Glutamine sensing licenses cholesterol synthesis

The mevalonate pathway produces essential lipid metabolites such as cholesterol. Although this pathway is negatively regulated by metabolic intermediates, little is known of the metabolites that positively regulate its activity. We found that the amino acid glutamine is required to activate the meva...

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Veröffentlicht in:The EMBO journal Jg. 43; H. 23; S. 5837 - 5856
Hauptverfasser: Garcia, Bruna Martins, Melchinger, Philipp, Medeiros, Tania, Hendrix, Sebastian, Prabhu, Kavan, Corrado, Mauro, Kingma, Jenina, Gorbatenko, Andrej, Deshwal, Soni, Veronese, Matteo, Scorrano, Luca, Pearce, Erika, Giavalisco, Patrick, Zelcer, Noam, Pernas, Lena
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 02.12.2024
Schlagworte:
Animals
Biomedical and Life Sciences
Cholesterol - biosynthesis
Cholesterol - metabolism
EMBO20
EMBO21
Endoplasmic Reticulum - metabolism
Glutamine - metabolism
Golgi Apparatus - metabolism
Humans
Intracellular Signaling Peptides and Proteins - genetics
Intracellular Signaling Peptides and Proteins - metabolism
Life Sciences
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mevalonic Acid - metabolism
Sterol Regulatory Element Binding Protein 2 - genetics
Sterol Regulatory Element Binding Protein 2 - metabolism
SREBP2
MFN2
Nutrient Sensing
HMGCR
Cholesterol
ISSN:1460-2075, 0261-4189, 1460-2075
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Zusammenfassung:The mevalonate pathway produces essential lipid metabolites such as cholesterol. Although this pathway is negatively regulated by metabolic intermediates, little is known of the metabolites that positively regulate its activity. We found that the amino acid glutamine is required to activate the mevalonate pathway. Glutamine starvation inhibited cholesterol synthesis and blocked transcription of the mevalonate pathway—even in the presence of glutamine derivatives such as ammonia and α-ketoglutarate. We pinpointed this glutamine-dependent effect to a loss in the ER-to-Golgi trafficking of SCAP that licenses the activation of SREBP2, the major transcriptional regulator of cholesterol synthesis. Both enforced Golgi-to-ER retro-translocation and the expression of a nuclear SREBP2 rescued mevalonate pathway activity during glutamine starvation. In a cell model of impaired mitochondrial respiration in which glutamine uptake is enhanced, SREBP2 activation and cellular cholesterol were increased. Thus, the mevalonate pathway senses and is activated by glutamine at a previously uncharacterized step, and the modulation of glutamine synthesis may be a strategy to regulate cholesterol levels in pathophysiological conditions. Synopsis Whether cholesterol biosynthesis can be adjusted to the availability of input carbon sources remains unclear. This study demonstrates that glutamine is directly sensed by and required for activation of the mevalonate pathway, coupling precursor availability to cellular lipid formation. Glutamine starvation inhibits cholesterol synthesis in human cells. Glutamine, but not its derivatives nor glucose, maintains expression of the rate-limiting lipid biosynthesis enzyme HMGCR. Glutamine synthesis from ammonia and glutamate sustains HMGCR in a cell-type-specific manner. Glutamine is required for the ER-to-Golgi trafficking of the SCAP-SREBP2 complex. Chronic mitochondrial dysfunction increases glutamine uptake and cholesterol levels in murine fibroblasts. The amino acid glutamine is directly sensed by the mevalonate pathway and acts as an anabolic switch coupling precursor availability to lipid biosynthesis.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1460-2075
0261-4189
1460-2075
DOI:10.1038/s44318-024-00269-0