Rondini Elizabeth A, Mladenovic-Lucas Ljiljana, Roush William R, Halvorsen Geoff T, Green Alex E, Granneman James G
Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan (E.A.R., L.M.-L., J.G.G.); Department of Chemistry, Scripps Research Institute, Jupiter, Florida (W.R.R., G.T.H.); and Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada (A.E.G.).
Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan (E.A.R., L.M.-L., J.G.G.); Department of Chemistry, Scripps Research Institute, Jupiter, Florida (W.R.R., G.T.H.); and Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada (A.E.G.)
J Pharmacol Exp Ther. 2017 Dec;363(3):367-376. doi: 10.1124/jpet.117.243253. Epub 2017 Sep 19.
Current knowledge regarding acute regulation of adipocyte lipolysis is largely based on receptor-mediated activation or inhibition of pathways that influence intracellular levels of cAMP, thereby affecting protein kinase A (PKA) activity. We recently identified synthetic ligands of --hydrolase domain containing 5 (ABHD5) that directly activate adipose triglyceride lipase (ATGL) by dissociating ABHD5 from its inhibitory regulator, perilipin-1 (PLIN1). In the current study, we used these novel ligands to determine the direct contribution of ABHD5 to various aspects of lipolysis control in white (3T3-L1) and brown adipocytes. ABHD5 ligands stimulated adipocyte lipolysis without affecting PKA-dependent phosphorylation on consensus sites of PLIN1 or hormone-sensitive lipase (HSL). Cotreatment of adipocytes with synthetic ABHD5 ligands did not alter the potency or maximal lipolysis efficacy of the -adrenergic receptor (ADRB) agonist isoproterenol (ISO), indicating that both target a common pool of ABHD5. Reducing ADRB/PKA signaling with insulin or desensitizing ADRB suppressed lipolysis responses to a subsequent challenge with ISO, but not to ABHD5 ligands. Lastly, despite strong treatment differences in PKA-dependent phosphorylation of HSL, we found that ligand-mediated activation of ABHD5 led to complete triglyceride hydrolysis, which predominantly involved ATGL, but also HSL. These results indicate that the overall pattern of lipolysis controlled by ABHD5 ligands is similar to that of isoproterenol, and that ABHD5 plays a central role in the regulation of adipocyte lipolysis. As lipolysis is critical for adaptive thermogenesis and in catabolic tissue remodeling, ABHD5 ligands may provide a means of activating these processes under conditions where receptor signaling is compromised.
目前关于脂肪细胞脂解急性调节的知识主要基于受体介导的对影响细胞内cAMP水平的信号通路的激活或抑制，从而影响蛋白激酶A（PKA）的活性。我们最近鉴定出含α-水解酶结构域5（ABHD5）的合成配体，其通过使ABHD5与其抑制性调节因子脂滴包被蛋白-1（PLIN1）解离，直接激活脂肪甘油三酯脂肪酶（ATGL）。在本研究中，我们使用这些新型配体来确定ABHD5对白色（3T3-L1）和棕色脂肪细胞脂解控制各个方面的直接作用。ABHD5配体刺激脂肪细胞脂解，而不影响PLIN1或激素敏感性脂肪酶（HSL）共有位点上PKA依赖性磷酸化。用合成ABHD5配体对脂肪细胞进行共处理，不会改变β-肾上腺素能受体（ADRB）激动剂异丙肾上腺素（ISO）的效力或最大脂解效力，表明两者作用于共同的ABHD5库。用胰岛素降低ADRB/PKA信号或使ADRB脱敏可抑制对随后ISO刺激的脂解反应，但不影响对ABHD5配体的反应。最后，尽管HSL的PKA依赖性磷酸化存在显著的处理差异，但我们发现配体介导的ABHD5激活导致甘油三酯完全水解，这主要涉及ATGL，但也涉及HSL。这些结果表明，ABHD5配体控制的脂解总体模式与异丙肾上腺素相似，且ABHD5在脂肪细胞脂解调节中起核心作用。由于脂解对于适应性产热和分解代谢组织重塑至关重要，ABHD5配体可能提供一种在受体信号受损的情况下激活这些过程的方法。
