Role of Abnormal L-Serine Metabolism by Lowered Expression of 3-Phosphoglycerated Dehydrogenase in Fatty Liver Disease

Abstract

Fatty liver disease is early-stage liver disease that fat makes up more than 5% of the organs weight. Fatty liver is a reversible state and benign, but without proper treatments, it can lead to liver dysfunction. In this study, we propose that 3-phosphoglycerate dehydrogenase (PHGDH), which is a rate-limiting enzyme in serine biosynthesis, can affect lipid metabolism by regulating L-serine pool in fatty liver disease. Previous study showed that hepatic L-serine is decreased in chronically ethanol-fed rats. Based on the result, L-serine was treated in alcoholic fatty liver model and it reversed ethanol-induced fatty liver by metabolizing homocysteine via methionine synthase (MS) and cystathionine β-synthase (CβS). L-serine also increased intracellular NAD+ and silent information regulator 1 (SIRT1) activity via lactate dehydrogenase (LDH). L-serine increased mitochondrial gene expression, mass and function by deacetylated PGC-1α.. Increased SIRT1 activity by L-serine ameliorated lipid accumulation and insulin resistance in vitro. PHGDH and L-serine were found to be significantly lowered in chronic ethanol diet and high-fat diet fatty liver model. Free fatty acids and ethanol also decreased PHGDH expression in vitro. Diminished synthesis of L-serine led to increase in abnormal sphingolipids and ceramides in PHGDH-KO MEF cells and alcoholic fatty liver model. GEO analysis of hepatitis patients revealed phgdh gene expression was diminished. Serum L-serine of fatty liver patients was also down-regulated and negatively correlated with MRI fat fraction, serum ALT and triglyceride (TG). Increased synthesis of L-serine by PHGDH gain of function reversed lipid accumulation in various cells by increasing intracellular NAD+ and SIRT1 activity. PHGDH is found to be positively regulated by nuclear factor like 2 (NRF2) at both transcriptional and translational levels. Fatty liver disease model showed the decreased expression of NRF2 and increased NRF2 activity reversed free fatty acid-induced decrease in PHGDH expression. In conclusion, PHGDH plays an important role in regulating lipid metabolism by synthesizing L-serine in the liver. This study showed that PHGDH can be used as a therapeutic target for hepatosteatosis and L-serine has a potential for curing fatty liver disease.