Lipogenesis by reductive carboxylation is regulated by Bcr‐Abl signaling

Abstract

Lipogenesis in rapidly growing cells requires an efficient metabolism of nutrients to supply the acetyl‐CoA building blocks. Acetyl‐CoA is usually formed from glucose‐derived pyruvate via citrate. An alternate route to citrate is the reductive carboxylation of α‐ketoglutarate (αKG) by isocitrate dehydrogenase (IDH). Purified IDH catalyzed NADP+‐dependent decarboxylation of isocitrate proceeds until the substrates are nearly depleted; however, the NADPH‐dependent carboxylation reaction is stringently inhibited by NADP+ and isocitrate. Cell labeling with 13C‐precursors was used to measure the contribution of reductive carboxylation to lipogenesis by determining the isotopomer distribution in intracellular acetyl‐CoA. αKG carboxylation is responsible for forming only 10% of acetyl‐CoA in 293T cells; however, this pathway supports a majority of acetyl‐CoA synthesis when mitochondrial function is compromised. In contrast, reductive carboxylation is a major route to acetyl‐CoA in an Arf‐null, Bcr‐Abl‐positive pre‐B cell model of acute lymphoblastic leukemia. Inhibition of Bcr‐Abl kinase rapidly switches metabolism from αKG as a principal source for acetyl‐CoA to glucose‐derived pyruvate. Carbon acquisition by reductive carboxylation is an efficient and unappreciated mechanism to acquire carbon for lipid assembly that is regulated by Bcr‐Abl signaling. (Supported by CA21765 & ALSAC)