The adipose tissue triglyceride lipase ATGL/PNPLA2 is downregulated by insulin and TNF-alpha in 3T3-L1 adipocytes and is a target for transactivation by PPARgamma.
The adipose tissue triglyceride lipase ATGL/PNPLA2 is downregulated by insulin and TNF-alpha in 3T3-L1 adipocytes and is a target for transactivation by PPARgamma.
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发表时间：
2006
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通讯作者：
Ji Young Kim;Kristin Tillison;Jun‐Ho Lee;D. Rearick;C. Smas
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作者：
Ji Young Kim;Kristin Tillison;Jun‐Ho Lee;D. Rearick;C. Smas
激素敏感脂肪酶（HSL）缺失小鼠的最小脂肪表型表明，脂肪细胞中存在其他激素反应性脂肪酶。最近的研究发现了一种新的脂肪组织甘油三酯脂肪酶ATGL/PNPLA2/destnutrin/iPLA2zeta/TTS2.2 （ATGL）。我们之前通过鉴别筛选克隆了一个新的富含脂肪的转录物，最近确定了它与小鼠ATGL的身份。我们在这里报道了3T3-L1脂肪细胞中tnf - α和胰岛素对ATGL的调控，并确定ATGL是关键的脂肪生成转录因子PPARgamma转录激活的靶标。胰岛素在100 nM时导致ATGL转录显著降低，该转录可被PI 3-激酶和p70核糖体蛋白S6激酶抑制剂有效阻断。tnf - α处理以时间依赖性的方式降低ATGL转录，与tnf - α下调PPARgamma相似，最大降低时间为6小时。PD-98059、LY-294002或雷帕霉素预处理可减弱tnf - α对ATGL的作用，提示涉及p44/42 MAP激酶、PI 3激酶和p70核糖体蛋白S6激酶信号。为了研究ATGL的转录调控，我们克隆了2,979 bp的小鼠ATGL 5'侧区。与无启动子pGL2-Basic相比，-2979/+21 ATGL荧光素酶结构在白色和棕色脂肪细胞中的活性分别增加了120倍和40倍。8个ATGL启动子缺失的荧光素酶报告活性表明-928/+21、-1738/+21、-1979/+21和-2979/+21结构被PPARgamma反激活。我们的研究结果确定了新的脂肪酶ATGL是脂肪细胞中tnf - α和胰岛素作用的靶基因，并揭示了它受ppargamma介导信号的转录控制。
The minimal adipose phenotype of hormone-sensitive lipase (HSL)-null mice suggested that other hormonally responsive lipase(s) were present in adipocytes. Recent studies have characterized a new adipose tissue triglyceride lipase, ATGL/PNPLA2/destnutrin/iPLA2zeta/TTS2.2 (ATGL). We had previously cloned a novel adipose-enriched transcript by differential screening and recently determined its identity with murine ATGL. We report here on the regulation of ATGL by TNF-alpha and insulin in 3T3-L1 adipocytes and identify ATGL as a target for transcriptional activation by the key adipogenic transcription factor PPARgamma. Insulin at 100 nM resulted in a marked decrease in ATGL transcript that was effectively blocked by inhibitors for PI 3-kinase and p70 ribosomal protein S6 kinase. TNF-alpha treatment decreased ATGL transcript in a time-dependent manner that paralleled TNF-alpha downregulation of PPARgamma with a maximal decrease noted by 6 h. TNF-alpha effects on ATGL were attenuated by pretreatment with PD-98059, LY-294002, or rapamycin, suggesting involvement of the p44/42 MAP kinase, PI 3-kinase, and p70 ribosomal protein S6 kinase signals. To study transcriptional regulation of ATGL, we cloned 2,979 bp of the murine ATGL 5'-flanking region. Compared with promoterless pGL2-Basic, the -2979/+21 ATGL luciferase construct demonstrated 120- and 40-fold increases in activity in white and brown adipocytes, respectively. Luciferase reporter activities for a series of eight ATGL promoter deletions revealed that the -928/+21, -1738/+21, -1979/+21, and -2979/+21 constructs were transactivated by PPARgamma. Our findings identify the novel lipase ATGL to be a target gene for TNF-alpha and insulin action in adipocytes and reveal that it is subject to transcriptional control by PPARgamma-mediated signals.