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Principal Investigator: Pranoti Mandrekar
Organization: UNIV OF MASSACHUSETTS MED SCH WORCESTER
Fiscal Year: 2022
Award: $557,787
Funding agency: National Institute on Alcohol Abuse and Alcoholism
ABSTRACT
Liver immune cell activation is central to alcohol associated liver disease (ALD) and is poorly understood.
The protein homeostasis network/pathways are crucial in safeguarding the cellular proteome from cellular stress.
Amongst these, proteostasis mediator HSP90 is widely studied and extensively explored as a therapeutic target
in cancer. We reported two isoforms of HSP90, HSP90AA1 (stress inducible cytoplasmic HSP90) and
HSP90B1/GP96 (Endoplasmic reticulum paralog of HSP90) are important in ALD. These studies point to a
pathophysiological role for HSP90 in ALD. Studies during the last funding period of this project established that
liver targeting of HSP90 inhibitor 17-DMAG using nanoparticles in ALD can prevent and reverse liver injury,
GP96/HSP90B1 deficiency in macrophages facilitates resolution of liver inflammation and ALD, M-TLR4 deficient
mice are not protected from ALD, inhibition of HSP90 reduced NLRP3 inflammasome activity decreasing IL-1β
protein and HSF1 partially contributes to reduced pro-inflammatory signaling, whereas deficiency of HSF1 did
not protect from ALD, suggesting that HSF1 does not contribute to resolution of ALD. In the next project period
we will investigate mechanisms mediated by HSP90AA1 and HSP90B1/GP96 in alcohol induced liver
macrophage activation resulting in ALD. We propose that HSP90 induces inflammation by alternate mechanisms
(independent of HSP90/TLR4 axis), for instance macrophage aerobic glycolysis via epigenetic mechanisms or
HIF1α. In our preliminary data, we found that HSP90AA1 is detected in the nucleus in ALD and its inhibition can
modulate expression of chromatin-modifying enzymes. Pilot data also reveal that inhibition of HSP90AA1
reduces alcohol mediated induction of glucose transporter (SLC2a1/GLUT1) and hexokinase II, two important
mediators of glycolysis, suggesting a role for HSP90 in metabolic programming of M1 macrophages in ALD. On
the other hand, HSP90B1/GP96 induced preferably in liver macrophages promotes inflammation via glycolysis
and its inhibition induces GRP78+ATF3+Trem2+ restorative/reparative macrophages resolving ALD. We
hypothesize that alcohol induced HSP90AA1 facilitates macrophage aerobic glycolysis via epigenetic
mechanisms whereas HSP90B1/GP96 and ER stress facilitate macrophage glycolysis via HIF1α in ALD.
Inhibition of HSP90 in ALD induces ATF3+Trem2+ reparative macrophages using OXPHOS facilitating
protection. The specific Aims of this proposal are - 1) To identify HSP90AA1 mediated epigenetic and metabolic
programming of macrophages in murine ALD in vivo and human AH PBMCs in vitro. 2) To characterize the
significance of macrophage-specific HSP90B1/GP96 in macrophage metabolism and assess significance of
ATF3 and TREM2 in macrophages conferring protection from liver injury. Collectively, during the next project
period our studies will identify novel metabolic and epigenetic mechanisms regulated by HSP90 and characterize
reparative macrophages crucial in resolution of ALD. Studying these pathways in mouse ALD model and human
AH patient monocytes will provide basis for future clinical development of HSP90 in ALD.
