Hepatocyte-Specific Phgdh-Deficient Mice Culminate in Mild Obesity, Insulin Resistance, and Enhanced Vulnerability to Protein Starvation.

Momoko Hamano,Kayoko Esaki,Shigeki Furuya,Yoshio Hirabayashi,Sinya Mohri,Kazuki Moriyasu,Kosuke Tashiro,Tokio Yasuda

doi:10.3390/nu13103468

Abstract

l-Serine (Ser) is synthesized de novo from 3-phosphoglycerate via the phosphorylated pathway committed by phosphoglycerate dehydrogenase (Phgdh). A previous study reported that feeding a protein-free diet increased the enzymatic activity of Phgdh in the liver and enhanced Ser synthesis in the rat liver. However, the nutritional and physiological functions of Ser synthesis in the liver remain unclear. To clarify the physiological significance of de novo Ser synthesis in the liver, we generated liver hepatocyte-specific Phgdh KO (LKO) mice using an albumin-Cre driver. The LKO mice exhibited a significant gain in body weight compared to Floxed controls at 23 weeks of age and impaired systemic glucose metabolism, which was accompanied by diminished insulin/IGF signaling. Although LKO mice had no apparent defects in steatosis, the molecular signatures of inflammation and stress responses were evident in the liver of LKO mice. Moreover, LKO mice were more vulnerable to protein starvation than the Floxed mice. These observations demonstrate that Phgdh-dependent de novo Ser synthesis in liver hepatocytes contributes to the maintenance of systemic glucose tolerance, suppression of inflammatory response, and resistance to protein starvation.

Highlights

“Basal transcription factors” were detected as negatively correlated KEGG pathways with higher normalized enrichment scores (Table 4D and Figure 5G,H). These results suggest that multiple biological processes, such as RNA metabolism, mitochondrial function, and energy metabolism, were altered by the hepatocyte-specific deletion of phosphoglycerate dehydrogenase (Phgdh) in the liver
Since the current KEGG pathway analysis in DAVID points to an alteration in the intracellular insulin signaling cascade in the liver of liver hepatocyte-specific Phgdh KO (LKO) mice (Table 2B), we examined protein phosphorylation of components in the cascade
(500–700 μM) caused a downregulation of Phgdh in isolated hepatocytes [12]. These observations raise the possibility that the downregulation of hepatic Phgdh may be implicated in the onset and/or progression of fatty liver disease, the pathophysiological consequences of genetic Phgdh disruption in liver hepatocytes have not been previously explored experimentally

Summary

Introduction

L -Serine (Ser), a nutritionally dispensable amino acid, serves as an indispensable metabolite essential for mammalian fetal development [1,2]. Ser is synthesized de novo from 3-phosphoglycerate, which is catalyzed by the phosphorylated pathway composed of. 3-phosphoglycerate dehydrogenase (Phgdh), phosphoserine aminotransferase 1 (Psat1), and phosphoserine phosphatase (Psph). Ser is utilized for the synthesis of important metabolic components, such as glycine, nucleotides, glutathione, tetrahydrofolate derivatives, and membrane lipids. We have previously demonstrated the physiological significance of de novo Ser synthesis at the cellular level. Extracellular Ser limitation leads to cell growth arrest and cell death, which is associated with the enhanced phosphorylation of p38MAPK and SAPK/JNK in Phgdh-deficient embryonic fibroblasts (KO-MEFs) under conditions of reduced intracellular Ser availability [3].

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Conclusion