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Revealing the contribution of liver macrophage populations to NASH in insulin resistance

Project description

Role of liver macrophages in the development of non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is the most common chronic liver disease worldwide with debilitating consequences for patients and a lack of approved therapies. Obesity-associated insulin resistance represents a high-risk factor for the development of NASH. The current explanation for NASH development involves lipid accumulation in the liver of obese patients leading to oxidative stress and increased production of inflammatory cytokines by liver macrophages (LMs). The working hypothesis of the EU-funded MacinNASH project is that LMs predispose insulin-resistant patients to NASH independently of their inflammatory status. The multidisciplinary project will use multiple single-cell and in situ omics technologies tailored to identify genes and pathways involved in the development of NASH in obese insulin-resistant patients.

Objective

Non-alcoholic steatohepatitis (NASH), the most common chronic liver disease worldwide, is an unmet medical need with no approved therapies and debilitating consequences for patients. Obesity-associated insulin resistance is a high-risk factor for the development of NASH. The prevailing paradigm is a multiple hit process, whereby lipid accumulation in the liver of obese patients leads to oxidative stress and increased production of inflammatory cytokines by macrophages. However, my research group's comprehensive investigations in mice and humans have revealed that liver macrophages (LMs) contribute to insulin resistance and oxidative stress independently of their inflammatory status. I thereby propose that LMs predispose insulin resistant patients to NASH independently of their inflammatory status.  In this ambitious multidisciplinary project, we will use a novel platform encompassing multiple single cell and in situ omics technologies tailored by my research group to characterize the phenotype of LM populations in healthy individuals and insulin resistant patients with or without NASH. We will strengthen this approach with functional validation in animal models as well as human liver organoids using a patented technology that I have developed to specifically manipulate gene expression in macrophages. We will then decipher how hepatic insulin resistance creates a spatiotemporal environment facilitating NASH. My group's unique access to patient material combined with cutting-edge methodologies to reveal the phenotype of single LMs provides an exceptional starting point from which to identify genes and pathways involved in the development of NASH in obese insulin resistant patients. This project will set the stage for a paradigm-shift in studying and treating life-threatening liver diseases.

Fields of science (EuroSciVoc)

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Host institution

KAROLINSKA INSTITUTET
Net EU contribution
€ 1 999 781,00
Address
Nobels Vag 5
17177 Stockholm
Sweden

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Region
Östra Sverige Stockholm Stockholms län
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 1 999 781,00

Beneficiaries (1)