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Principal Investigator: Natalia Nieto
Organization: UNIVERSITY OF ILLINOIS AT CHICAGO
Fiscal Year: 2024
Award: $495,418
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Non-alcoholic steatohepatitis (NASH) is emerging as a major worldwide cause of liver disease in children and adults. Recent studies demonstrate substantial heterogeneity in the phenotype of macrophages (MFs) infiltrating the liver during NASH. Recruited MFs exist as two subsets, with distinct activation states: (1) those closely resembling homeostatic Kupffer cells (KCs), or (2) lipid-associated MFs (LAMs). In 2020, a cluster of LAMs with high expression of osteopontin (OPN) was identified in livers with NASH. Notably, LAMs are differentially activated, compared to resident- and monocyte-derived KCs, and with a distinct ability to metabolize lipids. However, whether they also crosstalk with neighboring cells, to prevent steatosis and fibrosis in NASH, remains unknown. While recruitment of MFs into the liver, and subsequent activation, are considered proinflammatory and profibrotic events, currently a significant knowledge gap is a lack of understanding of whether OPNHigh MFs, are detrimental or protective in NASH. Preliminary data demonstrates that Spp1KI Mye are protected, whereas Spp1ΔMye have worse NASH activity scores than WT mice. Thus, our results suggest a paradigm shift, in that OPNHigh MFs may protect from NASH. Yet, the intercellular communication, and preventive and therapeutic potential of OPNHigh MFs, remain to be determined. Our overarching hypothesis is that OPNHigh MFs, by signaling to hepatocytes (HEPs) and hepatic stellate cells (HSCs), reduce liver steatosis and fibrosis, and protect from NASH. Aim 1 is to identify how OPNHigh MFs protect from steatosis. We hypothesize that OPNHigh MFs signal HEPs to upregulate arginase-2 (ARG2), which increases mitochondrial bioenergetics and fatty acid oxidation (FAO), reduces nitrosative stress, and protects from steatosis. To test this, first, we will identify the OPNHigh MF ‘secretome’ proteins that signal HEPs to upregulate ARG2; second, we will determine how the identified OPNHigh MF secretome proteins transactivate the ARG2 promoter, in HEPs; and third, we will elucidate how ARG2 increases mitochondrial bioenergetics and FAO, and reduces nitrosative stress, in HEPs. Aim 2 is to dissect how OPNHigh MFs protect from fibrosis. We hypothesize that OPNHigh MFs signal through secretome proteins to lower collagen-I, and/or modify the ‘matrisome’ landscape, to prevent fibrosis, and regulate cell behavior, in NASH. To prove this, first, we will identify the OPNHigh MF secretome proteins that signal HSCs to lower collagen-I deposition and/or increase its degradation; second, we will analyze whether OPNHigh MFs modify the matrisome landscape, and establish the OPNHigh MF-ECM correlation network; and third, we will perform liver scRNA-seq, and computationally identify how the OPNHigh MF-ECM network regulates cell behavior in NASH.
Terms: <0-11 years old><21+ years old><2aR phosphoprotein I><2ar peptide><ARG2><ARG2 gene><Adipose tissue><Adult><Adult Human><Bioenergetics><Blood Plasma><Blood monocyte><Body Fluids><Body Tissues><Breast Milk><Breastmilk><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cell to Cell Communication and Signaling><Cell-Cell Signaling><Cell-Extracellular Matrix><Cells><Cellular Function><Cellular Physiology><Cellular Process><Child><Child Youth><Children (0-21)><Cholesterol><Clinical><Collagen><Data><Deposit><Deposition><Development><Diet><ECM><Embryo><Embryonic><Endogenous Nitrate Vasodilator><Endothelium-Derived Nitric Oxide><Equilibrium><Eta-1 protein><Eta-1-Op protein><Event><Expression Signature><Extracellular Matrix><Fats><Fatty Liver><Fatty Tissue><Fatty acid glycerol esters><Fibrosis><Fructose><Gene Expression Profile><Hepatic><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatic Stellate Cell><Hepatic Transplantation><Hepatocyte><Heterogeneity><Human><Human Milk><Human Mother's Milk><Immune system><Infant><Infiltration><Inflammatory><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Ito Cell><KO mice><Knock-in><Knock-out Mice><Knockout Mice><Knowledge><Kupffer Cells><Laboratories><Levulose><Link><Lipids><Liver><Liver Cells><Liver Fibrosis><Liver Grafting><Liver Steatosis><Liver Transplant><Liver diseases><Location><Macrophage><Mammary Gland Milk><Marrow monocyte><Messenger RNA><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Mononitrogen Monoxide><Monounsaturated Fatty Acids><Mother's Milk><Murine><Mus><Myeloid Cells><Mφ><NASH><Nitric Oxide><Nitrogen Monoxide><Nitrogen Protoxide><Null Mouse><Obesity><Organism-Level Process><Organismal Process><Pathogenesis><Pathologic><Pathway interactions><Patients><Phenotype><Physiologic Processes><Physiological Processes><Plasma><Plasma Serum><Preventive><Production><Proteins><Regimen><Regulator Genes><Reticuloendothelial System, Serum, Plasma><Role><Saturated Fatty Acids><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Stellate Sinusoidal Macrophage><Subcellular Process><Testing><Therapeutic><Tissues><Transcriptional Regulatory Elements><Triacylglycerol><Triglycerides><Umbilical Cord><Umbilical cord structure><Up-Regulation><Upregulation><adipose><adiposity><adulthood><arginase 2><arginase II><balance><balance function><biological signal transduction><bone sialoprotein 1><bone sialoprotein I><cell behavior><cellular behavior><corpulence><developmental><diets><early T-lympocyte activation-1 protein><endothelial cell derived relaxing factor><fat metabolism><fatty acid oxidation><feeding><fibrotic liver><gene expression pattern><gene expression signature><global gene expression><global transcription profile><hepatic body system><hepatic disease><hepatic fibrosis><hepatic organ system><hepatic steatosis><hepatopathy><hepatosteatosis><intercellular communication><interventional strategy><kids><knockin><lipid metabolism><lipidomics><liver disorder><liver macrophage><liver transplantation><mRNA><mRNA Expression><maternal milk><mitochondrial><monocyte><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><nitrosative stress><non-alcohol induced steatohepatitis><non-alcoholic steato-hepatitis><non-alcoholic steatohepatitis><nonalcoholic steato-hepatitis><nonalcoholic steatohepatitis><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><osteopontin><overexpress><overexpression><pathway><prevent><preventing><promoter><promotor><recruit><regulatory gene><scRNA-seq><secreted phosphoprotein 1><sialoprotein 1><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><therapeutic evaluation><therapeutic testing><trans acting element><transcriptional profile><transcriptional signature><transcriptome><transcriptomics><urea cycle><white adipose tissue><yellow adipose tissue><youngster>