Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Germany.
Exp Cell Res. 2011 Sep 10;317(15):2200-9. doi: 10.1016/j.yexcr.2011.06.016. Epub 2011 Jul 2.
Adipocyte apoptosis is an important regulator of adipocyte number in fat depots. We have previously shown that an inhibition of protein synthesis sensitizes human adipocytes for apoptosis. In vivo, dramatic changes in the fat cell's protein expression should be anticipated under special conditions such as calorie restriction. Here, we studied the underlying mechanism by which human preadipocytes and adipocytes are sensitized for death receptor induced apoptosis in vitro. The protein synthesis blocker cycloheximide (CHX) sensitized human fat cells for CD95-induced apoptosis in a caspase-dependent manner. Treatment with CHX differentially changed expression of pro- and anti-apoptotic proteins. Most noticeably, FLICE-like inhibitory protein (FLIP) expression rapidly decreased during CHX treatment. Reduction of FLIP levels resulted in undetectable amounts of FLIP at the CD95 death-inducing signaling complex (DISC) upon CD95 stimulation, thereby enhancing recruitment and activation at caspase-8. Down-regulation of FLIP by shRNA sensitized preadipocytes for CD95-induced apoptosis. In mice, adipose tissue mRNA levels of Flip were down-regulated upon fasting. In conclusion, we identify FLIP as an important regulator of apoptosis sensitivity in fat cells. Modulating adipocyte homeostasis by apoptosis might provide a new therapeutic concept to get rid of excess adipose tissue, and FLIP might be a possible target molecule.
脂肪细胞凋亡是脂肪组织中脂肪细胞数量的重要调节因子。我们之前的研究表明，抑制蛋白质合成可使人类脂肪细胞对凋亡敏感。在体内，在特殊条件下（如热量限制），脂肪细胞的蛋白质表达应该会发生剧烈变化。在这里，我们研究了体外条件下，人前脂肪细胞和脂肪细胞如何通过死亡受体诱导的凋亡而变得敏感的潜在机制。蛋白合成抑制剂环己酰亚胺（CHX）以半胱天冬酶依赖性方式使人类脂肪细胞对 CD95 诱导的凋亡敏感。用 CHX 处理会改变促凋亡和抗凋亡蛋白的表达。最值得注意的是，FLICE 样抑制蛋白（FLIP）的表达在 CHX 处理过程中迅速下降。FLIP 水平的降低导致在 CD95 诱导的死亡信号复合物（DISC）中检测不到 FLIP，从而增强了半胱天冬酶-8 的募集和激活。用 shRNA 下调 FLIP 可使前脂肪细胞对 CD95 诱导的凋亡敏感。在小鼠中，禁食可使脂肪组织中 Flip 的 mRNA 水平下调。总之，我们确定 FLIP 是脂肪细胞凋亡敏感性的重要调节因子。通过凋亡调节脂肪细胞稳态可能为消除多余脂肪组织提供一种新的治疗概念，而 FLIP 可能是一个潜在的靶标分子。
