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Unlocking the therapeutic potential of RARRES-1: innovative treatment strategy for liver fibrosis through bioenergetics regulation

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dc.contributor.authorIrshad, Iram
dc.date.accessioned2025-12-08T08:38:19Z
dc.date.available2025-12-08T08:38:19Z
dc.date.issued2024en
dc.identifier.urihttps://hdl.handle.net/2123/34585
dc.description.abstractBackground & aims: Liver fibrosis is ultimate outcome of all untreated liver-related diseases that can progress to cirrhosis, cancer and liver failure. Our epigenome-wide-association study suggested increased methylation at the RARRES-1 locus in metabolic dysfunction associated fatty liver disease (MAFLD) patients with advanced fibrosis. Hypermethylation of RARRES-1 causes transcriptional silencing in various cancers. The functional status of RARRES-1 in liver fibrosis is unknown. Methods: The changes of RARRES-1 expression in liver fibrosis were investigated. Expression of RARRES-1 was restored by genome editing and pharmacological activation. The impact of RARRES1 on hepatic stellate cells activation and fibrosis was investigated at mRNA and protein levels using RTqPCR and immunofluorescence for the expression of fibrotic markers. Structural changes in mitochondria and autophagosomes with RARRES-1 activation were visualized using electron microscopy. Results: The mRNA expression of RARRES-1 by RTqPCR was found to be downregulated in human in-vitro culture model (p <0.01), multiple mouse fibrotic models (p <0.05, for all) and in two cohorts of patients with hepatitis C virus (HCV) (p <0.01) and MAFLD (p <0.0001). Genetic and pharmacological activation of RARRES-1 significantly reduced the mRNA expression of fibrotic markers, namely alpha SMA, COL1A1, CTGF & TGF-β (p <0.05, for all). Mechanistically I found that RARRES-1 reduces energy release during myofibroblast activation via regulating autophagy initiation, mitochondrial function and preserving lipid droplets. Discussion & conclusion: The data presented in this thesis indicates that the silencing of RARRES-1 is involved in liver fibrosis. Activation of RARRES-1 has the potential to reverse liver fibrosis by regulating ROS generation, autophagy, and lipid preservation. In conclusion, my findings highlight that regulating RARRES-1 may offer therapeutic benefits for treating liver fibrosis.en
dc.language.isoenen
dc.subjectMAFLD Metabolic dysfunction associated fatty liver diseaseen
dc.subjectECM Extracellular matrixen
dc.subjectASIR Age-standardized death rateen
dc.subjectCLD Chronic liver diseaseen
dc.subjectGGT Gamma-glutamyl transferaseen
dc.subjectAST Aspartate aminotransferaseen
dc.subjectALT Aspartate aminotransferaseen
dc.subjectMMP Matrix metalloproteinaseen
dc.subjectIGF Insulin-like growth factoren
dc.subjectTIMP Tissue inhibitor of metalloproteinaseen
dc.subjectα2M α-2-macroglobulinen
dc.subjectHA Hyaluronic aciden
dc.subjectPIIINP Pro-collagen III N-terminal pro-peptideen
dc.subjectHSCs Hepatic stellate cellsen
dc.subjectEMT Epithelial-to-mesenchymal transitionen
dc.subjectLSECs Liver sinusoidal endothelial cellsen
dc.subjecteNOS Endothelial-NO-synthaseen
dc.subjectNO Nitric oxideen
dc.subjectTNF-α Tumor necrotic factor αen
dc.subjectPDGF Platelet growth factoren
dc.subjectSHH Sonic hedgehogen
dc.subjectIGFs Insulin like growth factorsen
dc.subjectIL-6 Interleukin-6en
dc.subjectTGF-β Tumor growth factor betaen
dc.subjectMAPK Mitogen-activated protein kinaseen
dc.subjectJNK c-jun-N terminal kinaseen
dc.subjectTCA Tri-carboxylic aciden
dc.subjectETC Electron transport chainen
dc.subjectPal-1 Pro-fibrogenic mediatorsen
dc.subjectmPTP Permeability transition poreen
dc.subjectCCL4 Carbon tetrachlorideen
dc.subjectEWAS Epigenome wide association studyen
dc.subjectROS Reactive oxygen speciesen
dc.subjectDMEM Dulbecco’s Modified Eagle Mediumen
dc.subjectμl Microliteren
dc.subjectPVDF Polyvinylidene difluorideen
dc.subjectCCCP Carbonyl cyanide3-chlorophenyl hydrazoneen
dc.subjectGAPDH Glyceraldehyde-3-phosphate dehydrogenaseen
dc.subjectRTqPCR Polymerase chain reactionen
dc.subjectHHSTEC Human hepatic stellate cellsen
dc.subjectHH Human hepatocytesen
dc.subjectBDL Bile duct ligationen
dc.subjectMCD Methionine and choline deficienten
dc.subjectα-SMA Alpha-smooth muscle actinen
dc.subjectCOL1A1 Alpha-1-type I Collagenen
dc.subjectCTGF Connective tissue growth factoren
dc.subjectmPTP Mitochondrial-permeability–transition-poreen
dc.subjectTEM Transmission electron microscopeen
dc.subjectTOM20 Outer mitochondrial membrane 20en
dc.subjectMFN1 Mitofusin protein 1en
dc.subjectTMRE Tetramethylrhodamineen
dc.subjectethyl esteren
dc.subjectDCFDA 2’7’-dichlorofluorescin diacetateen
dc.subjectmROS Mitochondrial ROSen
dc.subjectELISA Enzyme linked immunosorbent Assayen
dc.subjectGFP Green fluorescent proteinen
dc.subjectRFP Red fluorescent proteinen
dc.subjectRARRES-1 Retinoic acid receptor responder 1en
dc.subjectNADPH Nicotinamide adenine dinucleotide phosphateen
dc.subjectmRNA Messenger RNAen
dc.titleUnlocking the therapeutic potential of RARRES-1: innovative treatment strategy for liver fibrosis through bioenergetics regulationen
dc.typeThesis
dc.type.thesisDoctor of Philosophyen
dc.rights.otherThe author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.en
usyd.facultySeS faculties schools::Faculty of Medicine and Health::Westmead Clinical Schoolen
usyd.degreeDoctor of Philosophy Ph.D.en
usyd.awardinginstThe University of Sydneyen
usyd.advisorEslam, Professor Mohammed


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