天津医科大学孙海鹏等研究人员合作发现，支链氨基酸通过抑制FGF21-ERK通路促进肝脏Cyp7a1表达和胆汁酸合成。这一研究成果于2024年11月20日在线发表在国际学术期刊《中国药理学报》上。

研究人员表示，支链氨基酸（BCAA），包括亮氨酸、异亮氨酸和缬氨酸，已被与代谢和心血管疾病相关联。BCAA的稳态通过其代谢途径严格调控。BCKA脱氢酶（BCKD）复合体是BCAA代谢的限速步骤。线粒体磷酸酶2C（PP2Cm）去磷酸化BCKD E1α亚基并激活BCKD复合体。PP2Cm缺乏会损害BCAA的代谢，导致血浆BCAA浓度升高。新兴证据表明，胆汁酸是葡萄糖、脂质和能量代谢的关键调节因子。

研究人员探讨了BCAA和胆汁酸代谢之间是否存在直接联系。野生型小鼠被喂食正常BCAA或高BCAA饮食，而PP2Cm缺乏小鼠则喂食正常饮食14周。在组织采集之前，小鼠禁食6小时以排除由于即时进食引起的代谢变化。研究人员发现，野生型小鼠在喂食高BCAA饮食以及PP2Cm缺乏小鼠喂食正常饮食后，组织和粪便中的胆汁酸显著升高。这些小鼠表现出肝脏胆汁酸合成限速酶——胆固醇7α-羟化酶（CYP7A1）的表达显著增加，以及血浆中CYP7A1下游自由扩散代谢物7α-羟基-4-胆甾烯-3-酮（C4）的升高。

研究人员还发现，BCAA能诱导培养的肝细胞中Cyp7a1的表达。在小鼠肝脏和培养的肝细胞中，研究人员证明了BCAA的升高抑制了成纤维生长因子21（FGF21）表达和ERK信号通路的活性。通过U0126（800nM）直接抑制ERK信号，可以显著诱导培养肝细胞中Cyp7a1的表达。此外，在小鼠肝脏和培养肝细胞中，重组FGF21蛋白的处理消除了BCAA诱导的Cyp7a1表达和对ERK信号通路的抑制作用。

综合来看，该研究揭示了BCAA和胆汁酸合成之间的直接联系。BCAA通过抑制FGF21-ERK信号通路促进肝脏Cyp7a1的表达和胆汁酸合成。BCAA调节的胆汁酸合成和稳态可能有助于为代谢紊乱的治疗开发新的治疗策略。

附：英文原文

Title: Branched-chain amino acids promote hepatic Cyp7a1 expression and bile acid synthesis via suppressing FGF21-ERK pathway

Author: Wang, Ji, Zhong, Meng-yu, Liu, Yun-xia, Yu, Jia-yu, Wang, Yi-bin, Zhang, Xue-jiao, Sun, Hai-peng

Issue&Volume: 2024-11-20

Abstract: Branched-chain amino acids (BCAAs) including leucine, isoleucine and valine have been linked with metabolic and cardiovascular diseases. BCAAs homeostasis is tightly controlled by their catabolic pathway. BCKA dehydrogenase (BCKD) complex is the rate-limiting step for BCAA catabolism. Mitochondrial phosphatase 2C (PP2Cm) dephosphorylates the BCKD E1alpha subunit and activates BCKD complex. Deficiency of PP2Cm impairs BCAA catabolism, leading to higher plasma BCAA concentrations. Emerging evidence shows that bile acids are key regulators of glucose, lipid and energy metabolism. In this study, we investigated whether a direct link existed between BCAAs and bile acids metabolism. Wild-type mice were fed with normal-BCAA or high-BCAA diet, while PP2Cm deficiency mice were fed with normal chow for 14 weeks. The mice were fasted for 6h before tissue harvest to exclude metabolic changes due to immediate food intake. We showed that the bile acids in tissues and feces were significantly elevated in wild-type mice fed with high-BCAA diet as well as in PP2Cm deficiency mice fed with normal chow. These mice displayed significantly increased expression of cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme of bile acid synthesis in liver, and 7α-hydroxy-4-cholesten-3-one (C4), a freely diffusible metabolite downstream of CYP7A1 in plasma. BCAAs induced Cyp7a1 expression in cultured hepatocytes. In mouse liver and cultured hepatocytes, we demonstrated that elevated BCAAs inhibited fibroblast growth factor 21 (FGF21) expression and ERK signaling pathway. Direct inhibition of ERK by U0126 (800nM) markedly induced Cyp7a1 expression in cultured hepatocytes. Moreover, the induced Cyp7a1 expression and inhibitory effects of BCAAs on ERK signaling pathway were abolished by treatment with recombinant FGF21 protein in mouse liver and cultured hepatocytes. Collectively, this study demonstrates a direct link between BCAAs and bile acid synthesis. BCAAs promotes Cyp7a1 expression and bile acid synthesis in liver via inhibiting FGF21-ERK signaling pathway. BCAAs-regulated bile acid synthesis and homeostasis may contribute to developing novel therapeutic strategies for the treatment of metabolic disorders.

DOI: 10.1038/s41401-024-01417-2

Source: https://www.nature.com/articles/s41401-024-01417-2