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

Woo Cheol Sim, Wonseok Lee, Hyungtai Sim, Kang Yo Lee, Seung Hwan Jung, You Jin Choi, Hyun Young Kim, Keon Wook Kang, Ji Yoon Lee, Young Jae Choi, Sang Kyum Kim, Dae Won Jun, Won Kim, Byung Hoon Lee

Research output: Contribution to journalArticle

Abstract

Objective: 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. Methods: 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. Results: 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. Conclusions: Human and experimental data suggest that reduced Phgdh expression and serine levels are closely associated with the development of FLD.

Original languageEnglish
Article number154000
JournalMetabolism: Clinical and Experimental
Volume102
DOIs
StatePublished - Jan 2020

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Phosphoglycerate Dehydrogenase
Fatty Liver
Serine
Liver Diseases
Down-Regulation
Liver
Animal Models
High Fat Diet
Knockout Mice
Triglycerides
Fibroblasts
Serum
Fats
Alcoholic Fatty Liver
Lipogenesis
Biosynthetic Pathways
Homocysteine
Choline
Alanine Transaminase
Nonesterified Fatty Acids

Keywords

  • 3-Phosphoglycerate dehydrogenase (PHGDH)
  • High-fat diet
  • Non-alcoholic fatty liver disease (NAFLD)
  • NRF2
  • Serine
  • SIRT1

Cite this

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. / Downregulation of PHGDH expression and hepatic serine level contribute to the development of fatty liver disease. In: Metabolism: Clinical and Experimental. 2020 ; Vol. 102.
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title = "Downregulation of PHGDH expression and hepatic serine level contribute to the development of fatty liver disease",
abstract = "Objective: 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. Methods: 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. Results: 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. Conclusions: Human and experimental data suggest that reduced Phgdh expression and serine levels are closely associated with the development of FLD.",
keywords = "3-Phosphoglycerate dehydrogenase (PHGDH), High-fat diet, Non-alcoholic fatty liver disease (NAFLD), NRF2, Serine, SIRT1",
author = "Sim, {Woo Cheol} and Wonseok Lee and Hyungtai Sim and Lee, {Kang Yo} and Jung, {Seung Hwan} and Choi, {You Jin} and Kim, {Hyun Young} and Kang, {Keon Wook} and Lee, {Ji Yoon} and Choi, {Young Jae} and Kim, {Sang Kyum} and Jun, {Dae Won} and Won Kim and Lee, {Byung Hoon}",
year = "2020",
month = "1",
doi = "10.1016/j.metabol.2019.154000",
language = "English",
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Downregulation of PHGDH expression and hepatic serine level contribute to the development of fatty liver disease. / 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.

In: Metabolism: Clinical and Experimental, Vol. 102, 154000, 01.2020.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Downregulation of PHGDH expression and hepatic serine level contribute to the development of fatty liver disease

AU - Sim, Woo Cheol

AU - Lee, Wonseok

AU - Sim, Hyungtai

AU - Lee, Kang Yo

AU - Jung, Seung Hwan

AU - Choi, You Jin

AU - Kim, Hyun Young

AU - Kang, Keon Wook

AU - Lee, Ji Yoon

AU - Choi, Young Jae

AU - Kim, Sang Kyum

AU - Jun, Dae Won

AU - Kim, Won

AU - Lee, Byung Hoon

PY - 2020/1

Y1 - 2020/1

N2 - Objective: 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. Methods: 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. Results: 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. Conclusions: Human and experimental data suggest that reduced Phgdh expression and serine levels are closely associated with the development of FLD.

AB - Objective: 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. Methods: 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. Results: 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. Conclusions: Human and experimental data suggest that reduced Phgdh expression and serine levels are closely associated with the development of FLD.

KW - 3-Phosphoglycerate dehydrogenase (PHGDH)

KW - High-fat diet

KW - Non-alcoholic fatty liver disease (NAFLD)

KW - NRF2

KW - Serine

KW - SIRT1

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DO - 10.1016/j.metabol.2019.154000

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