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Targeting the ER stress response in non-alcoholic fatty liver disease

Projectomschrijving

Farmacologische manipulatie van ER stress in vette leverziekte

Cellulaire stress veroorzaakt door overgewicht en vetophoping in de lever kan via de activatie van de “Unfolded Protein Response” in het endoplasmatisch reticulum (UPRER) verminderd worden. De onderzoekers gaan de rol en “druggability” van UPRER componenten identificeren en hun potentiële bruikbaarheid in de behandeling van niet - alcoholische leververvetting onderzoeken.

Targeting the ER stress response in non-alcoholic fatty liver disease

Cellular stress caused by obesity and accumulation of fat in the liver can be reversed via activation of the Unfolded Protein Response of the endoplasmic reticulum (UPRER). Here we will investigate the involvement and “druggability” of UPRER targets and explore their potential for the treatment of non-alcoholic fatty liver disease.

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Samenvatting van de aanvraag

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in Western societies (prevalence of 20-50%) and one of the most serious conditions associated with obesity. Yet there is still no approved pharmacologic treatment option. An overload of fat in metabolically highly active organs such as the liver is both a cause and a consequence of stress in the endoplasmic reticulum (ER), the organelle central to protein synthesis and folding as well as of lipid biosynthesis. This creates a vicious cycle that promotes NAFLD. When the protein folding and secretory capacity of the ER are dysregulated, adaptive processes including the Unfolded Protein Response of the ER (UPR-ER) are activated to restore homeostasis. The UPR-ER pathway provides a potential therapeutic target for metabolic and degenerative diseases as well as cancer. At the foundation of this exciting new investigation is my recent identification of Fibroblast Growth Factor 1 (FGF1) as a hormone with beneficial metabolic properties, including potent reversal of NAFLD. My finding that reversal of NAFLD by FGF1 is mediated via unconventional activation of the UPR-ER, characterized by increased protein folding without stimulation of ER associated degradation offers the prospect of finding novel therapeutic treatments for NAFLD. Thus, in this Vici project I will define the molecular mechanism by which modulation of the ER stress response affects hepatic lipid secretion and how this can be used in the treatment of NAFLD. To achieve this , I will: (i) dissect the unconventional UPR pathway at the molecular level and establish its effect on chaperone-mediated folding of components of the lipid secretory machinery; (ii) determine the physiologic and therapeutic consequences of modulation of folding for hepatic lipid secretion using cellular and mouse models of NAFLD, and (iii) examine the therapeutic and diagnostic potential of folding in NAFLD using iPSC-derived hepatocytes and liver biopsies of patients. By combining the power of state-of-the art proteomics and CRISPR-Cas9 gene editing techniques with studies investigating the regulation of hepatic lipid secretion by the UPRER in mouse models and in patient-derived cells, we will be at the forefront of providing new insights into disease-mechanisms. The novel cellular and mouse models generated in this project will allow us to unravel the physiological relevance of specific target molecules in hepatic lipid metabolism. The ultimate outcome will be novel therapeutic targets and treatment options for NAFLD and, potentially, other ER stress-related diseases.

Onderwerpen

Kenmerken

Projectnummer:
91818640
Looptijd: 100%
Looptijd: 100 %
2018
2023
Gerelateerde subsidieronde:
Projectleider en penvoerder:
prof. dr. H. Jonker
Verantwoordelijke organisatie:
Universitair Medisch Centrum Groningen