Title | Serine catabolism generates liver NADPH and supports hepatic lipogenesis. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Zhang, Z, TeSlaa, T, Xu, X, Zeng, X, Yang, L, Xing, G, Tesz, GJ, Clasquin, MF, Rabinowitz, JD |
Journal | Nat Metab |
Volume | 3 |
Issue | 12 |
Pagination | 1608-1620 |
Date Published | 2021 Dec |
ISSN | 2522-5812 |
Keywords | Acetyl 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> |
DOI | 10.1038/s42255-021-00487-4 |
Alternate Journal | Nat Metab |
PubMed ID | 34845393 |
PubMed Central ID | PMC8721747 |
Grant List | DP1 DK113643 / DK / NIDDK NIH HHS / United States F32 DK118856 / DK / NIDDK NIH HHS / United States |