UpDownregulation of Components of TAG Storage and Mobilization 11481 HSL

Recently, the functional significance of HSL in adipose tissue metabolism has begun to be clarified in studies using HSL null mice [510-512]. These mice showed normal growth rates and body weights. While the epididymal retroperitoneal and femoral WAT depots of HSL null mice remained unchanged, they displayed a 65% increase in brown adipose tissue mass compared with wild-type control mice. Inactivation of HSL resulted in the complete absence of neutral cholestery-lester hydrolase activity in adipose tissue (both white and brown). However, TAG lipase activity in WAT was reduced by only 40% and TAG lipase activity in brown adipose tissue was similar to wild-type mice [510]. Basal lipolysis, i.e. glycerol release, was reduced in isolated adipose cells from HSL null mice in one study [498], but was unaffected and seemingly increased in another [511]. Nonetheless, there was a marked defect or complete absence of catecholamine-stimulated glycerol release in adipose cells from HSL null mice, whereas catecholamine-stimu-lated NEFA release was still observed, but attenuated [510, 511]. This apparent discrepancy in the release of glycerol and NEFA from adipose cells of HSL null mice has been clarified by the observation that the basal and catecholamine-induced DAG content increased markedly in white and brown adipose tissue of HSL null mice [512]. Therefore, the studies with HSL null mice appear to substantiate that HSL is the rate-limiting enzyme for DAG hydrolysis in adipose tissue and is essential for hormone-stimulated lipolysis. Remarkably, the absence of HSL was not associated with the development of obesity. However, adipose cells from HSL null mice, while displaying size heterogeneity, tended to be hypertrophic [510, 511]. Moreover, due to defective lipolysis during fasting, there was a reduction in circulating NEFA and a decreased hepatic production of VLDL secondary to the diminished release of NEFA from adipose tissue [513]. This was associated with an induction of LPL in WAT, as well as in skeletal and cardiac muscle, but a decrease of LPL in brown adipose tissue [513]. It remains to be determined whether operation of the TAG lipase in HSL null mice is a consequence of its compensatory up-regulation in HSL-deficient adipocytes, only, or is indicative for expression of a second TAG-specific HSL-like lipase in wild-type adipocytes, too. Taken together, the findings on the lack of obesity and mild adipocyte hypertrophy observed in HSL null mice suggest that other lipases could also play a role in TAG mobilization.

Interestingly, in HSL null mice after prolonged fasting, plasma NEFA and TAG levels as well as hepatic TAG stores were reported to be significantly lower than with wild-type mice [513, 514]. This low hepatic TAG content was associated with improved hepatic insulin sensitivity since insulin caused a greater reduction in endogenous hepatic glucose production in HSL null mice (by ~71%) than in wild-type mice (by ~31%). This increase in hepatic insulin sensitivity was associated with elevated insulin receptor protein levels and activation of components of the insulin signaling cascade, such as phosphorylation of PKB and activity of PI3K [514]. The low hepatic TAG content in HSL null mice can be explained by their low plasma NEFA levels, since liver-specific NEFA uptake is commonly regarded to be a concentration-driven process facilitated by specific membrane transporters (see above). The inverse relationship between insulin sensitivity and hepatic TAG content may be explained by alterations in gene expression during activation of nuclear transcription factors such as peroxisome proliferator-activated receptors by intracellular TAG and/or fatty acyl derivatives. Furthermore, the diminished plasma NEFA levels per se cannot be excluded from being, at least partly, responsible for the increased hepatic insulin sensitivity, since plasma NEFA concentrations are inversely correlated with insulin sensitivity (see above). Strikingly, in HSL null mice, no differences were observed in insulin-mediated whole-body glucose uptake compared with wild-type mice as revealed during hyperinsuli-nemic euglycemic clamp studies [514]. The lack of improvement of whole-body insulin sensitivity may be explained by the reported absence of significant differences in muscle TAG content in combination with unchanged insulin-induced PKB phosphorylation in HSL null compared with wild-type mice despite lower plasma NEFA levels.

