Sanders Matthew A, Madoux Franck, Mladenovic Ljiljana, Zhang Huamei, Ye Xiangqun, Angrish Michelle, Mottillo Emilio P, Caruso Joseph A, Halvorsen Geoff, Roush William R, Chase Peter, Hodder Peter, Granneman James G
Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Lead Identification Division, The Scripps Research Institute, Jupiter, FL 33458, USA.
Cell Metab. 2015 Nov 3;22(5):851-60. doi: 10.1016/j.cmet.2015.08.023. Epub 2015 Sep 24.
Fat and muscle lipolysis involves functional interactions of adipose triglyceride lipase (ATGL), α-β hydrolase domain-containing protein 5 (ABHD5), and tissue-specific perilipins 1 and 5 (PLIN1 and PLIN5). ABHD5 potently activates ATGL, but this lipase-promoting activity is suppressed when ABHD5 is bound to PLIN proteins on lipid droplets. In adipocytes, protein kinase A (PKA) phosphorylation of PLIN1 rapidly releases ABHD5 to activate ATGL, but mechanisms for rapid regulation of PLIN5-ABHD5 interaction in muscle are unknown. Here, we identify synthetic ligands that release ABHD5 from PLIN1 or PLIN5 without PKA activation and rapidly activate adipocyte and muscle lipolysis. Molecular imaging and affinity probe labeling demonstrated that ABHD5 is directly targeted by these synthetic ligands and additionally revealed that ABHD5-PLIN interactions are regulated by endogenous ligands, including long-chain acyl-CoA. Our results reveal a new locus of lipolysis control and suggest ABHD5 ligands might be developed into novel therapeutics that directly promote fat catabolism.
脂肪和肌肉的脂解作用涉及脂肪甘油三酯脂肪酶（ATGL）、含α-β水解酶结构域蛋白5（ABHD5）以及组织特异性的脂滴包被蛋白1和5（PLIN1和PLIN5）之间的功能相互作用。ABHD5能有效激活ATGL，但当ABHD5与脂滴上的PLIN蛋白结合时，这种促进脂肪酶的活性就会受到抑制。在脂肪细胞中，蛋白激酶A（PKA）对PLIN1的磷酸化作用会迅速释放ABHD5以激活ATGL，但肌肉中快速调节PLIN5-ABHD5相互作用的机制尚不清楚。在此，我们鉴定出了一些合成配体，它们无需PKA激活就能从PLIN1或PLIN5中释放ABHD5，并能迅速激活脂肪细胞和肌肉的脂解作用。分子成像和亲和探针标记表明，这些合成配体直接作用于ABHD5，此外还揭示了ABHD5与PLIN的相互作用受包括长链酰基辅酶A在内的内源性配体调控。我们的研究结果揭示了脂解作用控制的一个新位点，并表明ABHD5配体可能会被开发成直接促进脂肪分解代谢的新型治疗药物。
