Hyperlipidemia-induced hepassocin in the liver contributes to insulin resistance in skeletal muscle
Hyperlipidemia-induced hepassocin in the liver contributes to insulin resistance in skeletal muscle
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DOI：
10.1016/j.mce.2017.10.014
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发表时间：
2018-07-15
影响因子：
4.1
通讯作者：
Jeong, Ji Hoon
中科院分区：
文献类型：
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作者：
Jung, Tae Woo;Chung, Yoon Hee;Jeong, Ji Hoon
肝磷脂（HPS）最近被确定为一种导致肝脂肪变性的新型肝因子。然而，HPS在肥胖骨骼肌胰岛素抵抗发展中的作用尚不清楚。研究了高脂血症对小鼠原代肝细胞和肝脏HPS表达的影响。利用特定基因或抑制剂的小干扰（si） rna探索hps介导的信号通路。我们发现棕榈酸盐处理原代肝细胞可以通过C/EBP β介导的转录激活诱导HPS表达。此外，在高脂肪饮食（HFD）喂养或tunicamycin处理的小鼠肝脏中观察到HPS表达增加。4-苯基丁酸（4-BPA）（内质网应激抑制剂）预处理和siRNA抑制p38可消除棕榈酸酯对原代肝细胞HPS表达的影响。重组HPS处理分化的C2C12细胞导致c-Jun n -末端激酶（JNK）磷酸化，并以剂量依赖的方式损害胰岛素敏感性。sirna介导的JNK抑制降低了HPS对胰岛素信号传导的影响。此外，siRNA抑制表皮生长因子受体（EGFR）可减轻hps诱导的JNK磷酸化和胰岛素抵抗。此外，HPS不影响分化的C2C12细胞的炎症和内质网应激。综上所述，我们阐明了棕榈酸盐诱导的内质网应激可增加肝细胞中HPS的表达，并通过EGFR/ jnk介导的途径进一步促进骨骼肌胰岛素抵抗的发展。综上所述，我们认为HPS可能是肥胖相关胰岛素抵抗的治疗靶点。(C) 2017 Elsevier B.V.版权所有
Hepassocin (HPS) has recently been identified as a novel hepatokine that causes hepatic steatosis. However, the role of HPS in the development of insulin resistance in skeletal muscle under obesity remains unclear. The effect of hyperlipidemia on hepatic HPS expression was evaluated in primary hepatocytes and liver of mice. HPS-mediated signal pathways were explored using small interfering (si) RNAs of specific genes or inhibitors. We found that treatment of primary hepatocytes with palmitate could induce HPS expression through C/EBP beta-mediated transcriptional activation. Furthermore, increased HPS expression was observed in the liver of high fat diet (HFD)-fed or tunicamycin-treated mice. Pretreatment with 4-phenylbutyrate (4-BPA) (an endoplasmic reticulum (ER) stress inhibitor) and suppression of p38 by siRNA abrogated the effect of palmitate on HPS expression in primary hepatocytes. Treatment of differentiated C2C12 cells with recombinant HPS caused c-Jun N-terminal kinase (JNK) phosphorylation and impairment of insulin sensitivity in a dose-dependent manner. siRNA-mediated suppression of JNK reduced the effect of HPS on insulin signaling. Furthermore, the suppression of epidermal growth factor receptor (EGFR) by siRNA mitigated both HPS-induced JNK phosphorylation and insulin resistance. In addition, HPS did not affect inflammation and ER stress in differentiated C2C12 cells. In conclusion, we elucidated that ER stress induced by palmitate could increase the expression of HPS in hepatocytes and further contribute to the development of insulin resistance in skeletal muscle via EGFR/JNK-mediated pathway. Taken together, we suggest that HPS could be a therapeutic target for obesity-linked insulin resistance. (C) 2017 Elsevier B.V. All rights reserved.