Hormone-sensitive lipase - structure, function and regulation

Hormone-sensitive lipase (HSL) catalyses the rate-limiting step in the hydrolysis of stored triacylglycerols in adipose tissue. Phosphorylation of HSL by protein kinase A (PKA) leads to its activation, whereas the antilipolytic effect of insulin is exerted mainly through prevention of this phosphorylation. Several types of analyses suggest that HSL is composed of two structural domains; an N-terminal domain with unknown function and a C-terminal, catalytic, domain. Furthermore, a three-dimensional model of the catalytic core has been built based on the structural relationship between HSL and a superfamily of esterases and lipases, that includes acetylcholinesterase, bile-salt stimulated lipase and several fungal lipases. The model has allowed the identification of the catalytic triad and a fatty acid binding cavity, into which the fatty acid to be hydrolysed accommodates. The known phosphorylation sites of HSL, are contained within a regulatory module, inserted into the catalytic domain. Two novel PKA sites have been identified and shown to govern activation properties in vitro, in contrast to the previously identified PKA site (Ser-563). Besides the 3 PKA sites, there is at least one additional phosphorylation site in HSL, Ser-565. This site is presumably phosphorylated by AMP-activated protein kinase (AMPK). Phosphorylation of Ser-565 and the PKA sites appears to be mutually exclusive, and based on this it has been proposed that phosphorylation of Ser-565 has an antilipolytic role. Besides PKA and AMPK, preliminary data indicate that also other kinases are involved in the activation of HSL that occurs in response to isoprenaline stimulation of rat adipocytes. The mechanism behind activation upon phosphorylation is poorly understood, but involves translocation of HSL from the cytosol to the lipid droplet.