Serine catabolism generates NADPH to support hepatic lipogenesis

Carbohydrate can be converted into fat by de novo lipogenesis[1][1],[2][2]. This process is known to occur in adipose and liver, and its activity is upregulated in fatty liver disease[3][3]. Chemically, de novo lipogenesis involves polymerization and reduction of acetyl-CoA, using NADPH as the electron donor[1][1]. While regulation of the responsible enzymes has been extensively studied, the feedstocks used to generate acetyl-CoA and NADPH remain unclear. Here we show that, while de novo lipogenesis in adipose is supported by glucose and its catabolism via the pentose phosphate pathway to make NADPH, liver makes fat without relying on glucose. Instead, liver derives acetyl-CoA from acetate and lactate, and NADPH from folate-mediated serine catabolism. Such NADPH generation involves the cytosolic serine pathway running in liver in the opposite direction observed in most tissues and tumors[4][4],[5][5], with NADPH made by the SHMT1-MTHFD1-ALDH1L1 reaction sequence. Thus, specifically in liver, folate metabolism is wired to support cytosolic NADPH production for lipogenesis. More generally, while the same enzymes are involved in fat synthesis in liver and adipose, different substrates are utilized, opening the door to tissue-specific pharmacological interventions. ### Competing Interest Statement J.D.R. is a consultant to Pfizer and an advisor and stock owner in Colorado Research Partners, L.E.A.F. Pharmaceuticals, Rafael Pharmaceuticals, Raze Therapeutics, Kadmon Pharmaceuticals, and Agios Pharmaceuticals. J.D.R. is co-inventor of SHIN2 and related SHMT inhibitors, which have been patented by Princeton University. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5