
currently available for patients with NAFLD/NASH. An ideal therapeutic would target multiple hepatic lipid
homeostatic processes, including de novo lipogenesis (DNL), fatty acid oxidation (FAO), and very-low-density
lipoprotein (VLDL)-triglyceride (TG) secretion, as attempts to modulate a single lipid homeostatic process have
often led to undesirable compensation from the remaining pathways. Our lab has identified the protein folliculin
(FLCN) as a potential therapeutic target. Mice with hepatic deletion of FLCN are robustly protected against
steatosis when challenged with NAFLD-inducing diets via an FLCN-mTORC1-TFE3 signaling axis. TFE3
suppresses DNL and induces genes involved in FAO to decrease hepatic TG content in FLCN-null livers. Given
that VLDL-TG secretion is heavily regulated by TG availability, we expected to see a compensatory decrease in
VLDL-TG secretion rate in FLCN-null mice. Strikingly, however, we saw marked upregulation of VLDL-TG
secretion in FLCN deficient mice, which makes FLCN even more appealing as a therapeutic target. I hypothesize
that upregulated VLDL-TG secretion is critical to the robust protection against steatosis afforded by liver deletion
of FLCN, and that activated TFE3 is necessary and sufficient for VLDL-TG secretion. To test this, I will generate
FLCN knockout (KO), TFE3 KO, and FLCN/TFE3 double knockout (DKO) mice and assess VLDL-TG secretion
rates. I will overexpress constitutively active TFE3 in wild-type mice to test if TFE3 is sufficient for VLDL-TG
secretion. My preliminary data further lead me to hypothesize that the upregulated VLDL-TG secretion in FLCN-
null livers is mediated by TFE3-dependent transcriptional activation of CTP:phosphocholine cytidylyltransferase
alpha (CCTa). CCTa is the rate-limiting enzyme in the synthesis of phosphatidylcholine, a critical necessary
component for VLDL-TG secretion. My preliminary data show increased CCTa mRNA and protein levels in FLCN
knockout mice. I will generate FLCN KO, CCTa KO, FLCN/CCTa DKO mice. I will assess their susceptibility to
NAFLD/NASH and perform VLDL-TG secretion assays. Completion of this work would provide insight into the
regulation of hepatic lipid homeostatic processes affected in NAFLD/NASH, as well as demonstrate FLCN to be
a promising therapeutic target for treatment.
Terms: <Adult-Onset Diabetes Mellitus><Affect><American><Assay><Basal Transcription Factor><Basal transcription factor genes><Bioassay><Biological Assay><Blood Circulation><Bloodstream><Body Tissues><Cell Communication and Signaling><Cell Signaling><Choline Chloride Dihydrogen Phosphate><Choline Glycerophospholipids><Choline Phosphate><Choline Phosphate Chloride><Choline Phosphoglycerides><Cirrhosis><Compensation><Data><Development><Diet><Disease><Disorder><Drug Therapy><Enzyme Gene><Enzymes><FDA approved><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Fats><Fatty acid glycerol esters><Feedback><Fibrosis><Folliculin><Gene Transcription><Gene variant><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Hepatic><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatoma><Histology><Human><Human Genetics><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Infection><Inflammation><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigation><KO mice><Ketosis-Resistant Diabetes Mellitus><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Lead><Lecithin><Left><Lipids><Liver><Liver Cells Carcinoma><Maturity-Onset Diabetes Mellitus><Measures><Mechanistic Target of Rapamycin><Mediating><Messenger RNA><Metabolic><Mice><Mice Mammals><Modern Man><Murine><Mus><NAFLD><NASH><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nuclear><Null Mouse><Obesity><Organ><Pathogenesis><Pathway interactions><Patients><Pb element><Peripheral><Persons><Pharmacotherapy><Phosphatidylcholines><Phosphocholine><Phosphorylcholine><Phosphorylcholine Chloride><Prebeta-Lipoproteins><Predisposition><Primary carcinoma of the liver cells><Process><Proteins><Public Health><RAFT1><RNA Expression><Regulation><Research><Risk><Risk Factors><Role><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Steatohepatitis><Susceptibility><T2 DM><T2D><T2DM><Testing><Therapeutic><Tissues><Transcription><Transcription Activation><Transcription Factor Proto-Oncogene><Transcription factor genes><Transcriptional Activation><Triacylglycerol><Triglycerides><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Up-Regulation><Upregulation><VLDL><VLDL Lipoproteins><VLDL triacylglycerol><VLDL triglyceride><VLDL triglyceride lipoprotein><Very low density lipoprotein><Wild Type Mouse><Work><adipogenesis><adiposity><adult onset diabetes><allele variant><allelic variant><biological signal transduction><career><cirrhotic><corpulence><defined contribution><detection of nutrient><developmental><diets><drug treatment><fatty acid oxidation><feeding><genetic variant><genomic variant><heavy metal Pb><heavy metal lead><hepatic body system><hepatic metabolism><hepatic organ system><human disease><improved><insight><interventional strategy><ketosis resistant diabetes><lipid biosynthesis><lipogenesis><liver carcinoma><liver metabolism><mRNA><mTOR><mammalian target of rapamycin><maturity onset diabetes><mouse model><murine model><non-alcohol fatty liver><non-alcohol fatty liver disease><non-alcohol induced steatohepatitis><non-alcoholic fatty liver><non-alcoholic fatty liver disease><non-alcoholic liver disease><non-alcoholic steato-hepatitis><non-alcoholic steatohepatitis><nonalcohol fatty liver><nonalcoholic fatty liver><nonalcoholic fatty liver disease><nonalcoholic steato-hepatitis><nonalcoholic steatohepatitis><nutrient sensing><overexpress><overexpression><particle><pathway><perception of nutrients><prevent><preventing><social role><therapeutic target><transcription factor><type 2 DM><type II DM><type two diabetes><uptake><very low density lipoprotein triglyceride><wildtype mouse>