Disease relevance of Lipe

• Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lep ob/ob mice [1].
• HSL-/- mice did not have hypogonadism or adrenal insufficiency [2].
• Mice homozygous for the mutant HSL allele (HSL-/-) were superficially normal except that the males were sterile because of oligospermia [2].
• Therefore, expression of HSLtes and cognate cholesteryl ester hydrolase activity leads to a rescue of the infertility observed in HSL-deficient male mice [3].
• The testicular form of hormone-sensitive lipase HSLtes confers rescue of male infertility in HSL-deficient mice [3].

Psychiatry related information on Lipe

• Thus, deficiency of both leptin and HSL has unmasked novel roles of HSL in adipogenesis as well as in feeding behavior [1].

High impact information on Lipe

• We show here that targeted disruption of Plin results in healthy mice that have constitutively activated fat-cell HSL [4].
• Perilipin (encoded by the gene Plin), an adipocyte protein, has been postulated to modulate HSL activity [4].
• Hormone-sensitive lipase (HSL) mediates the hydrolysis of triacylglycerol, the major form of stored energy in the body [4].
• A similar degree of differentiation was seen in both vector alone and HSL transfectants when based on the induction of lipoprotein lipase [5].
• Hormone-sensitive lipase (HSL) is a cytosolic neutral lipase that hydrolyzes intracellular stores of triglycerides within adipocytes and is thought to be the rate limiting enzyme in lipolysis; however, direct evidence to prove this concept has been lacking [5].

Chemical compound and disease context of Lipe

• Hormone-sensitive lipase (HSL) is a rate-determining enzyme in the hydrolysis of triglyceride in adipocytes, and HSL-deficient mice have reduced circulating fatty acids and are resistant to diet-induced obesity [6].
• We have previously reported that oestrogens (oestradiol-benzoate) significantly decrease the body weight in male rats, increase anterior pituitary and serum levels of the intracellular messenger cAMP, which activates cAMP-dependent protein kinase A, their targets include hormone-sensitive lipase and they influence the brain sympathetic system [7].

Biological context of Lipe

• RESEARCH METHODS AND PROCEDURES: We performed constitutive gene targeting of the mouse HSL gene (Lipe), subsequently studied the adipose tissue phenotype clinically and histologically, and measured lipolysis in isolated adipocytes [8].
• Thus, the lipolytic action(s) of HSL at the LD surface requires PKA-dependent perilipin phosphorylation [9].
• Unlike perilipin, which is one of the most extensively studied lipid droplet-associated proteins, Prp19p is not essential for cAMP- and hormone-sensitive lipase-dependent lipolysis pathways, even though Prp19p is a component of the lipid droplet phospholipid monolayer, and down-regulation of Prp19p represses fat accretion significantly [10].
• PKA-stimulated HSL translocation was confirmed in differentiated brown adipocytes from perilipin null mice expressing an adipose-specific Peri Adelta1-6 transgene [9].
• Because HSL-mediated lipolysis of TG in adipose tissue (AT) directly feeds non-esterified fatty acids (NEFA) into the vascular system, the enzyme is expected to affect many metabolic processes including the metabolism of plasma lipids and lipoproteins [11].

Anatomical context of Lipe

• Akey step in lipolytic activation of adipocytes is the translocation of hormone-sensitive lipase (HSL) from the cytosol to the surface of the lipid storage droplet [12].
• We have also reconstructed the HSL translocation reaction in the nonadipocyte Chinese hamster ovary cell line by introduction of GFP-tagged HSL with and without perilipin A [12].
• ATGL and HSL are robustly expressed by adipocytes that we generated from murine embryonic fibroblasts of perilipin knock-out mice [13].
• Since HSL is expressed in hypothalamus, we speculate that defective generation of free fatty acids in the hypothalamus due to the absence of HSL mediates the altered expression of these orexigenic neuropeptides [1].
• Conversely, insulin inhibited HSL in macrophages, but unlike adipocytes, this effect did not require PI 3-kinase [14].

Associations of Lipe with chemical compounds

• Studies addressing how Peri A PKA sites regulate adipocyte lipolysis have relied on non-adipocyte cell models, which express neither adipose triglyceride lipase (ATGL), the rate-limiting enzyme for triglyceride catabolism in mice, nor the "downstream" lipase, hormone-sensitive lipase (HSL) [13].
• Except for the increased HDL cholesterol concentrations, these differences were not observed in fed animals, in which HSL activity is generally low [11].
• Studies with ATGL-and HSL-directed small hairpin RNAs demonstrate that 1) ATGL activity is required for all PKA-stimulated FA and glycerol release in murine embryonic fibroblast adipocytes and 2) all PKA-stimulated FA release in the absence of HSL activity requires serine 517 phosphorylation [13].
• Importantly, each FABP form stimulated HSL activity approximately 2-fold using cholesteryl oleate as substrate but exhibited no activation using p-nitrophenyl butyrate [15].
• Maximum corticosterone production was identical in HSL(-/-) and double-LDLR/HSL(-/-) mice [16].

Physical interactions of Lipe

• Translocation of hormone-sensitive lipase bound to the adipocyte lipid binding protein to the lipid droplet seems to be an important step during lipolytic activation [17].

Regulatory relationships of Lipe

• The overexpression of cholesterol acceptors in HSL-apoA-IV double-transgenic mice increases plasma HDL levels and decreases diet-induced atherosclerosis compared to HSL Tg mice, with aortic lesions reduced to sizes in nontransgenic littermates [18].

Other interactions of Lipe

• Hormone-sensitive lipase deficiency in mice changes the plasma lipid profile by affecting the tissue-specific expression pattern of lipoprotein lipase in adipose tissue and muscle [11].
• The activation by A-FABP was dependent upon its fatty acid binding properties because a non-fatty acid binding mutant, R126Q, failed to activate HSL [15].
• In contrast, expression of genes associated with cholesterol metabolism (sterol-regulatory element-binding protein-2, 3-hydroxy-3-methylglutaryl-CoA reductase, acyl-CoA:cholesterol acyltransferase-1) and thermogenesis (uncoupling protein-2) was upregulated in both WAT and BAT of HSL-/- mice [19].
• Phosphorylation of HSL by PKA occurs at three sites, the serines 563, 659 and 660, both in vitro and in primary rat adipocytes [20].
• Lipid metabolic enzymes identified in both preparations include hormone-sensitive lipase, lanosterol synthase, NAD(P)-dependent steroid dehydrogenase-like protein, acyl-CoA synthetase, long chain family member (ACSL) 1, and CGI-58 [21].

Analytical, diagnostic and therapeutic context of Lipe

• To examine the relationship between the binding of FABP to HSL and activation of catalytic activity, isothermal titration microcalorimetry as well as kinetic analysis using a variety of FABP isoforms have been employed [15].
• In addition, immunohistochemistry of pancreatic specimens was undertaken for study of expression of insulin, GLUT-2 and hormone-sensitive lipase (HSL) [22].
• HSL gene expression, as measured by Northern blotting analysis with 32P-labeled cloned HSL-cDNA, was also suppressed [23].
• Nondifferentiated, transfected cells were screened for HSL overexpression by indirect immunofluorescence microscopy and confirmed by immunoblotting cell extracts with anti-HSL/fusion protein antibodies and by Northern blots for HSL mRNA [5].
• HSL mRNA and protein were detected in all segments of the small intestine by Northern and Western blot analyses, respectively [24].

References