Regulation of hepatic insulin signaling and glucose homeostasis by sphingosine kinase 2.
Regulation of hepatic insulin signaling and glucose homeostasis by sphingosine kinase 2.
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DOI：
10.1073/pnas.2007856117
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发表时间：
2020-09-29
影响因子：
11.1
通讯作者：
Qi Y
中科院分区：
文献类型：
--
作者：
Aji G;Huang Y;Ng ML;Wang W;Lan T;Li M;Li Y;Chen Q;Li R;Yan S;Tran C;Burchfield JG;Couttas TA;Chen J;Chung LH;Liu D;Wadham C;Hogg PJ;Gao X;Vadas MA;Gamble JR;Don AS;Xia P;Qi Y
肝脏胰岛素抵抗是2型糖尿病发生发展的主要致病因素，常与肝脏脂质调节异常有关。鞘脂是肝脏中的一类必需脂质，其中鞘氨醇激酶2（SphK 2）是其分解代谢途径中的关键酶。然而，SphK 2及其相关鞘脂在肝胰岛素抵抗中的作用仍然是难以捉摸的。在这里，我们产生了肝脏特异性SphK 2基因敲除小鼠，证明肝脏中的SphK 2对胰岛素敏感性和葡萄糖稳态至关重要。我们还确定鞘氨醇作为一个真正的内源性抑制剂的肝脏胰岛素信号。这些发现为SphK 2和鞘氨醇提供了生理学见解，这可能是胰岛素抵抗和糖尿病管理的治疗靶点。鞘脂失调通常与胰岛素抵抗相关，而控制鞘脂代谢的酶正在成为改善胰岛素敏感性的治疗靶点。我们在此报告，鞘氨醇激酶2（SphK 2），在鞘脂catalysts中的关键酶，在肝脏胰岛素信号转导和葡萄糖稳态在体外和体内的调节中起着至关重要的作用。肝细胞特异性Sphk 2基因敲除小鼠表现出明显的胰岛素抵抗和葡萄糖耐受不良。同样，SphK 2缺陷型肝细胞对胰岛素诱导的磷酸肌醇3-激酶（PI 3 K）-Akt-FoxO 1途径活化和肝葡萄糖生成升高具有抗性。从机制上讲，SphK 2缺乏导致鞘氨醇的积累，进而通过抑制肝细胞中的PI 3 K活化来抑制肝胰岛素信号传导。在SphK 2缺陷的肝细胞中，无论是重新表达功能性SphK 2还是抑制鞘氨醇产生的β-葡聚糖都能恢复胰岛素敏感性。总之，目前的研究提供了实验结果和机制数据，表明肝脏中的SphK 2和鞘氨醇是胰岛素敏感性和葡萄糖稳态的关键调节剂。
Hepatic insulin resistance is a chief pathogenic determinant in the development of type 2 diabetes, which is often associated with abnormal hepatic lipid regulation. Sphingolipids are a class of essential lipids in the liver, where sphingosine kinase 2 (SphK2) is a key enzyme in their catabolic pathway. However, roles of SphK2 and its related sphingolipids in hepatic insulin resistance remain elusive. Here we generate liver-specific Sphk2 knockout mice, demonstrating that SphK2 in the liver is essential for insulin sensitivity and glucose homeostasis. We also identify sphingosine as a bona fide endogenous inhibitor of hepatic insulin signaling. These findings provide physiological insights into SphK2 and sphingosine, which could be therapeutic targets for the management of insulin resistance and diabetes. Sphingolipid dysregulation is often associated with insulin resistance, while the enzymes controlling sphingolipid metabolism are emerging as therapeutic targets for improving insulin sensitivity. We report herein that sphingosine kinase 2 (SphK2), a key enzyme in sphingolipid catabolism, plays a critical role in the regulation of hepatic insulin signaling and glucose homeostasis both in vitro and in vivo. Hepatocyte-specific Sphk2 knockout mice exhibit pronounced insulin resistance and glucose intolerance. Likewise, SphK2-deficient hepatocytes are resistant to insulin-induced activation of the phosphoinositide 3-kinase (PI3K)-Akt-FoxO1 pathway and elevated hepatic glucose production. Mechanistically, SphK2 deficiency leads to the accumulation of sphingosine that, in turn, suppresses hepatic insulin signaling by inhibiting PI3K activation in hepatocytes. Either reexpressing functional SphK2 or pharmacologically inhibiting sphingosine production restores insulin sensitivity in SphK2-deficient hepatocytes. In conclusion, the current study provides both experimental findings and mechanistic data showing that SphK2 and sphingosine in the liver are critical regulators of insulin sensitivity and glucose homeostasis.
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DOI：
10.1038/nrendo.2017.80
发表时间：
2017-10
期刊：
Nature reviews. Endocrinology
影响因子：
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作者：
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影响因子：
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DOI：
10.1038/nrm.2017.107
发表时间：
2018-03
期刊：
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影响因子：
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作者：
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影响因子：
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Toker A