Exogenous and Endogenous Serine Deficiency Exacerbates Hepatic Lipid Accumulation.

Liuqin He,Yonghui Liu,Jie Yin,Xihong Zhou,Yanzhong Feng,Di Liu,Demin Cai

doi:10.1155/2021/4232704

Abstract

Serine is involved in the regulation of hepatic lipid metabolism. However, whether exogenous or endogenous serine deficiency affects lipid accumulation in the liver and related mechanisms is unclear. Here, we investigated the effects of serine deficiency on hepatic fat accumulation in mice fed a serine-deficient diet or in mice supplemented with the D-3-phosphoglycerate dehydrogenase (PHGDH) inhibitor NCT-503. Both treatments produced an increase in body weight and liver weight and higher triglyceride content in the liver. Both treatments also exacerbated hepatic inflammatory responses and oxidative stress. Importantly, NCT-503 supplementation significantly inhibited PHGDH activity and decreased the serine content in the liver. Dietary serine deficiency significantly affected the colonic microbiota, characterized by a decreased ratio of Firmicutes/Bacteroidetes and decreased proportion of Bifidobacterium. Dietary serine deficiency additionally resulted in significantly decreased colonic and serum acetate and butyrate levels. The collective results indicate that NCT-503 supplementation may contribute to overaccumulation of hepatic lipid, by causing hepatic serine deficiency, while dietary serine deficiency may produce similar outcomes by affecting the gut-microbiota-liver axis.

Highlights

Hepatocytes are the most metabolically active cell type in the body, with diverse physiological and metabolic functions [1]
The results indicated that NCT-503 supplementation may contribute to overaccumulation of hepatic lipid, by causing hepatic serine deficiency, while dietary serine deficiency may produce similar outcomes by affecting the gut-microbiota-liver axis
All mice were randomly assigned into three treatment groups: (i) mice were fed on the control diet (CONT); (ii) mice were fed on the serine- and glycine-deficient diet (NS); and (iii) mice were fed on the control diet and supplemented with NCT-503 (NCT), a specific inhibitor of phosphoglycerate dehydrogenase (PHGDH)

Summary

Introduction

Hepatocytes are the most metabolically active cell type in the body, with diverse physiological and metabolic functions [1]. Decreased or increased metabolism of hepatocytes can result in complicated disorders and development of diseases, including fatty liver disease and cancer [2]. Imbalance in lipid metabolism in the liver is a hallmark of nonalcoholic fatty liver disease [3]. Genome-scale metabolic modeling of hepatocytes has demonstrated the involvement of serine deficiency in the development of fatty liver disease [1]. 3-phosphoglycerate dehydrogenase (PHGDH), the key enzyme involved in the de novo synthesis of serine, is closely associated with the development of fatty liver diseases [6]. The aforementioned findings indicate that both exogenous and endogenous serine have critical roles in the regulation of hepatic lipid metabolism. Whether exogenous serine deficiency affects hepatic lipid deposition remains unknown.

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Conclusion