de Lima Balico Lais, Gaucher Eric A
Department of Biology, Georgia State University, Atlanta, 30312, USA.
Department of Chemistry, Georgia State University, Atlanta, 30312, USA.
Sci Rep. 2025 Jul 18;15(1):26093. doi: 10.1038/s41598-025-10551-8.
The biological role of urate (uric acid) during primate evolution has been unclear ever since it was discovered over 100 years ago that humans have unusually high levels of the small molecule compared to most other mammals. Humans (including all apes) are uncharacteristically susceptible to the build-up of urate because we no longer have a functional uricase enzyme capable of oxidizing this highly insoluble molecule. We have now utilized CRISPR technology to insert functional ancestral uricase into the genome of human liver cells to address recent metabolic hypotheses that our ancestral primates inactivated uricase as a mechanism to increase triglyceride production in response to fructose and/or starvation. Uricase expression is confirmed in both hepatocyte monolayer and spheroid tissue cultures, and its expression reduces intracellular urate levels. The presence of uricase is also shown to prevent an increase in triglyceride production upon cellular uptake of fructose in both culture conditions. Our results make progress that further describes a potential advantageous biological role of urate during primate evolution.
自从100多年前发现人类与大多数其他哺乳动物相比，这种小分子的水平异常高以来，尿酸在灵长类动物进化过程中的生物学作用一直不清楚。人类（包括所有猿类）对尿酸的积累异常敏感，因为我们不再拥有能够氧化这种高度不溶性分子的功能性尿酸酶。我们现在利用CRISPR技术将功能性祖先尿酸酶插入人类肝细胞基因组中，以应对最近的代谢假说，即我们的灵长类祖先使尿酸酶失活，作为对果糖和/或饥饿作出反应增加甘油三酯生成的一种机制。在肝细胞单层和球体组织培养中均证实了尿酸酶的表达，其表达降低了细胞内尿酸水平。在两种培养条件下，尿酸酶的存在还显示可防止细胞摄取果糖后甘油三酯生成增加。我们的研究结果取得了进展，进一步描述了尿酸在灵长类动物进化过程中潜在的有利生物学作用。
