Cao Jia, Peng Jinghua, An Hongying, He Qiyi, Boronina Tatiana, Guo Shaodong, White Morris F, Cole Philip A, He Ling
Division of Metabolism, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
Department of Medicine, Southern Medical University, Guangzhou, 510515, China.
Nat Commun. 2017 Jul 25;8(1):131. doi: 10.1038/s41467-017-00163-w.
Diabetes and obesity are characterized by insulin resistance and chronic low-grade inflammation. An elevated plasma concentration of lipopolysaccharide (LPS) caused by increased intestinal permeability during diet-induced obesity promotes insulin resistance in mice. Here, we show that LPS induces endoplasmic reticulum (ER) stress and protein levels of P300, an acetyltransferase involved in glucose production. In high-fat diet fed and genetically obese ob/ob mice, P300 translocates from the nucleus into the cytoplasm of hepatocytes. We also demonstrate that LPS activates the transcription factor XBP1 via the ER stress sensor IRE1, resulting in the induction of P300 which, in turn, acetylates IRS1/2, inhibits its association with the insulin receptor, and disrupts insulin signaling. Pharmacological inhibition of P300 acetyltransferase activity by a specific inhibitor improves insulin sensitivity and decreases hyperglycemia in obese mice. We suggest that P300 acetyltransferase activity may be a promising therapeutic target for the treatment of obese patients.Elevated plasma LPS levels have been associated with insulin resistance. Here Cao et al. show that LPS induces ER stress and P300 activity via the XBP1/IRE1 pathway. P300 acetylates IRS1/2 and inhibits its binding with the insulin receptor. The consequent impairment of insulin signaling can be rescued by pharmacological inhibition of P300.
糖尿病和肥胖症的特征是胰岛素抵抗和慢性低度炎症。饮食诱导的肥胖期间肠道通透性增加导致血浆脂多糖（LPS）浓度升高，从而促进小鼠的胰岛素抵抗。在此，我们表明LPS诱导内质网（ER）应激以及参与葡萄糖生成的乙酰转移酶P300的蛋白水平升高。在高脂饮食喂养的和基因肥胖的ob/ob小鼠中，P300从细胞核转移至肝细胞的细胞质中。我们还证明，LPS通过ER应激传感器IRE1激活转录因子XBP1，从而诱导P300，而P300反过来会使IRS1/2乙酰化，抑制其与胰岛素受体的结合，并破坏胰岛素信号传导。用一种特异性抑制剂对P300乙酰转移酶活性进行药理学抑制可改善肥胖小鼠的胰岛素敏感性并降低高血糖症。我们认为，P300乙酰转移酶活性可能是治疗肥胖患者的一个有前景的治疗靶点。血浆LPS水平升高与胰岛素抵抗有关。在此，曹等人表明，LPS通过XBP1/IRE1途径诱导ER应激和P300活性。P300使IRS1/2乙酰化并抑制其与胰岛素受体的结合。对P300进行药理学抑制可挽救由此导致的胰岛素信号传导受损。