Recently, HSL null mice have been shown to have impaired insulin secretion, a 2- to 2.5-fold increase in islet TAG content, and elevated basal insulin secretion from isolated islets that fails to rise further upon challenge with glucose [515]. Comparison of the gene expression profile between islets isolated from wild-type and HSL null mice using microarray chip technology and Taqman quantitative PCR for selected genes revealed changes in genes that are involved in lipid metabolism (methyl sterol oxidase, short chain acyl-CoA dehydrogenase), insulin response (insulin-induced growth response protein) and cytoskeleton (profilin, cofi-lin). In particular, the mRNAs for UCP-2, SREBP-1c, and PPARy were up-regulated in islets from HSL null mice as compared with wild-type mice. The transcriptional up-regulation of UCP-2, which is regulated by SREBP-1c and PPAR-y, was associated with elevated NEFA and correlated with impaired glucose-stimulated insulin secretion. Finally, C/EBPa, which is involved in cytokine-regulated apoptosis of pancreatic /5-cells, was also up-regulated. Collectively, these findings suggest that HSL is important in maintaining lipid homeostasis in /5-cells by directly and indirectly controlling gene expressing for multiple metabolic and signaling pathways and hence in the regulation of glucose-stimulated insulin secretion.

A recent study using transgenic mice overexpressing HSL specifically in /5-cells provided novel and important insights with regard to the role of HSL in the development of lipotoxicity [516]. These transgenic mice were characterized by im-

paired glucose and severely blunted glucose-stimulated insulin secretion upon challenge with a high-fat diet. Their islets displayed both elevated HSL activity and forskolin-induced lipolysis compared with wild-type islets, which resulted in significantly reduced TAG levels in transgenic compared with wild-type islets provided the mice have been fed a high-fat diet. Thus, the rate of influx of NEFA into TAG of the islet LD and the capacity to mobilize this TAG pool seem to determine the emergence of islet lipotoxicity. This is in accord with the recently reported inverse correlation between apoptosis and TAG accumulation in cultured ß-cells, suggesting a cytoprotective function of TAG in cytoplasmic LD formed by normal ß-cells against NEFA-induced islet dysfunction [517]. Moreover, prolonged high-fat feeding of mice is accompanied by down-regulation of the expression of islet HSL [518]. Consequently, physiological down-regulation of HSL or pharmacological inhibition of HSL and possibly of other as yet unknown TAG lipases in ß-cells could be interpreted in terms of the operation of a defense mechanism against the emergence of NEFA-induced islet cell dysfunction.

In conclusion, HSL degrading TAG of LD in islets seems to exert at least three different functions in the regulation of insulin secretion and its coupling to external stimuli. (i) In the short-term, upon challenge of ß-cells with an insulin secreta-gogue, HSL is phosphorylated and activated via (glucagon-like peptide 1 and gastric inhibitory polypeptide) receptor/cAMP-dependent mechanisms lipolytically releasing NEFA and/or NEFA derivatives from islet TAG. These may act as acute stimulus (glucose)-secretion coupling factors for the exocytosis of insulin-containing secretory vesicles. (ii) In the long-term diet-induced NIDDM and the increased influx of NEFA derived from plasma lipoproteins through the action of LPL and plasma NEFA into ß-cells lead to the accumulation of TAG in LD of ß-cells which apparently exceeds the degradation capacity of the basal HSL. Thus the low activity state of HSL under these conditions guarantees the storage of NEFA (derivatives) which potentially compromise the insulin secretory mechanism and induce ß-cell apoptosis. (iii) Long-lasting aberrations in the regulation of lipolytic activity, such as overexpression of HSL, failure to down-regulate HSL during prolonged high-fat feeding or the mass effect of TAG overstorage per se leading to incremental lipolytic release of NEFA even at low constitutive HSL activity, may result in exceeding a certain threshold level of NEFA flux. This triggers the lipotoxic pathway, presumably involving binding of NEFA (derivatives) as ligands to transcription factors, such as PPAR, and other mechanisms. The resulting alterations in the expression of genes regulating insulin secretory vesicle biogenesis and exocytosis finally lead to dampening of glucose-induced insulin secretion.

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