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.

中文翻译：

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PHGDH表达和肝丝氨酸水平的下调有助于脂肪肝疾病的发展。

目的补充丝氨酸可通过调节同型半胱氨酸代谢和脂肪生成来减轻酒精性脂肪肝。但是，关于脂肪肝疾病（FLD）中丝氨酸代谢的了解还很少。我们旨在研究人和动物脂肪肝模型中丝氨酸生物合成途径的变化及其对FLD发育的贡献。方法采用高脂饮食（HFD）引起的脂肪变性和蛋氨酸-胆碱缺乏饮食引起的脂肪性肝炎动物模型。从患有FLD的患者获得人血清样品，其质子密度脂肪分数通过磁共振成像估算。使用3-磷酸甘油酸脱氢酶（Phgdh）敲除小鼠胚胎成纤维细胞（MEF）和过表达Phgdh的转基因小鼠（Tg-phgdh）来评估丝氨酸代谢在FLD发育中的作用。结果在动物模型中，Phgdh的表达显着降低。患有FLD的患者中，血清丝氨酸与肝脂肪含量，血清丙氨酸转氨酶和甘油三酯水平呈显着负相关。在Phgdh基因敲除的MEF和与游离脂肪酸孵育的原代肝细胞中观察到脂质积累增加，NAD +和SIRT1活性降低。Phgdh的过表达逆转了这些影响。与喂食HFD的野生型同窝幼仔相比，Tg-Phgdh小鼠显示出明显降低的肝甘油三酸酯蓄积，并伴有SIRT1活性增加以及脂肪基因和蛋白质表达降低。结论人类和实验数据表明，降低的Phgdh表达和丝氨酸水平与FLD的发展密切相关。