Terms: <ATF-3><ATF3><Absolute ethanol><Acetylation><Affect><Alcohol Chemical Class><Alcohol Drinking><Alcohol abuse><Alcohol consumption><Alcoholic Hepatitis><Alcoholic Liver Diseases><Alcohols><Beta Proprotein Interleukin 1><BiP gene><BiP protein><Bioenergetics><Blood monocyte><Cancers><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cellular Stress><Chaperone><Chromatin><Chronic><Cirrhosis><Data><Disease model><EC 2.7.1.1><ER stress><ETOH><Economic Burden><Endoplasmic Reticulum><Endothelial Cells><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Ergastoplasm><Erythrocyte/Hepatoma Glucose Transporter><EtOH abuse><EtOH drinking><EtOH use><Ethanol><Ethanol-induced hepatitis><Ethyl Alcohol><Fatty Liver><Funding><Future><GLUT><GLUT1><GRP78><GRP78 gene><Gene Expression><Genes><Glucose Binding Protein><Glucose Transport Protein><Glucose Transporter><Glucose Transporter 1><Glucose-Regulated Protein, 78-kD><Glycolysis><Grain Alcohol><HIF 1 alpha><HIF-1alpha><HIF1-Alpha><HIF1A><HIF1A gene><HIF1α><HK II><HK2 Protein><HSF1><HSP 90 inhibition><HSP-90><HSP90><HSP90 inhibition><HSPA5><Health><Heat-Shock 70-kD Protein 5><Heat-Shock Proteins 90><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatocyte><Hepatoma><Hexokinase 2><Hexokinase II><Homolog of Drosophila TOLL><Human><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><Immune Cell Activation><In Vitro><Inflammasome><Inflammation><Inflammatory><Inflammatory Response><Injury to Liver><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Intermediary Metabolism><Intracellular Communication and Signaling><Investigation><Isoforms><Kupffer Cells><Liver><Liver Cells><Liver Cells Carcinoma><Liver Steatosis><Liver diseases><MOP1><Macrophage Activation><Malignant Neoplasms><Malignant Tumor><Marrow monocyte><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Messenger RNA><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Methylcarbinol><Mice><Mice Mammals><Modern Man><Molecular Chaperones><Murine><Mus><Muscle Form Hexokinase><Muscle Hexokinase-2><Myelogenous><Myeloid><Mφ><Nucleus><PBMC><Pathogenicity><Pathway interactions><Patients><Peripheral Blood Mononuclear Cell><Preinterleukin 1 Beta><Primary carcinoma of the liver cells><Protein Isoforms><Proteins><Proteome><Receptor Signaling><Reporting><Resolution><Role><SLC2A1><SLC2A1 gene><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Solute Carrier Family 2, Facilitated Glucose Transporter, Member 1><Steatohepatitis><Stellate Sinusoidal Macrophage><Stress><TLR4><TLR4 gene><TREM2><TREM2 gene><Toll Homologue><Triggering Receptor Expressed on Myeloid Cells 2><Type II Hexokinase><activating transcription factor 3><aerobic glycolysis><alcohol co-abuse><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol ingestion><alcohol intake><alcohol problem><alcohol product use><alcohol use><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 beverage consumption><alcoholic drink intake><alcoholic liver injury><biological signal transduction><cell stress><cirrhotic><clinical development><disorder model><endoplasmic reticulum stress><ethanol abuse><ethanol consumption><ethanol drinking><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol ingestion><ethanol intake><ethanol product use><ethanol use><ethanol-induced hepatic dysfunction><ethanol-induced liver disease><ethanol-induced liver dysfunction><ethanol-mediated liver dysfunction><ethanol-mediated liver injury><extracellular vesicles><fat metabolism><hazardous alcohol use><heat shock protein 90 inhibition><hepatic body system><hepatic damage><hepatic disease><hepatic inflammation><hepatic injury><hepatic organ system><hepatic steatosis><hepatopathy><hepatosteatosis><hsp90 Family><immune activation><immunoglobulin heavy chain-binding protein><in vivo><inflamed liver><inhibitor><injury to tissue><lipid metabolism><liver carcinoma><liver damage><liver disorder><liver inflammation><liver injury><liver macrophage><mRNA><macrophage><malignancy><monocyte><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><paralog><paralogous gene><pathway><prevent><preventing><problem alcohol use><problem drinking><problematic alcohol consumption><problematic alcohol use><protein homeostasis><proteostasis><social role><therapeutic target><tissue injury><toll-like receptor 4>