尿酸水平升高通过损害脂肪酸代谢加重心力衰竭。

Increased circulating uric acid aggravates heart failure via impaired fatty acid metabolism.

机构信息

Cardiovascular Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.

Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, 710061, Shaanxi, China.

出版信息

J Transl Med. 2023 Mar 16;21(1):199. doi: 10.1186/s12967-023-04050-5.

BACKGROUND

Increased circulating uric acid (UA) concentration may disrupt cardiac function in heart failure patients, but the specific mechanism remains unclear. Here, we postulate that hyperuremia induces sterol regulatory element binding protein 1 (SREBP1), which in turn activate hepatic fatty acid biosynthesis response, leading to cardiac dysfunction.

METHODS AND RESULTS

Increased circulating uric acid was observed in heart failure patients and inversely correlated to cardiac function. Besides, uric acid correlated to circulating lipids profile based on metabolomics in heart failure patients. Using cultured human hepatoellular carcinomas (HepG2) and Tg(myl7:egfp) zebrafish, we demonstrated that UA regulated fatty acid synthase (FASN) via SREBP1 signaling pathway, leading to FFA accumulation and impaired energy metabolism, which could be rescued via SREBP1 knockdown. In ISO treated zebrafish, UA aggravated heart failure via increased cardiovascular cavity size, decreased heart beats, pericardial edema and long-stretched heart deformation.

CONCLUSIONS

Our findings suggest that UA-SREBP1-FASN signaling exacerbates cardiac dysfunction during FFA accumulation. Identification of this mechanism may help in treatment and prevention of heart failure.

背景

循环尿酸（UA）浓度升高可能会破坏心力衰竭患者的心脏功能，但具体机制尚不清楚。在这里，我们假设高尿酸血症诱导固醇调节元件结合蛋白 1（SREBP1），进而激活肝脂肪酸生物合成反应，导致心脏功能障碍。

方法和结果

心力衰竭患者中观察到循环尿酸增加，与心脏功能呈负相关。此外，根据心力衰竭患者的代谢组学，尿酸与循环脂质谱相关。使用培养的人肝癌细胞（HepG2）和 Tg(myl7:egfp)斑马鱼，我们证明 UA 通过 SREBP1 信号通路调节脂肪酸合酶（FASN），导致 FFA 积累和能量代谢受损，通过 SREBP1 敲低可以得到挽救。在 ISO 处理的斑马鱼中，UA 通过增加心血管腔大小、减少心跳、心包水肿和拉长的心脏变形来加重心力衰竭。