Phosphodiesterase -lipids

Increased lipid synthesis/inhibi-tion of lipolysis Activation of lipoprotein lipase (LPL)/induc-tion of fatty acid synthase (FAS)/inactivation of hormone sensitive lipase (HSL) Facilitated uptake of fatty acids by LPL-dependent hydrolysis of triacylglycerol from circulating lipoproteins. Increased lipid synthesis through Akt-mediated FAS-expression. Inhibition of lipolysis by preventing cAMP-dependent activation of HSL (insulin-dependent activation of phosphodiesterases )... 

In adipose tissue, insulin stimulation suppresses triglyceride hydrolysis (to free fatty acids and glycerol) by activating cAMP phosphodiesterase (cAMP PDE). Cyclic AMP, (3, 5 cAMP), is required to stimulate hormone sensitive lipase (HSL), the enzyme which hydrolyses triglyceride within adipocytes PDE converts active 3, 5 cAMP to inactive 5 AMP thus preventing the stimulation of HSL. The net effect of insulin on lipid metabolism is to promote storage. 

This enzyme [EC 3.1.4.39], also known as alkylglycero-phosphoethanolamine phosphodiesterase, catalyzes the hydrolysis of l-alkyl-sn-glycero-3-phosphoethanolamine to produce 1-alkyl-xn-glycerol 3-phosphate and ethanol-amine. The enzyme will also act on the acyl and choline analogs of the lipid. 

In general, the MC2 receptor is Gs protein-coupled (Table 1), and two studies in the rabbit pulmonary artery indicate that this is also true for the presynaptic receptor. The evidence is, indirect, however, in that it suggests activation of adenylyl cyclase, the typical transduction step downstream from Gs. In the study by Gothert and Hentrich (1984), the facilitatory effect of ACTH was increased by simultaneous administration of forskolin, an activator of the catalytic subunit of adenylyl cyclase, and AH 21-132, a phosphodiesterase inhibitor. In the study by Costa and Majewski (1988), the facilitatory effect of ACTH was occluded when the vessel was super-fused with a lipid-soluble cAMP analogue. 

Fig. 2. Ptdlns 4,5-P2-derived second messengers. Ptdlns 4,5-P2 is hydrolysed when a phospholipase C (Ptdlns 4,5-P2 phosphodiesterase) is activated following the binding of specific agonists to their surface receptor proteins. The Ptdlns 4,5-P2 is cleaved to yield diacylglycerol (DG), which is a co-activator of protein kinase C and other enzymes, and Ins( 1,4,5)P, which is capable of releasing Ca2 from intracellular stores. The DG often contains arachidonic acid, which is the source of the prostanoids, which are also capable of controlling diverse cellular functions. The arachidonic acid is cleaved from the parent lipid or from DG by specific phospholipase A2 enzymes.

Catecholamines inhibit phosphodiesterase from beef heart [44] and guinea-pig lung [45], and so does N, 2 -0-dibutyryl cyclic AMP [47] which has been used to mimic cyclic AMP effects as it is more lipid-soluble and, therefore, assumed to penetrate cell membranes more readily than cyclic AMP [6,46]. A large number of other drugs inhibit the phosphodiesterase activity of rat brain and cat heart [48]. 

Schmid HH, Schmid PC, Natarajan V (1996) The N-acylation-phosphodiesterase pathway and cell signalhng. Chem Phys Lipids 80 133-142... 

Fatty acid compositional changes in the retina of the rodent eye can also impact the development of vision, which, in turn, will affect behavior of the animal. Recent biochemical and biophysical studies have demonstrated how the response of rhodopsin to different membrane lipids may significantly affect vision. DHA is primarily associated with membrane proteins of the 7-TM motif (i.e., seven transmembrane spanning regions). Such 7- fM proteins are also associated with a G-protein-coupled event (activation of a phosphodiesterase which cleaves GTP to GDP). Rhodopsin is a typical 7-TM G-protein-coupled... 

It shows considerable inhibition of cAMP-phosphodiesterase in rat adipose tissues and inhibits non-enzymic lipid peroxidation. It is a potent scavenger of superoxide and increases the beat rate on isolated atria, stimulates lipolysis and causes a concentration-dependent increase in Ca release from the heavy fraction of fragmented sarcoplasmic reticulum of rabbit skeletal muscle. ... 

The promotion of the synthesis of lipids (lipogenesis) and the inhibition of the release of free fatty acids (lipolysis) by insulin also requires a complex network of signalling pathways, partially coupled to those for the Glut4 activation. In adipocytes, insulin inhibits lipolysis primarily through inhibition of a hormone-sensitive lipase via reduction of the amount of cyclic adenosine monophosphate (cAMP) present in the cells. In this specific action, a phosphodiesterase is involved, ] a level where again the phosphate antagonist vanadate can interfere. 

After metabolic degradation by phosphodiesterase, both nucleosides are released as 5 -nucleotides. In case of different hydrolysis kinetics, other active intermediate products may be formed. The structure of the glycerol-lipid-heteronucleotides provides a programmed release of differently active drugs that can penetrate a cell membrane when the cleavage takes place outside of a cell. These compounds may also be formulated in DDS, such as liposomes or micellar systems. 

Kuppusamy UR, Das NP. Effects of flavonoids on cyclic AMP phosphodiesterase and lipid mobilization in rat adipocytes. Biochem Pharmacol 1992 44 1307-1315. 

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