Holm C
Department of Cell and Molecular Biology, Section for Molecular Signalling, Lund University, Lund, Sweden.
Biochem Soc Trans. 2003 Dec;31(Pt 6):1120-4. doi: 10.1042/bst0311120.
HSL (hormone-sensitive lipase) is a key enzyme in the mobilization of fatty acids from acylglycerols in adipocytes as well as non-adipocytes. In adipocytes, catecholamines stimulate lipolysis mainly through PKA (protein kinase A)-mediated phosphorylation of HSL and perilipin, a protein coating the lipid droplet. The anti-lipolytic action of insulin is mediated mainly via lowered cAMP levels, accomplished through activation of phosphodiesterase 3B. Phosphorylation of HSL by PKA occurs at three sites, the serines 563, 659 and 660, both in vitro and in primary rat adipocytes. Phosphorylation of Ser-659 and -660 is required for in vitro activation as well as translocation from the cytosol to the lipid droplet, whereas the role of the third PKA site remains elusive. Adipocytes isolated from homozygous HSL-null mice, generated in our laboratory, exhibit completely blunted catecholamine-induced glycerol release and reduced fatty acid release, suggesting the presence of additional, although not necessarily hormone-activatable, triacylglycerol lipase(s). Basal hyperinsulinaemia, release of exaggerated amounts of insulin during glucose challenges and retarded glucose disposal during insulin tolerance tests suggest that HSL-null mice are insulin resistant. Liver, adipose tissue and skeletal muscle appear all to be sites of impaired insulin sensitivity in HSL-null mice.
激素敏感性脂肪酶（HSL）是脂肪细胞以及非脂肪细胞中从酰基甘油动员脂肪酸的关键酶。在脂肪细胞中，儿茶酚胺主要通过蛋白激酶A（PKA）介导的HSL和围脂滴蛋白（一种包裹脂滴的蛋白质）磷酸化来刺激脂肪分解。胰岛素的抗脂肪分解作用主要通过激活磷酸二酯酶3B降低cAMP水平来介导。PKA对HSL的磷酸化发生在三个位点，即丝氨酸563、659和660，在体外和原代大鼠脂肪细胞中均如此。丝氨酸659和660的磷酸化对于体外激活以及从细胞质转运到脂滴是必需的，而第三个PKA位点的作用仍然难以捉摸。从我们实验室培育的纯合HSL基因敲除小鼠分离出的脂肪细胞，儿茶酚胺诱导的甘油释放完全减弱，脂肪酸释放减少，这表明存在其他（尽管不一定是激素可激活的）三酰甘油脂肪酶。基础高胰岛素血症、葡萄糖刺激期间胰岛素过量释放以及胰岛素耐量试验期间葡萄糖处置延迟表明HSL基因敲除小鼠存在胰岛素抵抗。肝脏、脂肪组织和骨骼肌似乎都是HSL基因敲除小鼠胰岛素敏感性受损的部位。
