Protective role of OPN-High macrophages in NASH

OPN-High 巨噬细胞在 NASH 中的保护作用

基本信息

批准号：
10752928
负责人：
Natalia Nieto
金额：
$ 53.38万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-05 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752928
关键词：
ARG2 gene Adipose tissue Adult Bioenergetics Body Fluids Cell physiology Cells Child Cholesterol Clinical Collagen Data Deposition Development Diet Embryo Equilibrium Event Extracellular Matrix Fatty Liver Fatty acid glycerol esters Fibrosis Fructose Gene Expression Profile Hepatic Hepatic Stellate Cell Hepatocyte Heterogeneity Human Human Milk Immune system Infant Infiltration Inflammatory Intervention Knock-in Knockout Mice Knowledge Kupffer Cells Laboratories Link Lipids Liver Liver Fibrosis Liver diseases Location Macrophage Messenger RNA Mitochondria Modeling Monounsaturated Fatty Acids Mus Myeloid Cells Nitric Oxide Obesity Pathogenesis Pathologic Pathway interactions Patients Phenotype Physiological Processes Plasma Preventive Production Proteins Regimen Regulator Genes Role Saturated Fatty Acids Signal Transduction Signaling Protein Testing Therapeutic Tissues Triglycerides Umbilical cord structure Up-Regulation cell behavior fatty acid oxidation feeding intercellular communication lipid metabolism lipidomics liver transplantation mRNA Expression monocyte nitrosative stress nonalcoholic steatohepatitis novel therapeutics osteopontin overexpression prevent promoter recruit single-cell RNA sequencing therapeutic evaluation transcriptome transcriptomics urea cycle

项目摘要

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.

非酒精性脂肪性炎（NASH）是儿童和成人的主要肝脏疾病的主要肝脏疾病。 1）与脂质相关的MF（LAM）相似的那些类似于稳态的kupffer细胞（KC）。单核细胞衍生的KCS VER，是否与Neithboring细胞，Top Revent Steatosis和Nash中的Firosis的串扰尚不清楚nash活性比WT小鼠分数较差。星状细胞（HSC）1是为了确定opnhigh MF如何免受脂肪性的侵害，首先，我们将确定发出hepne arg2的opnhigh MF“分泌”蛋白；要从Fiteins到下部胶原蛋白和/或修改“ Matri”一些景观，以防止Firosis和调节细胞行为，以证明这一点。降低胶原蛋白沉积和/或增加的HSC是降解的；调节NASH中的细胞行为。