Lipolysis model

Dahan, A. and A. Hoffman (2006). Use of a dynarfriicvitro lipolysis model to rationalize oral formulation development for poor water soluble drugs correlation witforivo data and the relationship to intra-enterocyte processes in rStoarm. Res., 23 2165-2174. 

Zangenberg, N.H. et al. (2001) A dynamic vitro lipolysis model I. Controlling the rate of lipolysis by continuous addition of calciunEur. J. Pharmaceut. Sci., 14 115-122. 

Dahan, A. and Hoffman, A. (2008) Rationalizing the selection of oral lipid based drug delivery systems by an in vitro dynamic lipolysis model for improved oral bioavailability of poorly water soluble drugs. Journal of Controlled Release, 129 (1), 1-10. 

Zangenberg, N.H., Mullertz, A., Gjelstrup Kristensen, H. and Hovgaard, L. (2001) A dynamic in vitro lipolysis model. II. Evaluation of the model. European Journal of Pharmaceutical Sciences, 14 (3), 237. 

ZangenbergNH, MullertzA, Kristensen HG, and HovgaardL. A Dynamic in Vitro Lipolysis Model I. Controlling the Rate of Lipolysis by Continuous Addition of Calcium. EurJPharm Sci 2001a 14 115-122. 

Shimizu, M., Miyaji, H., Yamauchi, K. 1982. Inhibition of lipolysis by milk fat globule membrane materials in model milk fat emulsion. Agric. Biol. Chem. 46, 795-99. 

There are similar issues when considering lipolysis of emulsions. Armand et ah (1992) found that pancreatic lipase activity was increased with decreasing emulsion size. However, modification of the interface of emulsions by heat treatment of the encapsulant (a mixture of caseinate and modified starch) prior to emulsion formation altered the rate of lipolysis of emulsions in model systems (Chung et al., 2008). The structuring of interfaces for the target delivery of oils and oil-soluble bioactives is currently an active field of research (Singh et ah, 2009). 

In the lumen of the small intestine, dietary fat does not only meet bile salt but the much more complex bile in which bile salts are about half saturated with lecithin in a mixed micellar system of bile salt-lecithin-cholesterol. On dilution in the intestinal content, the micelles grow in size as the phase limit is approached and large disk-like micelles form which fold into vesicles [49]. These changes are due to the phase transition that occurs when the bile salt concentration is decreased and the solubility limit for lecithin in the mixed micelles is exceeded. The information is mostly derived from in vitro studies with model systems but most probably is applicable to the in vivo situation. What in fact takes place when the bile-derived lamellar bile salt-lecithin-cholesterol system meets the partly digested dietary fat can only be pictured. Most probably it involves an exchange of surface components, a continuous lipolysis at the interphase by pancreatic enzymes and the formation of amphiphilic products which go into different lamellar systems for further uptake by the enterocyte. Due to the relatively low bile salt concentration and the potentially high concentration of product phases in intestinal content early in fat digestion, the micellar and monomeric concentration of bile salt can be expected to be low but to increase towards the end of absorption. 

The process of triacylglycerol hydrolysis is a complex phenomenon that involves at least three lipases, lipid droplet associated proteins, and FABPs, although other adipocyte lipases (i.e., triacylglycerol hydrolase) may play a role in basal lipolysis. The data at this time support the model that three lipases are the major contributors to adipocyte lipolysis. Complete hydrolysis of triacylglycerol involves the hydrolysis of three ester bonds to liberate three fatty acids and a glycerol moiety. ATGL catalyzes hydrolysis of the first... 

The source of TG used for assembly with apo B has been proposed to originate primarily (-70%) from the cytosolic TG storage pool rather than from the pool of TG made by de novo synthesis in the ER [10]. One model for the assembly of TG with apo B is that cytosolic TG is hydrolyzed, perhaps by the microsomal TG hydrolase (R. Lehner, 1999), to diacylglycerol/monoacylglycerol, which are subsequently re-esterified in the ER lumen to TG which assembles with apo B. However, many questions remain regarding the topology of this proposed lipolysis/re-esterification cycle and the molecular identity of the players. For example, it is not known if the active site of the enzyme that makes TG for assembly with apo B resides on the lumenal or cytosolic side of the ER membrane. If the formation of TG by re-esterification occurred within the ER lumen, one would also need to explain how fatty acids entered the ER lumen. 

Fig. 5. Mechanism of remnant lipoprotein formation at the endothelial surface. Apo B is not illustrated. FFA, unesterified fatty acid MG, monoacylglycerol closed triangles, apo C2 closed circles, apo E. This model reflects the appearance of partially lipolyzed lipoprotein particles in the circulation during lipoprotein lipase-mediated lipolysis of triacylglycerol-rich lipoproteins.

The second broad peak between 24 and 48 hr represents labeled /3C secreted by the liver associated with very low density lipoproteins (VLDL) and very likely encompasses the period during which these VLDL particles undergo lipolysis to IDL and LDL. As this lipolytic process occurs relatively rapidly, the broad and extented nature of this second peak probably reflects recycling of labeled /8C into and out of the liver, i.e., hepatic reprocessing of VLDL or LDL particles. This phenomenon may be investigated further using modeling approaches and is reflected in the compartmental model recently proposed by Novotny et al. (1995). 

Fig. 4.4 A schematic representation indicating those events that are triggered by energy failure in the brain. In global models, the onset of ionic fluxes, lipolysis, lacticacidosis and neurotransmitter release occur almost immediately and the processes continue with time. The individual resulting events are shown in the lower boxes...

A main part of the research on CLA is focused on its potential to reduce body adipose tissue. Many studies on CLA with mice models of different strains and some studies with hamsters demonstrated extreme adipose tissue loss after feeding CLA in the diet. For example, dietary intake of relatively low levels of CLA caused complete ablation of the adipose tissue in mice (6—8). Different modes of action of CLA on the decrease of adipose tissue have been su ested. Increased fatty acid oxidation via PPARa, a decrease in fat deposition in adipose tissue via the SREBP-1 or PPARy pathway, inhibition of adipocyte differentiation, an increase in lipolysis and apoptosis are all pathways that have been suggested as the underlying mechanism. The mechanisms are not mutually exclusive and may occur simultaneously in different tissues (9, 10). 

Prazeres, D.M., Lemos, R, Garcia, F.A.P, Cabral, J.M.S. 1993. Modeling lipolysis in a reversed micellar system Part II. Membrane reactor. Biotechnol. Bioeng. 42, 765-771. 

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