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Mechanisms of cellular fatty acid homeostasis

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

Periodo di rendicontazione: 2019-08-01 al 2020-07-31

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.
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.
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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