Downregulation of PHGDH expression and hepatic serine level contribute to the development of fatty liver disease

• Published in: Metabolism, clinical and experimental Vol. 102; p. 154000
• Main Authors: Sim, Woo-Cheol, Lee, Wonseok, Sim, Hyungtai, Lee, Kang-Yo, Jung, Seung-Hwan, Choi, You-Jin, Kim, Hyun Young, Kang, Keon Wook, Lee, Ji-Yoon, Choi, Young Jae, Kim, Sang Kyum, Jun, Dae Won, Kim, Won, Lee, Byung-Hoon
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2020
• Subjects: 3-Phosphoglycerate dehydrogenase (PHGDH); Animals; Cells, Cultured; Cohort Studies; Diet, High-Fat; Down-Regulation; Embryo, Mammalian; Female; Gene Expression Regulation, Enzymologic; Glyceraldehyde-3-Phosphate Dehydrogenases - genetics; Glyceraldehyde-3-Phosphate Dehydrogenases - metabolism; High-fat diet; Humans; Lipid Metabolism - genetics; Lipogenesis - genetics; Liver - chemistry; Liver - metabolism; Liver - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic fatty liver disease (NAFLD); Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; NRF2; Serine; Serine - analysis; Serine - metabolism; SIRT1; NRF2; 3-Phosphoglycerate dehydrogenase (PHGDH); SIRT1; Serine; High-fat diet; Non-alcoholic fatty liver disease (NAFLD)
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2019.154000

Supplementation with serine attenuates alcoholic fatty liver by regulating homocysteine metabolism and lipogenesis. However, little is known about serine metabolism in fatty liver disease (FLD). We aimed to investigate the changes in serine biosynthetic pathways in humans and animal models of fatty liver and their contribution to the development of FLD.
High-fat diet (HFD)-induced steatosis and methionine-choline-deficient diet-induced steatohepatitis animal models were employed. Human serum samples were obtained from patients with FLD whose proton density fat fraction was estimated by magnetic resonance imaging. 3-Phosphoglycerate dehydrogenase (Phgdh)-knockout mouse embryonic fibroblasts (MEF) and transgenic mice overexpressing Phgdh (Tg-phgdh) were used to evaluate the role of serine metabolism in the development of FLD.
Expression of Phgdh was markedly reduced in the animal models. There were significant negative correlations of the serum serine with the liver fat fraction, serum alanine transaminase, and triglyceride levels among patients with FLD. Increased lipid accumulation and reduced NAD+ and SIRT1 activity were observed in Phgdh-knockout MEF and primary hepatocytes incubated with free fatty acids; these effects were reversed by overexpression of Phgdh. Tg-Phgdh mice showed significantly reduced hepatic triglyceride accumulation compared with wild-type littermates fed a HFD, which was accompanied by increased SIRT1 activity and reduced expression of lipogenic genes and proteins.
Human and experimental data suggest that reduced Phgdh expression and serine levels are closely associated with the development of FLD.
•PHGDH is an enzyme catalyzing the committed step of serine biosynthesis pathway.•Hepatic expression of PHGDH and serine concentration are decreased in steatosis animal models.•There is a significant negative correlation between the serine concentration and liver fat fraction in patients with NAFLD.•Transgenic overexpression of PHGDH in mice attenuates HFD-induced fatty liver accompanied by increased SIRT1 activity.