蛋白激酶B
PI3K/AKT/mTOR通路
胰岛素抵抗
胰岛素受体
内分泌学
细胞生物学
内科学
化学
生物
mTORC1型
癌症研究
脂肪组织
细胞生长
下调和上调
胰岛素
磷酸化
细胞凋亡
mTORC2型
作者
Richa Aggarwal,Zhechu Peng,Ni Zeng,Joshua Silva,Lina He,Jingyu Chen,Anketse Debebe,Taojian Tu,Mario M. Alba,Chien-Yu Chen,Eileen X. Stiles,Handan Hong,Bangyan L. Stiles
标识
DOI:10.1016/j.ajpath.2021.09.008
摘要
High circulating lipids occurring in obese individuals and insulin-resistant patients are considered a contributing factor to type 2 diabetes. Exposure to high lipids is proposed to both protect and damage beta-cells under different circumstances. Here, by feeding mice a high-fat diet (HFD) for 2 weeks up to 14 months, the authors showed HFD initially causes the beta-cells to expand in population, whereas long-term exposure to HFD is associated with failure of beta-cells and the inability of animals to respond to glucose challenge. To prevent the failure of beta-cells and the development of type 2 diabetes, the molecular mechanisms that underlie this biphasic response of beta-cells to lipid exposure were explored. Using palmitic acid (PA) in cultured beta-cells and islets, the authors demonstrated that chronic exposure to lipids leads to reduced viability and inhibition of cell cycle progression concurrent with down-regulation of a pro-growth/survival kinase AKT, independent of glucose. This AKT down-regulation by PA is correlated with the induction of mTOR/S6K activity. Inhibiting mTOR activity with rapamycin induces Raptor and restores AKT activity, allowing beta-cells to gain proliferation capacity that was lost after HFD exposure. In summary, a novel mechanism for which lipid exposure may cause the dipole effects on beta-cell growth was elucidated, where mTOR acts as a lipid sensor. These mechanisms can be novel targets for future therapeutic developments.
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