Molecular mechanisms regulating hormone-sensitive lipase and lipolysis.
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.
Holm
C
C
Department of Cell and Molecular Biology, Section for Molecular Signalling, Lund University, Lund, Sweden. cecilia.holm@medkem.lu.se
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D002395:Catecholamines / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D007328:Insulin / Q000502:physiology; D008066:Lipolysis; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D051381:Rats; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism*
D002395:Catecholamines; D007328:Insulin; D017868:Cyclic AMP-Dependent Protein Kinases; D002787:Sterol Esterase