Branched-chain amino acids promote occurrence and development of cardiovascular disease dependent on triglyceride metabolism via activation of the mTOR/SREBP-1/betatrophin pathway

• Published in: Molecular and cellular endocrinology Vol. 584; p. 112164
• Main Authors: Zhang, Jie, Liu, Ziyu, Ni, Yaojun, Yu, Yang, Guo, Fei, Lu, Yanwen, Wang, Xiaoqing, Hao, Hairong, Li, Shayan, Wei, Pan, Yu, Weinan, Hu, Wen
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 15.04.2024
• Subjects: amino acid metabolism; amino acids; animal models; Betatrophin; Branched-chain amino acids; Cardiovascular disease; cardiovascular diseases; dose response; endocrinology; fibrosis; fluorescent antibody technique; High fructose diet; pathogenesis; risk; triacylglycerols; Triglyceride; Cardiovascular disease; Branched-chain amino acids; Triglyceride; High fructose diet; Betatrophin
• ISSN: 0303-7207; 1872-8057; 1872-8057
• DOI: 10.1016/j.mce.2024.112164

Branched-chain amino acid (BCAA) metabolism is associated with triglyceride (TG) metabolism and the development of cardiovascular disease (CVD). However, the underlying mechanism remains uncertain. This study included 1302 subjects and followed for 4–5 years. A hyperbranched-chain aminoacidemia rat model was induced by high fructose diet (HFTD). The relationship between BCAAs and TG level and its regulatory mechanism was investigated in vitro. As results, as baseline BCAA percentile increased, subjects had higher prevalence and incidence of T2DM, NAFLD, and CVD risk (P < 0.05). In animal model, the accumulation of BCAAs and TG and betatrophin expression were significantly elevated in the HFTD group when comparing with those in the SD group(P < 0.05). Immunofluorescence and Masson's trichrome staining revealed that the area of interstitial fibrosis was significantly increased in the HFTD group compared with control group. Met treatment significantly decreased TG levels and betatrophin expression and reversed myocardial fibrosis (P < 0.05). In vitro, LO2 cells, stimulated with 0.1–5 mM BCAAs, displayed a significant dose-dependent increase in betatrophin expression (P < 0.05). And 5 mM BCAAs stimulation significantly increased the p-mTOR and SREBP-1 expression (P < 0.05). However, this effect could be reversed by using the corresponding inhibitor or siRNAs. In conclusions, BCAAs promote occurrence and development of cardiovascular disease dependent on TG metabolism via activation of the mTOR/SREBP-1/betatrophin pathway. The study provides a new theory for the pathogenesis of CVD caused by amino acid metabolism disorders. •BCAAs are associated with increased risk of cardiovascular disease in humans.•High fructose diet induced insulin resistance, high BCAA levels, myocardial damage in rat model.•BCAAs induced higher TG levels and betatrophin expression in hepatic cell model.•Activation of the mTOR/SREBP-1/betatrophin pathway by BCAAs regulates TG metabolism.•Reducing BCAAs by metformin may provide a therapeutic strategy to treat cardiovascular disease.