Acid sphingomyelinase regulates glucose and lipid metabolism in hepatocytes through AKT activation and AMP-activated protein kinase suppression.
Acid sphingomyelinase regulates glucose and lipid metabolism in hepatocytes through AKT activation and AMP-activated protein kinase suppression.
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DOI：
10.1096/fj.10-168351
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发表时间：
2011-04
期刊：
影响因子：
--
通讯作者：
Seishima M
中科院分区：
文献类型：
--
作者：
Osawa Y;Seki E;Kodama Y;Suetsugu A;Miura K;Adachi M;Ito H;Shiratori Y;Banno Y;Olefsky JM;Nagaki M;Moriwaki H;Brenner DA;Seishima M
酸性鞘磷脂酶（ASM）调节鞘脂（包括神经酰胺和鞘氨醇-1-磷酸（S1 P））的稳态。由于鞘脂调节AKT活化，我们研究了ASM在肝脏葡萄糖和脂质代谢中的作用。最初，我们通过腺病毒载体（Ad 5 ASM）在野生型和糖尿病db/db小鼠的肝脏中过表达ASM。在这些小鼠中，葡萄糖耐量得到改善，肝脏中的糖原和脂质积累增加。使用原代培养的肝细胞，我们证实ASM通过激活AKT和糖原合成酶激酶-3 β增加葡萄糖摄取、糖原沉积和脂质积累。此外，ASM诱导的葡萄糖转运蛋白2的上调伴随着抑制AMP激活的蛋白激酶（AMPK）磷酸化。鞘氨醇激酶-1（SphK 1）的缺失减少了ASM介导的AKT磷酸化，但外源性S1 P诱导肝细胞中AKT活化。相反，SphK 1缺陷不影响AMPK激活。这些结果表明，SphK/S1 P途径是必需的ASM介导的AKT激活，但不是AMPK失活。最后，我们发现高剂量葡萄糖处理增加了野生型肝细胞中的糖原沉积和脂质积累，但在ASM−/−细胞中没有。这一结果与ASM−/−小鼠的葡萄糖耐受不良一致。总之，ASM调节AKT激活和AMPK失活，从而调节肝脏中的葡萄糖和脂质代谢。Osawa，Y.，Seki，E.，科玉，Y.，Suetsugu，A.，Miura，K.，阿达奇，M.，伊藤，H.，Shiratori，Y.，Banno，Y.，Olefsky，J. M.，Nagaki，M.，Moriwaki，H.，Brenner，D.一、Seishima，M.酸性鞘磷脂酶通过激活AKT和抑制AMP激活的蛋白激酶来调节肝细胞中的葡萄糖和脂质代谢。
Acid sphingomyelinase (ASM) regulates the homeostasis of sphingolipids, including ceramides and sphingosine-1-phosphate (S1P). Because sphingolipids regulate AKT activation, we investigated the role of ASM in hepatic glucose and lipid metabolism. Initially, we overexpressed ASM in the livers of wild-type and diabetic db/db mice by adenovirus vector (Ad5ASM). In these mice, glucose tolerance was improved, and glycogen and lipid accumulation in the liver were increased. Using primary cultured hepatocytes, we confirmed that ASM increased glucose uptake, glycogen deposition, and lipid accumulation through activation of AKT and glycogen synthase kinase-3β. In addition, ASM induced up-regulation of glucose transporter 2 accompanied by suppression of AMP-activated protein kinase (AMPK) phosphorylation. Loss of sphingosine kinase-1 (SphK1) diminished ASM-mediated AKT phosphorylation, but exogenous S1P induced AKT activation in hepatocytes. In contrast, SphK1 deficiency did not affect AMPK activation. These results suggest that the SphK/S1P pathway is required for ASM-mediated AKT activation but not for AMPK inactivation. Finally, we found that treatment with high-dose glucose increased glycogen deposition and lipid accumulation in wild-type hepatocytes but not in ASM−/− cells. This result is consistent with glucose intolerance in ASM−/− mice. In conclusion, ASM modulates AKT activation and AMPK inactivation, thus regulating glucose and lipid metabolism in the liver.—Osawa, Y., Seki, E., Kodama, Y., Suetsugu, A., Miura, K., Adachi, M., Ito, H., Shiratori, Y., Banno, Y., Olefsky, J. M., Nagaki, M., Moriwaki, H., Brenner, D. A., Seishima, M. Acid sphingomyelinase regulates glucose and lipid metabolism in hepatocytes through AKT activation and AMP-activated protein kinase suppression.
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影响因子：
5.2
作者：
Glimcher LH;Lee AH
通讯作者：
Lee AH
影响因子：
64.8
作者：
OLIVERA, A;SPIEGEL, S
通讯作者：
SPIEGEL, S
影响因子：
4.8
作者：
Osawa, Y;Uchinami, H;Brenner, DA
通讯作者：
Brenner, DA
影响因子：
7.7
作者：
Foretz, M;Ancellin, N;Viollet, B
通讯作者：
Viollet, B
DOI：
10.1152/ajpendo.00172.2004
发表时间：
2004-11-01
影响因子：
5.1
作者：
Gonzalez, AA;Kumar, R;Saupe, KW
通讯作者：
Saupe, KW