Zhang Pengfei, Sun Huimin, Cheng Xinyu, Li Yajing, Zhao Yanli, Mei Wuxuan, Wei Xing, Zhou Hairong, Du Yunbo, Zeng Changchun
Department of Critical Care Medicine, Shenzhen Longhua District Central Hospital, Shenzhen, China.
Department of Medical Laboratory, Shenzhen Longhua District Central Hospital, Shenzhen, China.
Front Nutr. 2022 Dec 19;9:1045805. doi: 10.3389/fnut.2022.1045805. eCollection 2022.
Fructose consumption is a potential risk factor for hyperuricemia because uric acid (UA) is a byproduct of fructose metabolism caused by the rapid consumption of adenosine triphosphate and accumulation of adenosine monophosphate (AMP) and other purine nucleotides. Additionally, a clinical experiment with four gout patients demonstrated that intravenous infusion of fructose increased the purine synthesis rate, which implied fructose-induced hyperuricemia might be related to purine nucleotide synthesis. Moreover, the mechanistic (mammalian) target of rapamycin (mTOR) is a key protein both involved in fructose metabolism and purine synthesis. The present study was conducted to elucidate how fructose influences mTOR and purine synthesis in a hepatic cell line and livers of mice.
RNA-sequencing in NCTC 1469 cells treated with 0- and 25-mM fructose for 24 h and metabolomics analysis on the livers of mice fed with 0- and 30-g/kg fructose for 2 weeks were assessed. Gene and protein expression of phosphoribosyl pyrophosphate synthase (PRPSAP1), Glutamine PRPP aminotransferase (PPAT), adenyl succinate lyase (ADSL), adenyl succinate synthetase isozyme-1 (Adss1), inosine-5'-monophosphate dehydrogenase (IMPDH), and guanine monophosphate synthetase (GMPS) was measured. The location of PRPSAP1 and PPAT in the liver was assessed by an immunofluorescence assay.
Metabolite profiling showed that the level of AMP, adenine, adenosine, hypoxanthine, and guanine was increased significantly. RNA-sequencing showed that gene expression of phosphoribosyl pyrophosphate synthase (PRPS2), phosphoribosyl glycinamide formyl transferase (GART), AICAR transformylase (ATIC), ADSL, Adss1, and IMPDH were raised, and gene expression of adenosine monophosphate deaminase 3 (AMPD3), adenosine deaminase (ADA), 5',3'-nucleotidase, cytosolic (NT5C), and xanthine oxidoreductase (XOR) was also increased significantly. Fructose increased the gene expression, protein expression, and fluorescence intensity of PRPSAP1 and PPAT in mice livers by increasing mTOR expression. Fructose increased the expression and activity of XOR, decreased the expression of uricase, and increased the serum level of UA.
This study demonstrated that the increased purine synthesis may be a crucial mechanism for fructose-induced hyperuricemia.
果糖摄入是高尿酸血症的一个潜在风险因素，因为尿酸（UA）是果糖代谢的副产物，果糖快速消耗三磷酸腺苷并导致一磷酸腺苷（AMP）和其他嘌呤核苷酸积累所致。此外，一项针对4名痛风患者的临床实验表明，静脉输注果糖会提高嘌呤合成速率，这意味着果糖诱导的高尿酸血症可能与嘌呤核苷酸合成有关。此外，雷帕霉素的机制性（哺乳动物）靶点（mTOR）是一种关键蛋白质，既参与果糖代谢又参与嘌呤合成。本研究旨在阐明果糖如何影响肝细胞系和小鼠肝脏中的mTOR及嘌呤合成。
评估了用0 mM和25 mM果糖处理24小时的NCTC 1469细胞中的RNA测序，以及用0 g/kg和30 g/kg果糖喂养2周的小鼠肝脏的代谢组学分析。测量了磷酸核糖焦磷酸合成酶（PRPSAP1）、谷氨酰胺PRPP转氨酶（PPAT）、腺苷琥珀酸裂解酶（ADSL）、腺苷琥珀酸合成酶同工酶-1（Adss1）、肌苷-5'-单磷酸脱氢酶（IMPDH）和鸟苷单磷酸合成酶（GMPS）的基因和蛋白表达。通过免疫荧光测定评估PRPSAP1和PPAT在肝脏中的定位。
代谢物谱分析表明，AMP、腺嘌呤、腺苷、次黄嘌呤和鸟嘌呤水平显著升高。RNA测序显示，磷酸核糖焦磷酸合成酶（PRPS2）、磷酸核糖甘氨酰胺甲酰转移酶（GART）、AICAR转甲酰酶（ATIC）、ADSL、Adss1和IMPDH的基因表达升高，一磷酸腺苷脱氨酶3（AMPD3）、腺苷脱氨酶（ADA）、5',3'-核苷酸酶（胞质）（NT5C）和黄嘌呤氧化还原酶（XOR）的基因表达也显著增加。果糖通过增加mTOR表达来提高小鼠肝脏中PRPSAP1和PPAT的基因表达、蛋白表达及荧光强度。果糖增加了XOR的表达和活性，降低了尿酸酶的表达，并提高了血清UA水平。
本研究表明，嘌呤合成增加可能是果糖诱导高尿酸血症的关键机制。
