Mechanisms of cellular fatty acid homeostasis

Project Information

TGDNL

Grant agreement ID: 704647

DOI

10.3030/704647

Project closed

EC signature date 1 September 2016

Start date 1 August 2017

End date 31 July 2020

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 265 059,00

EU contribution

€ 265 059,00

Coordinated by

KAROLINSKA INSTITUTET
Sweden

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

Reporting period: 2019-08-01 to 2020-07-31

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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.

Project logo