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 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 alpha-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. 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.