Branched-Chain Amino Acids Exacerbate Obesity-Related Hepatic Glucose and Lipid Metabolic Disorders via Attenuating Akt2 Signaling
Branched-Chain Amino Acids Exacerbate Obesity-Related Hepatic Glucose and Lipid Metabolic Disorders via Attenuating Akt2 Signaling
复制标题
支链氨基酸通过减弱 Akt2 信号传导加剧肥胖相关的肝葡萄糖和脂质代谢紊乱。
DOI：
10.2337/db19-0920
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发表时间：
2020-06-01
期刊：
影响因子：
7.7
通讯作者：
Tao, Ling
中科院分区：
文献类型：
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作者：
Zhao, Huishou;Zhang, Fuyang;Tao, Ling
支链氨基酸（BCAAs）与肥胖相关代谢紊乱的进展有关，包括2型糖尿病和非酒精性脂肪肝疾病。然而，支链氨基酸是否会破坏肝脏糖脂代谢的稳态仍不清楚。在本研究中，我们观察到补充支链氨基酸可显著降低高脂肪饮食引起的肝脏脂质积累，同时增加血浆脂质水平，促进肌肉和肾脏脂质积累。进一步的研究表明，补充支链氨基酸可显著增加HF饮食诱导肥胖（DIO）小鼠的肝脏糖异生并抑制肝脏脂肪生成。这些表型是由于通过mTORC1-和mtorc2依赖途径的Akt2信号严重衰减造成的。BCAAs/支链α -酮酸（BCKAs）通过mTORC1和mTORC2信号通路慢性抑制Akt2激活，并通过mTORC2途径促进Akt2泛素-蛋白酶体依赖性降解。此外，E3连接酶Mul1在BCAAs/ bckas - mtorc2诱导的Akt2泛素依赖性降解中发挥了重要作用。我们还证明BCAAs通过阻断Akt2/SREBP1/INSIG2a信号通路抑制肝脏脂肪生成，并通过调节Akt2/ fox01信号通路增加肝糖生成。综上所述，这些数据表明，在DIO小鼠中，补充BCAAs会导致严重的肝脏代谢紊乱和严重的肝脏胰岛素抵抗：胰岛素不仅不能抑制糖异生，还不能激活脂肪生成。干预BCAA代谢是严重胰岛素抵抗疾病的潜在治疗靶点。
Branched chain amino acids (BCAAs) are associated with the progression of obesity-related metabolic disorders, including type 2 diabetes and nonalcoholic fatty liver disease. However, whether BCAAs disrupt the homeostasis of hepatic glucose and lipid metabolism remains unknown. In this study, we observed that BCAAs supplementation significantly reduced high-fat (HF) diet-induced hepatic lipid accumulation while increasing the plasma lipid levels and promoting muscular and renal lipid accumulation. Further studies demonstrated that BCAAs supplementation significantly increased hepatic gluconeogenesis and suppressed hepatic lipogenesis in HF diet-induced obese (DIO) mice. These phenotypes resulted from severe attenuation of Akt2 signaling via mTORC1- and mTORC2-dependent pathways. BCAAs/branched-chain alpha-keto acids (BCKAs) chronically suppressed Akt2 activation through mTORC1 and mTORC2 signaling and promoted Akt2 ubiquitin-proteasome-dependent degradation through the mTORC2 pathway. Moreover, the E3 ligase Mul1 played an essential role in BCAAs/BCKAs-mTORC2-induced Akt2 ubiquitin-dependent degradation. We also demonstrated that BCAAs inhibited hepatic lipogenesis by blocking Akt2/SREBP1/INSIG2a signaling and increased hepatic glycogenesis by regulating Akt2/Foxo1 signaling. Collectively, these data demonstrate that in DIO mice, BCAAs supplementation resulted in serious hepatic metabolic disorder and severe liver insulin resistance: insulin failed to not only suppress gluconeogenesis but also activate lipogenesis. Intervening BCAA metabolism is a potential therapeutic target for severe insulin-resistant disease.