Pyrimidine catabolism is implicated in hepatic steatosis. Dihydropyrimidine Dehydrogenase (DPYD) is an enzyme responsible for uracil and thymine catabolism, and DPYD human genetic variability affects clinically observed toxicity following 5-Fluorouracil (5-FU) administration. In an in vitro model of diet-induced steatosis, the pharmacologic inhibition of DPYD resulted in protection from lipid accumulation. Additionally, a gain-of-function mutation of DPYD, created through clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR-Cas9) engineering, led to an increased lipid burden, which was associated with altered mitochondrial functionality in a hepatocarcionma cell line. The studies presented herein describe a novel role for DPYD in hepatocyte metabolic regulation as a modulator of hepatic steatosis.

中文翻译：

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鉴定二氢嘧啶脱氢酶作为肝脏脂肪变性的新型调节剂

嘧啶分解代谢与肝脂肪变性有关。二氢嘧啶脱氢酶 (DPYD) 是一种负责尿嘧啶和胸腺嘧啶分解代谢的酶，DPYD 人类遗传变异会影响 5-氟尿嘧啶 (5-FU) 给药后临床观察到的毒性。在体外在饮食诱导的脂肪变性模型中，DPYD 的药理抑制可防止脂质积累。此外，通过成簇的规则间隔短回文重复相关蛋白 9 (CRISPR-Cas9) 工程产生的 DPYD 功能获得性突变导致脂质负担增加，这与肝癌细胞系中线粒体功能的改变有关。本文介绍的研究描述了 DPYD 作为肝脂肪变性调节剂在肝细胞代谢调节中的新作用。