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Principal Investigator: Devanand Sarkar
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
Fiscal Year: 2022
Award: $623,536
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Summary
Nonalcoholic steatohepatitis (NASH), the most common cause of chronic liver disease in the Western world
and a major global health problem, leads to cirrhosis and hepatocellular carcinoma (HCC). The lack of an
optimum therapy mandates better understanding of the molecular pathogenesis of NASH, identification of
regulatory molecules and development of targeted therapeutic approaches. Studies, supported by previous
cycle of this renewal application, unraveled a novel role of the oncogene Astrocyte elevated gene-1/Metadherin
(AEG-1/MTDH) in promoting NASH. AEG-1 induces steatosis by inhibiting PPARα, hence fatty acid β-oxidation
(FAO), and promoting translation of fatty acid synthesizing enzymes thus augmenting de novo lipogenesis
(DNL). Additionally, AEG-1 activates NF-κB, a master regulator of inflammation. Thus AEG-1 plays a key role
in NASH and NASH-HCC. We established the therapeutic efficacy of a hepatocyte-targeted nanoparticle
delivering AEG-1 siRNA to inhibit HFD-induced NASH in mice. Macrophages play a pivotal role in the
pathogenesis of NASH by regulating the functions of adipocytes and hepatocytes. We recently documented
that AEG-1 plays a vital role in regulating macrophage activation and mice with deletion of AEG-1 in myeloid
cells (AEG-1∆MAC) are profoundly resistant to N-nitrosodiethylamine (DEN)-induced inflammatory HCC. Our
preliminary studies now document that AEG-1∆MAC mice are also resistant to HFD-induced NASH, and identify
that a novel post-translational modification, cysteine palmitoylation, is required for protein translation and NF-
κB activation functions of AEG-1. These observations allow us to hypothesize that macrophage AEG-1
promotes NASH by regulating adipocytes and hepatocytes, cysteine palmitoylation regulates AEG-1 functions
which contribute to NASH development, and targeted inhibition of AEG-1 in macrophages and hepatocytes
might be an effective therapeutic intervention for NASH. Experiments using relevant mouse models and human
cells will be performed to address these hypotheses. Our proposed studies will unravel a novel role of AEG-1
in macrophages and a novel post-translational modification regulating AEG-1 function. Multiple clinical trials
document efficacy of inhibiting expression of genes in the liver by RNA interference (RNAi) strategy in a variety
of diseases thereby establishing potential application of this strategy to manage NASH in the clinics. Our
proposed studies thus have important mechanistic and translational significance.
Terms: <(TNF)-α><Address><Adipocytes><Adipose Cell><Adipose tissue><Assay><Astrocytes><Astrocytus><Astroglia><Beta Proprotein Interleukin 1><Bioassay><Biochemical><Biologic Assays><Biological Assay><Biology><CR3><CR3 Receptor><Cachectin><Cancer Genes><Cancer-Promoting Gene><Cell Body><Cells><Cirrhosis><Clinic><Clinical Trials><Complement 3 Receptor><Cysteine><DENA><Development><Diet><Diethylnitrosamine><Disease><Disorder><Enzyme Gene><Enzymes><Event><Failure><Fat Cells><Fats><Fatty Acids><Fatty Tissue><Fatty acid glycerol esters><Free Fatty Acids><Gene Expression><Genes><Half-Cystine><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatocyte><Hepatoma><High Fat Diet><Human><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><Impairment><Inflammation><Inflammatory><Integrin alpha-M beta-2><Integrin alphaMbeta2><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Intervention><Intervention Strategies><KI mice><KO mice><Knock-in Mouse><Knock-out Mice><Knockout Mice><L-Cysteine><L-Serine><Lipocytes><Lipolysis><Liver><Liver Cells><Liver Cells Carcinoma><Mac 1><Mac-1 Adhesive Receptor><Mac-1 Antigen><Mac-1 Receptor><Macrophage Activation><Macrophage-1 Antigen><Macrophage-Derived TNF><Mature Lipocyte><Mature fat cell><Mice><Mice Mammals><Mo1 Antigen Receptor><Mo1 Glycoprotein Receptor><Modern Man><Molecular><Monitor><Monocyte-Derived TNF><Murine><Mus><Mutate><Myeloid Cells><Mφ><N,N-diethylnitrosamine><N-Nitrosodiethylamine><N-diethylnitrosamine><N-ethyl-N-nitroso-ethanamine><NASH><NDEA><Nitrosodiethylamine><Nonesterified Fatty Acids><Null Mouse><Oncogenes><PPAR alpha><PPAR-α><PPARalpha><PPARα><Pathogenesis><Peroxisome Proliferator-Activated Receptor alpha><Peroxisome Proliferator-Activated Receptor α><Play><Post-Transcriptional Gene Silencing><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranscriptional Gene Silencing><Posttranslational Modifications><Posttranslational Protein Processing><Preinterleukin 1 Beta><Preventive><Primary carcinoma of the liver cells><Process><Protein Modification><Proteins><Publishing><Quelling><RNA Interference><RNA Silencing><RNAi><Resistance><Role><Seminal><Sequence-Specific Posttranscriptional Gene Silencing><Serine><Short interfering RNA><Small Interfering RNA><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Therapeutic><Therapeutic Intervention><Transforming Genes><Transgenic Mice><Translations><Treatment Efficacy><Triacylglycerol><Triglycerides><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Western World><adipogenesis><adipose><astrocytic glia><chronic hepatic disease><chronic hepatic disorder><chronic liver disease><chronic liver disorder><cirrhotic><cytokine><developmental><diets><experiment><experimental research><experimental study><global health><hepatic body system><hepatic organ system><insight><intervention efficacy><intervention therapy><interventional strategy><knock-down><knockdown><knockin mice><lipid biosynthesis><lipogenesis><liver carcinoma><loss of function><macrophage><mouse model><murine model><nano particle><nano particle delivery><nano-sized particle><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><non-alcohol induced steatohepatitis><non-alcoholic steato-hepatitis><non-alcoholic steatohepatitis><nonalcoholic steato-hepatitis><nonalcoholic steatohepatitis><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><optimal therapies><optimal treatments><oxidation><palmitoylation><resistant><scRNA-seq><siRNA><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><sugar><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapeutically effective><therapy efficacy><tumorigenic><white adipose tissue><yellow adipose tissue><αMβ2>