Universität zu Köln

Martins Garcia, Bruna ORCID: 0000-0002-2257-9370 (2024). GLUTAMINE SENSING LICENSES CHOLESTEROL SYNTHESIS. PhD thesis, Universität zu Köln.

PDF thesis_2024.pdf - Accepted Version Download (21MB)

Abstract

Cholesterol is an essential lipid required for cell function and viability. The levels of cholesterol are tightly regulated and metabolic intermediates negatively regulate its synthesis. However, little is known about metabolites that positively regulate cholesterol synthesis. Here I found that the non-essential amino acid glutamine activates the cholesterol synthesis pathway. Glutamine starvation decreased the cholesterol synthesis rate by reducing the expression of the cholesterol synthesis enzymes, including HMGCR, the rate-limiting enzyme in the pathway. In the absence of glutamine, the addition of glutamine derivatives was sufficient to rescue metabolic and cellular stress pathways, but not HMGCR levels. I pinpointed this glutamine-specific effect on cholesterol synthesis to the licensing of ER-to-Golgi trafficking of SREBP2, the major transcriptional regulator of cholesterol synthesis. Under glutamine starvation, there is a block in the ER-to-Golgi trafficking of SREBP2 which is required for SREBP2 activation. Enforced Golgi-to-ER retrotranslocation using brefeldin A or activated SREBP2 overexpression rescued SREBP2 activation and HMGCR levels during glutamine starvation. In a mitochondrial disease model in which glutamine uptake is enhanced, SREBP2 activation and cellular cholesterol were increased. Thus, the cholesterol synthesis pathway senses and is activated by glutamine, and the modulation of glutamine availability may be a strategy to regulate cholesterol levels in pathophysiological conditions.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Martins Garcia, Bruna UNSPECIFIED orcid.org/0000-0002-2257-9370 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-726769
Date:	2024
Place of Publication:	Cologne
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language Cholesterol synthesis English Glutamine English Mitochondria English
Date of oral exam:	20 October 2023
Referee:	Name Academic Title Pernas, Dr., Lena UNSPECIFIED Riemer, Prof. Dr., Jan UNSPECIFIED
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/72676