Department of Chemistry, Princeton University, Princeton, NJ, USA.
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
Nat Metab. 2021 Dec;3(12):1608-1620. doi: 10.1038/s42255-021-00487-4. Epub 2021 Nov 29.
Carbohydrate can be converted into fat by de novo lipogenesis, a process upregulated in fatty liver disease. Chemically, de novo lipogenesis involves polymerization and reduction of acetyl-CoA, using NADPH as the electron donor. The feedstocks used to generate acetyl-CoA and NADPH in lipogenic tissues remain, however, unclear. Here we show using stable isotope tracing in mice that de novo lipogenesis in adipose is supported by glucose and its catabolism via the pentose phosphate pathway to make NADPH. The liver, in contrast, derives acetyl-CoA for lipogenesis from acetate and lactate, and NADPH from folate-mediated serine catabolism. Such NADPH generation involves the cytosolic serine pathway in liver running in the opposite direction to that observed in most tissues and tumours, with NADPH made by the SHMT1-MTHFD1-ALDH1L1 reaction sequence. SHMT inhibition decreases hepatic lipogenesis. Thus, liver folate metabolism is distinctively wired to support cytosolic NADPH production and lipogenesis. More generally, while the same enzymes are involved in fat synthesis in liver and adipose, different substrates are used, opening the door to tissue-specific pharmacological interventions.
碳水化合物可以通过从头合成脂肪（de novo lipogenesis）转化为脂肪，这一过程在脂肪肝疾病中被上调。从化学角度来看，从头合成脂肪涉及乙酰辅酶 A 的聚合和还原，使用 NADPH 作为电子供体。然而，用于在脂肪组织中生成乙酰辅酶 A 和 NADPH 的原料仍然不清楚。在这里，我们使用稳定同位素示踪技术在小鼠中表明，脂肪中的从头合成脂肪由葡萄糖及其通过戊糖磷酸途径的分解代谢提供 NADPH。相比之下，肝脏通过乙酸盐和乳酸盐为脂肪生成提供乙酰辅酶 A，通过叶酸介导的丝氨酸分解代谢提供 NADPH。这种 NADPH 的产生涉及肝脏中胞质丝氨酸途径的相反方向，与大多数组织和肿瘤中观察到的方向相反，NADPH 由 SHMT1-MTHFD1-ALDH1L1 反应序列产生。SHMT 抑制可减少肝脂肪生成。因此，肝脏叶酸代谢明显与支持胞质 NADPH 生成和脂肪生成有关。更普遍地说，虽然肝脏和脂肪中参与脂肪合成的酶相同，但使用不同的底物，为组织特异性的药理学干预开辟了大门。
