Nonalcoholic fatty liver disease (NAFLD) is an independent predictor of systemic insulin resistance and type 2 diabetes mellitus (T2DM). However, converse correlates between excess liver fat content and β-cell function remain equivocal. Specifically, how the accumulation of liver fat consequent to the enhanced de novo lipogenesis (DNL) leads to pancreatic β-cell failure and eventually to T2DM is elusive. Here we have identified lowmolecular-weight calcium-binding protein S100A6 or calcyclin inhibits glucose-stimulated insulin secretion (GSIS) from β-cells through activation of the receptor for the advanced glycation end product (RAGE) and diminution of mitochondrial respiration. Serum S100A6 level is elevated both in human NAFLD patients and in a high-fat diet (HFD) induced mouse model of NAFLD. While serum S100A6 levels are negatively associated with β-cell insulin secretory capacity in human patients, depletion of hepatic S100A6 improves GSIS and glycemia in mice suggesting that S100A6 contributes to the pathophysiology of diabetes in NAFLD. Moreover, transcriptional induction of hepatic S100A6 is driven by the potent regulator of DNL, carbohydrate response element-binding protein (ChREBP), and ectopic expression of ChREBP in the liver suppresses GSIS in a S100A6 sensitive manner. Together, these data suggest elevated serum levels of S100A6 may serve as a biomarker in identifying NAFLD patients with a heightened risk of developing β-cell dysfunction. Overall, our data, implicate S100A6 as a hitherto unknown hepatokine to be activated by ChREBP and participates in the hepato-pancreatic communication to impair insulin secretion and drive the development of T2DM in NAFLD.

中文翻译：

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肝源性 S100A6 促进 NAFLD 中的 β 细胞功能障碍

非酒精性脂肪性肝病 (NAFLD) 是全身性胰岛素抵抗和 2 型糖尿病 (T2DM) 的独立预测因子。然而，肝脏脂肪含量过高与 β 细胞功能之间的反向相关性仍然模棱两可。具体而言，脂肪从头合成 (DNL) 增强后肝脏脂肪的积累如何导致胰腺 β 细胞衰竭并最终导致 T2DM 尚不清楚。在这里，我们已经确定低分子量钙结合蛋白 S100A6 或钙周期蛋白通过激活晚期糖基化终产物 (RAGE) 受体和减少线粒体呼吸来抑制 β 细胞的葡萄糖刺激胰岛素分泌 (GSIS)。血清 S100A6 水平在人类 NAFLD 患者和高脂肪饮食 (HFD) 诱导的 NAFLD 小鼠模型中均升高。虽然血清 S100A6 水平与人类患者的 β 细胞胰岛素分泌能力呈负相关，但肝脏 S100A6 的消耗可改善小鼠的 GSIS 和血糖，这表明 S100A6 有助于 NAFLD 中糖尿病的病理生理学。此外，肝脏 S100A6 的转录诱导由 DNL 的有效调节因子碳水化合物反应元件结合蛋白 (ChREBP) 驱动，肝脏中 ChREBP 的异位表达以 S100A6 敏感方式抑制 GSIS。总之，这些数据表明升高的 S100A6 血清水平可以作为生物标志物来识别具有更高的 β 细胞功能障碍风险的 NAFLD 患者。总的来说，我们的数据，