Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy.
Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy.
复制标题
支链氨基酸通过促进脂肪细胞脂解和抑制肝自噬导致肥胖/糖尿病小鼠肝损伤
DOI：
10.1016/j.ebiom.2016.10.013
复制
发表时间：
2016-11
期刊：
影响因子：
11.1
通讯作者：
Tao L
中科院分区：
文献类型：
--
作者：
Zhang F;Zhao S;Yan W;Xia Y;Chen X;Wang W;Zhang J;Gao C;Peng C;Yan F;Zhao H;Lian K;Lee Y;Zhang L;Lau WB;Ma X;Tao L
西方的肉类饮食富含蛋白质和脂肪。虽然高脂饮食（HFD）对肝脏结构和功能的危害性影响已得到公认，但高蛋白摄入的共同存在是否有助于或防止HF诱导的肝损伤仍不清楚。增加支链氨基酸（BCAA，必需氨基酸占总蛋白质摄入量的20%）的摄入量可以减轻体重。然而，循环BCAA升高与非酒精性脂肪肝疾病和损伤有关。造成这种困境的机制尚不清楚;支链氨基酸在HF诱导的肝损伤中的作用尚不清楚。利用HFD或HFD + BCAA模型，我们证明了BCAA补充剂减弱了HFD诱导的体重增加，减少了脂肪量，激活了哺乳动物雷帕霉素靶蛋白（mTOR），抑制了肝脏脂肪生成酶，并降低了肝脏甘油三酯含量。然而，支链氨基酸造成显着的肝损伤HFD小鼠，加剧肝氧化应激，增加肝细胞凋亡，升高循环肝酶证明。与单纯HFD喂养的动物相比，HFD + BCAA组的血浆游离脂肪酸（FFA）水平显著进一步升高，这主要是由于AMPKα2介导的脂肪细胞脂解。脂解抑制使血浆FFA水平正常化，并改善胰岛素敏感性。令人惊讶的是，阻止脂肪分解未能消除BCA诱导的肝损伤。从机制上讲，BCAA激活肝脏mTOR可抑制脂质诱导的肝脏自噬，增加肝脏细胞凋亡，阻断肝脏FFA/甘油三酯转化，并增加肝细胞对FFA介导的脂毒性的敏感性。这些数据表明，支链氨基酸降低HFD诱导的体重，以异常脂解和高脂血症为代价，引起肝脂毒性。此外，支链氨基酸通过减少肝细胞中的脂肪生成和抑制自噬而直接加剧肝脂毒性。支链氨基酸通过涉及脂肪细胞和肝细胞的复杂机制引起肝损伤。在脂肪细胞中，BCAA激活AMPKα2并刺激脂解，增加血浆游离脂肪酸（FFA），从而导致肝脏FFA蓄积。在肝脏中，BCAA激活mTOR并抑制FFA向TG的转化和自噬，从而增强FFA的脂毒性。高脂饮食（HFD）诱导全身BCAA分解代谢缺陷。在HFD条件下，增加BCAA消耗进一步增加循环BCAA丰度。支链氨基酸促进脂肪细胞脂解通过激活AMPKα2诱导高脂血症循环FFA升高导致胰岛素抵抗和肝脏脂毒性。此外，BCAA激活肝脏mTOR，抑制脂肪生成和自噬，从而增加肝脏对FFA介导的脂毒性的易感性。由于BCAA富含蛋白质，我们的研究结果要求在肥胖和糖尿病患者中谨慎摄入高蛋白饮食，除非他们的BCAA代谢途径被确定为正常。
The Western meat-rich diet is both high in protein and fat. Although the hazardous effect of a high fat diet (HFD) upon liver structure and function is well recognized, whether the co-presence of high protein intake contributes to, or protects against, HF-induced hepatic injury remains unclear. Increased intake of branched chain amino acids (BCAA, essential amino acids compromising 20% of total protein intake) reduces body weight. However, elevated circulating BCAA is associated with non-alcoholic fatty liver disease and injury. The mechanisms responsible for this quandary remain unknown; the role of BCAA in HF-induced liver injury is unclear. Utilizing HFD or HFD + BCAA models, we demonstrated BCAA supplementation attenuated HFD-induced weight gain, decreased fat mass, activated mammalian target of rapamycin (mTOR), inhibited hepatic lipogenic enzymes, and reduced hepatic triglyceride content. However, BCAA caused significant hepatic damage in HFD mice, evidenced by exacerbated hepatic oxidative stress, increased hepatic apoptosis, and elevated circulation hepatic enzymes. Compared to solely HFD-fed animals, plasma levels of free fatty acids (FFA) in the HFD + BCAA group are significantly further increased, due largely to AMPKα2-mediated adipocyte lipolysis. Lipolysis inhibition normalized plasma FFA levels, and improved insulin sensitivity. Surprisingly, blocking lipolysis failed to abolish BCAA-induced liver injury. Mechanistically, hepatic mTOR activation by BCAA inhibited lipid-induced hepatic autophagy, increased hepatic apoptosis, blocked hepatic FFA/triglyceride conversion, and increased hepatocyte susceptibility to FFA-mediated lipotoxicity. These data demonstrated that BCAA reduces HFD-induced body weight, at the expense of abnormal lipolysis and hyperlipidemia, causing hepatic lipotoxicity. Furthermore, BCAA directly exacerbate hepatic lipotoxicity by reducing lipogenesis and inhibiting autophagy in the hepatocyte. BCAA cause hepatic injury via complex mechanisms involving both adipocytes and hepatic cells. In the adipocyte, BCAA activate AMPKα2 and stimulate lipolysis, increasing plasma free fatty acids (FFA), which in turn results in hepatic FFA accumulation. In the liver, BCAA activate mTOR and inhibit FFA to TG conversion and autophagy, intensifying FFA lipotoxicity. High fat diet (HFD) induces systemic BCAA catabolic defects. Under HFD conditions, increased BCAA consumption further increases circulating BCAA abundance. BCAA-enhanced adipocyte lipolysis induces hyperlipidemia through activating AMPKα2. Elevated circulating FFA results in insulin resistance and hepatic lipotoxicity. Moreover, BCAA activate hepatic mTOR, inhibit lipogenesis and autophagy, therefore increasing hepatic susceptibility to FFA-mediated lipotoxicity. As BCAA are abundant in protein, our results call for caution regarding the ingestion of high protein diets in obesity and diabetic individuals, unless their BCAA metabolic pathways are determined normal.