Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China.
J Cell Mol Med. 2021 Jun;25(11):5250-5259. doi: 10.1111/jcmm.16532. Epub 2021 May 4.
Lipotoxicity has been shown to cause dysfunction of many organs and tissues. However, it is unclear whether lipotoxicity is harmful to the somatotrophs, a kind of cell that synthesize growth hormone (GH) in the pituitary. In this study, we performed an epidemiological study, serum levels of triglyceride (TG) and GH showed a negative correlation, even after adjustment for potential confounders. In an animal study, male Sprague-Dawley rats were fed a high-fat diet (HFD) or a control diet for 28 weeks. HFD rats showed impaired GH synthesis, resulting in a decrease in circulating GH levels. The expression of pituitary Pit-1, a key transcription factor of GH, was inhibited. We found that the inositol-requiring enzyme 1α (IRE1α) pathway of endoplasmic reticulum (ER) stress was triggered in HFD rat pituitary glands and palmitic acid-treated GH3 cells, respectively. On the contrary, applying 4-phenyl butyric acid (4-PBA) to alleviate ER stress or 4µ8c to specifically block the IRE1α pathway attenuated the impairment of both Pit-1 and GH expression. In conclusion, we demonstrated that lipotoxicity directly inhibits the synthesis of GH, probably by reducing Pit-1 expression. The IRE1α signaling pathway of ER stress may play an important role in this process.
脂毒性已被证明会导致许多器官和组织的功能障碍。然而，脂毒性是否对合成生长激素（GH）的垂体细胞有损害尚不清楚。在这项研究中，我们进行了一项流行病学研究，血清甘油三酯（TG）和 GH 水平呈负相关，即使在调整了潜在混杂因素后也是如此。在一项动物研究中，雄性 Sprague-Dawley 大鼠用高脂肪饮食（HFD）或对照饮食喂养 28 周。HFD 大鼠表现出 GH 合成受损，导致循环 GH 水平下降。GH 的关键转录因子 Pit-1 在垂体中的表达受到抑制。我们发现内质网（ER）应激的肌醇需求酶 1α（IRE1α）途径分别在 HFD 大鼠垂体和棕榈酸处理的 GH3 细胞中被触发。相反，应用 4-苯基丁酸（4-PBA）缓解 ER 应激或 4µ8c 特异性阻断 IRE1α 途径可减轻 Pit-1 和 GH 表达的损害。总之，我们证明了脂毒性直接抑制 GH 的合成，可能是通过降低 Pit-1 的表达。ER 应激的 IRE1α 信号通路可能在这个过程中发挥重要作用。
