Lipolysis and Reesterification

Adipocytes are highly differentiated cells specialized in handling large quantities of long-chain FA (Fig. 11.1). During lipid storage in the fed state, FA are released by LPL bound to the endothelial capillary wall into the blood from chylomicrons and lipoproteins assembled and secreted by intestinal and liver cells, respectively (step 1), or from albumin, move through the endothelium via passage through tight junctions or endothelial cells (step 2), bind to the outer leaflet of the plasma membrane of the target cells, and cross the membrane bilayer by simple diffusion or proteinmediated transport (step 3). While the direct involvement of FA not bound to albumin in FA uptake by adipocytes is generally accepted [17], it is still debated whether, and if so to what extent, the albumin-bound FA pool is directly engaged in this process [18]. Using the hindlimb perfusion technique it was demonstrated recently that FA incorporation into intramuscular TAG depends not only on the unbound to albumin FA concentration but also, to some extent, on the total FA concentration [19]. This supports the previous speculation that albumin-bound FA could be directly involved in the uptake process mediated by an interaction of the FA-albumin com-

Adipose Tissue Interstitial Space

Fig. 11.1 Working model for FA re-esterifica-tion and its control by the efficacy of removal of newly released NEFA from the interstitial space into the circulation. Elevation/reduction of the blood flow would decrease/increase the accumulation of NEFA in the interstitial space in the vicinity of adipocytes where the endog-enously released NEFA intermingle with and are diluted by the nefa generated by LPL action from lipoproteins (LP) in the endothelial capillaries, and thereby decrease/increase the probability of re-uptake and re-esterification of NEFA released from adipocytes by HSL and 2-monoacylglycerol lipase (2-MAGL) action. This allows rapid adaptation ofthe supply of NEFA from adipose tissue according to the acute requirements of the organism (e.g. during starvation), which, to a certain degree, operates independent of the actual (insulin-controlled) lipolytic/anti-lipolytic state of the adipocytes. The major portion of NEFA/nefa in the interstitial space and capillaries is bound to serum albumin (Alb). The transport of glucose (as precursor for glycerol-3-phosphate, G-3-P) and the bidirectional flux of NEFA/nefa across the adipocyte plasma membrane is facilitated by GLUT4 and CD36/FAT, respectively, whereas simple diffusion and/or specific transport via AQPap is involved in the release of glycerol from adipocytes. See text for details. Adapted from Ref. [28] with modifications.

plex with an albumin receptor located at the cell surface [20], putatives candidate for which are the albumin-binding proteins (ABP) [21]. They could either promote a direct transfer of FA from the complex into the plasma membrane or facilitate dissociation of FA molecules from albumin, and thus locally increase the number of FA molecules available for uptake. Subsequently, FA transported across the plasma membrane are trapped in the cytoplasm by conversion into mobilised acyl-CoA (step 4), (re-)esterified and stored primarily as TAG in LD (step 5). During lipolysis of stored TAG in the fasting state, FA are released from intracellular LD primarily by action of HSL and 2-monoacylglycerol lipase (step 6) [22], move to and cross the plas-

ma membrane (step 7), and are released into the interstitial space, where they bind to albumin (step 8). Subsequently, the FA pass through the endothelial cells via trans-cytosis or diffuse through the spaces between them (tight junctions) to reach the blood (step 9).

The temporal and spatial relationship between breakdown (lipolysis) and re-synthesis (re-esterification) of TAG (TAG-FA cycling) has to be tightly controlled to either provoke or avoid generation of heat and energy expenditure through the utilization of ATP during substrate cycling. A substrate cycle exists when opposing, non-equilibrium reactions catalyzed by different enzymes are operating simultaneously [23, 24]. At least one of the reactions must involve the hydrolysis of ATP. Thus, a substrate cycle both liberates heat and increases energy expenditure in the absence of net conversion of substrate into product. Some of the NEFA formed during lipolysis can be re-esterified to TAG [25, 26], whereas little or no glycerol is re-utilized by fat cells [27]. This pathway of lipolysis and NEFA re-ester-ification forms an important cycle for energy turnover, allowing the fat cell to respond rapidly to changes in peripheral requirements for NEFA (Fig. 11.1). This is reflected in the FA concentration gradient between plasma and adipose tissue (mainly fat cell cytosol) which is determined by both the blood stream and uptake of NEFA by peripheral tissues. Two types of NEFA re-esterification in fat cells can be recognized [28]. Primary re-esterification is the total amount of NEFA that is re-esterified during a given situation and reflects the TAG synthesis capacity of the fat cells. Fractional re-esterification is the proportion of NEFA re-esterified in relation to the amount of NEFA formed by lipolysis in fat cells [28]. The latter constitutes a futile cycle, energy-rich NEFA first being formed by lipolysis of TAG and then re-synthesized to TAG. There is experimental evidence that NEFA have to be released from adipocytes into the interstitial space, where they form a common pool with NEFA generated by LPL action, and subsequently be taken up by the adipocytes for efficient re-esterification rather than that NEFA accumulating in the cytoplasm can be used for a "short-circuif re-esterification [28, 29]. Fat cell re-esterification can be determined in vitro by simultaneous measurement of the release of glycerol and NEFA using fluorescence, luminescence or dual radioisotope techniques or a combination thereof [24].

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  • claudia pfeifer
    What is reesterification?
    8 years ago

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