Ghrelin promotes hepatic lipogenesis by activation of mTOR-PPARγ signaling pathway
Ghrelin promotes hepatic lipogenesis by activation of mTOR-PPARγ signaling pathway
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Ghrelin 通过激活 mTOR-PPAR gamma 信号通路促进肝脏脂肪生成
DOI：
10.1073/pnas.1411571111
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发表时间：
2014-09-09
影响因子：
11.1
通讯作者：
Zhang, Weizhen
中科院分区：
文献类型：
--
作者：
Li, Ziru;Xu, Geyang;Zhang, Weizhen
虽然胃饥饿素已被证明通过中枢机制刺激能量摄入和储存，但其对肝脏脂质代谢的影响在很大程度上仍未明确。胃饥饿素受体拮抗剂或基因缺失通过抑制新生脂肪生成显著降低肥胖相关的肝脏脂肪变性，而外源性胃饥饿素刺激脂肪生成，导致小鼠肝脏脂质积累。胃饥饿素的作用是通过其受体在肝细胞上的直接激活介导的。培养的肝细胞对胃饥饿素的反应是增加脂肪含量和脂肪生成相关基因的表达。在培养的肝细胞中，胃饥饿素增加了哺乳动物雷帕霉素（mTOR）信号传导下游靶点S6的磷酸化，而在db/db小鼠中，胃饥饿素受体拮抗剂降低了S6的肝脏磷酸化。雷帕霉素对mTOR信号的抑制显著减弱了胃饥饿素诱导的肝细胞脂肪生成的上调，而通过删除TSC1激活肝脏mTOR信号则增加了肝脏脂肪生成。通过与过氧化物酶体增殖激活受体γ (PPAR γ)相互作用，mTOR介导胃饥饿素诱导的肝细胞脂肪生成上调。在培养的肝细胞和PPAR γ基因缺失小鼠中，PPAR γ拮抗剂显著减弱了ghrelin对肝脏脂肪生成的刺激作用。我们的研究表明，胃饥饿素通过mTOR-PPAR信号通路激活其在肝细胞上的受体，促进脂肪生成。
Although ghrelin has been demonstrated to stimulate energy intake and storage through a central mechanism, its effect on hepatic lipid metabolism remains largely uncharacterized. Ghrelin receptor antagonism or gene deletion significantly decreased obesity-associated hepatic steatosis by suppression of de novo lipogenesis, whereas exogenous ghrelin stimulated lipogenesis, leading to hepatic lipid accumulation in mice. The effects of ghrelin were mediated by direct activation of its receptor on hepatocytes. Cultured hepatocytes responded to ghrelin with increased lipid content and expression of lipogenesis-related genes. Ghrelin increased phosphorylation of S6, the downstream target of mammalian target of rapamycin (mTOR) signaling in cultured hepatocytes, whereas ghrelin receptor antagonism reduced hepatic phosphorylation of S6 in db/db mice. Inhibition of mTOR signaling by rapamycin markedly attenuated ghrelin-induced up-regulation of lipogenesis in hepatocytes, whereas activation of hepatic mTOR signaling by deletion of TSC1 increased hepatic lipogenesis. By interacting with peroxisome proliferator-activated receptor-gamma (PPAR gamma), mTOR mediates the ghrelin-induced up-regulation of lipogenesis in hepatocytes. The stimulatory effect of ghrelin on hepatic lipogenesis was significantly attenuated by PPAR gamma antagonism in cultured hepatocytes and in PPAR gamma gene-deficient mice. Our study indicates that ghrelin activates its receptor on hepatocytes to promote lipogenesis via a mechanism involving the mTOR-PPAR gamma signaling pathway.