Mechanisms of cellular fatty acid homeostasis

Projektinformationen

TGDNL

ID Finanzhilfevereinbarung: 704647

DOI

10.3030/704647

Projekt abgeschlossen

EK-Unterschriftsdatum 1 September 2016

Startdatum 1 August 2017

Enddatum 31 Juli 2020

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 265 059,00

EU-Beitrag

€ 265 059,00

Koordiniert durch

KAROLINSKA INSTITUTET
Sweden

Periodic Reporting for period 2 - TGDNL (Mechanisms of cellular fatty acid homeostasis)

Berichtszeitraum: 2019-08-01 bis 2020-07-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

In life, access to metabolic energy fluctuates. Our cells have therefore developed the ability to store energy, predominantly as fat (triglycerides) in organelles known as lipid droplets (LDs). Although the capacity to store triglycerides is key for survival when access to nutrients is limited, increased energy intake combined with decreased energy utilization has led to a global increase in multiple metabolic diseases, e.g. obesity and non-alcoholic fatty liver disease, in today’s society. The overarching objective of this project is to determine how cells regulate and coordinate lipid storage processes in order to achieve energy homeostasis. The results generated may therefore uncover novel mechanisms controlling cellular lipid homeostasis and provide new therapeutic avenues to treat diseases characterized by overwhelming the storage capacity of cells.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

My main results obtained suggest that (1) SREBP-1 regulation by alterations in DGAT2 activity is a universal feature of cells as inhibition of DGAT2 reduces SREBP-1c mRNA levels (a proxy for SREBP-1 activity) in numerous different cell models and (2) DGAT2 inhibition decreases nuclear SREBP-1 protein levels and the expression of SREBP-1 target genes in a breast carcinoma cell line (SUM159 cells). These results have been corroborated in knockout mice lacking DGAT2 in liver. Taken together, these data suggest that inhibition/lack of DGAT2 decreases SREBP-1 cleavage and thereby activity via unknown mechanisms.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

I hope to identify key regulatory steps linking DGAT2 to SREBP-1. The pathophysiological relevance of the mechanisms deciphered through these studies will subsequently be assessed in carefully phenotyped clinical cohorts (obese with or without type 2 diabetes/metabolic syndrome) where tissue samples have already been collected. Altogether, these studies will help us delineate the role of DGAT2/SREBP1 in common metabolic disorders.

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