Serine catabolism generates liver NADPH and supports hepatic lipogenesis

Zhaoyue Zhang, Tara TeSlaa, Xincheng Xu, Xianfeng Zeng, Lifeng Yang, Gang Xing, Gregory J. Tesz, Michelle F. Clasquin, Joshua D. Rabinowitz

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1608-1620
Number of pages13
JournalNature Metabolism
Volume3
Issue number12
DOIs
StatePublished - Dec 2021

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Cell Biology
  • Physiology (medical)

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