Serine catabolism generates liver NADPH and supports hepatic lipogenesis.

TitleSerine catabolism generates liver NADPH and supports hepatic lipogenesis.
Publication TypeJournal Article
Year of Publication2021
AuthorsZhang, Z, TeSlaa, T, Xu, X, Zeng, X, Yang, L, Xing, G, Tesz, GJ, Clasquin, MF, Rabinowitz, JD
JournalNat Metab
Volume3
Issue12
Pagination1608-1620
Date Published2021 12
ISSN2522-5812
KeywordsAcetyl Coenzyme A, Adipose Tissue, Aminohydrolases, Animals, Fatty Acids, Female, Folic Acid, Formate-Tetrahydrofolate Ligase, Glutamine, Glycine Hydroxymethyltransferase, Hepatocytes, Lipid Metabolism, Lipogenesis, Liver, Male, Metabolic Networks and Pathways, Methylenetetrahydrofolate Dehydrogenase (NADP), Mice, Multienzyme Complexes, NADP, Oxidative Phosphorylation, Oxidoreductases Acting on CH-NH Group Donors, Serine
Abstract

<p>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.</p>

DOI10.1038/s42255-021-00487-4
Alternate JournalNat Metab
PubMed ID34845393
PubMed Central IDPMC8721747
Grant ListDP1 DK113643 / DK / NIDDK NIH HHS / United States
F32 DK118856 / DK / NIDDK NIH HHS / United States