Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.
Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI.
Hepatology. 2019 Feb;69(2):860-875. doi: 10.1002/hep.30229. Epub 2018 Dec 31.
Gastric mechanistic target of rapamycin (mTOR) signaling is inversely associated with the expression and secretion of ghrelin, a 28-aa peptide hormone produced by gastric X/A-like cells. Ghrelin contributes to obesity and hepatic steatosis. We sought to control global lipid metabolism via the manipulation of gastric mTOR signaling in X/A-like cells. We established a ghrl-cre transgene in which the Cre enzyme is expressed in X/A-like cells under the control of the ghrelin-promoter. mTOR and tuberous sclerosis 1 (TSC1) mice were separately bred with ghrl-cre mice to generate mTOR-ghrl-cre or TSC1-ghrl-cre mice, within which mTOR signaling was suppressed or activated, respectively. Lipid metabolism in liver and adipose depots was analyzed. Under the control of the ghrelin-promoter, the Cre enzyme was exclusively expressed in stomach X/A-like cells in adult animals. Knockout of mTOR in X/A-like cells increased circulating acyl-ghrelin and promoted hepatic lipogenesis with effects on adipose depots. Activation of mTOR signaling by deletion of its upstream inhibitor, TSC1, decreased ghrelin expression and secretion, altering lipid metabolism as evidenced by resistance to high-fat diet-induced obesity and hepatic steatosis. Both ghrelin administration and injection of rapamycin, an inhibitor of mTOR, altered the phenotypes of TSC1-ghrl-cre mice. Conclusion: Gastric mTOR signaling in X/A-like cells contributes to organism lipid homeostasis by regulating hepatic and adipose lipid metabolism. Gastric mTOR signaling may provide an alternative strategy for intervention in lipid disorders.
胃机械靶点雷帕霉素 (mTOR) 信号与胃 X/A 样细胞产生的 28 个氨基酸肽激素 ghrelin 的表达和分泌呈负相关。Ghrelin 有助于肥胖和肝脂肪变性。我们试图通过操纵 X/A 样细胞中的胃 mTOR 信号来控制全身脂质代谢。我们建立了一种 ghrl-cre 转基因，其中 Cre 酶在 ghrelin 启动子的控制下在 X/A 样细胞中表达。mTOR 和结节性硬化症 1 (TSC1) 小鼠分别与 ghrl-cre 小鼠交配，生成 mTOR-ghrl-cre 或 TSC1-ghrl-cre 小鼠，分别抑制或激活 mTOR 信号。分析肝脏和脂肪组织中的脂质代谢。在 ghrelin 启动子的控制下，成年动物中 Cre 酶仅在胃 X/A 样细胞中表达。X/A 样细胞中 mTOR 的缺失增加了循环酰基-ghrelin，并促进了肝脂肪生成，对脂肪组织有影响。通过删除其上游抑制剂 TSC1 激活 mTOR 信号会降低 ghrelin 的表达和分泌，改变脂质代谢，如抵抗高脂肪饮食诱导的肥胖和肝脂肪变性。ghrelin 的给药和 mTOR 抑制剂 rapamycin 的注射改变了 TSC1-ghrl-cre 小鼠的表型。结论：X/A 样细胞中的胃 mTOR 信号通过调节肝和脂肪脂质代谢有助于机体脂质稳态。胃 mTOR 信号可能为干预脂质紊乱提供一种替代策略。
