Back to Search
Start Over
Serine catabolism generates liver NADPH and supports hepatic lipogenesis
- Source :
- Nature metabolism. 3(12)
- Publication Year :
- 2021
-
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.
- Subjects :
- Glycine Hydroxymethyltransferase
Male
Methylenetetrahydrofolate Dehydrogenase (NADP)
Oxidoreductases Acting on CH-NH Group Donors
Glutamine
Lipogenesis
Fatty Acids
Lipid Metabolism
Oxidative Phosphorylation
Formate-Tetrahydrofolate Ligase
Mice
Folic Acid
Adipose Tissue
Liver
Acetyl Coenzyme A
Aminohydrolases
Multienzyme Complexes
Hepatocytes
Serine
Animals
Female
Metabolic Networks and Pathways
NADP
Subjects
Details
- ISSN :
- 25225812
- Volume :
- 3
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Nature metabolism
- Accession number :
- edsair.pmid..........3a24787e1b5694b5569738792f3f0133