Genetic Variation of Lysosomal Acid Lipase

Cortner, Jean A.; Coates, Paul M.; Swoboda, E; Schnatz, J. David

doi:10.1203/00006450-197611000-00005

Cited by 62 publications

(31 citation statements)

References 4 publications

(4 reference statements)

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“…Since the original reports of hepatic acid hydrolase deficiency in WD (20) and of acid lipase deficiency in CESD (2,22), several laboratories have reported very low acid hydrolase activities in cultured fibroblasts from WD or CESD subjects using either natural or artificial substrates (1,3,6,10). Neutral lipase activity has rarely been examined.…”

Section: Discussionmentioning

confidence: 99%

Abnormal Neutral Lipase Activity in Acid-Lipase-Deficient Cultured Human Fibroblasts

et al. 1983

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Acid and neutral lipase activities of homogenized or sonicated cultured fibroblasts were examined using [taHjglycerol triolein, glycerol tri[1-14CJoleate or cholesterol [l-14Clokate as substrates.In normal fibroblasts, optimal conditions for acid lipase activity were pH 4.5-5.0,0.15-0.2 m M triacylglycerol, and 0.25% Triton X-100. Fatty acid release was b a r to 2 h and between 0.2-2.0 mg fibroblast protein/ml. For the neutral lipase, activity was optimal at pH 6.0-7.0, >1.5 m M triacylglycerol or cholesterol oleate (suspended in 8 mg albumin/ml), and 160 pg pbosphatidylserine/ml. The reaction was b e a r to 60-120 min, and up to 1.0 mg protein/ml. In contrast to the situation at neutral pH, very little ["] and was less than 25% of controls when cholesterol oleate was the substrate. Neutral lipase activity in mixtures of conbol and WD fibroblast homogenates was similar to that predicted from individual activities. The triacylglycerol content of the control and mutant cells was within normal limits, and cbdesterol content was only slightly elevated, indicating that endogenous dilution of substrate was not the reason for the low activity in mutant cells. Hydrolysis of labeled endogenous triacylglyced was reduced by >75-80R, in the WD cells, indicating that low levels of activity measured with the exogenous substrate were not due solely to lack of accessibiUty to the neutral lipase. These results suggest a close relathmship between the acid and neutral activities of the normal cell in that mutations which affect one apparently affect the activity of the other.Abbreviations CESD, cholesterol ester storage disease FCS, fetal calf serum MEM, minimal essential medium WD. Wolman's disease Several investigators have described lipase activity with an acid pH optimum (3.5-4.5) in homogenates or subcellular fractions of cultured mammalian fibroblasts (1,3,(12)(13)(14)19). Tri-and diacylglycerols, cholesterol ester, and pnitrophenyl or Cmethylumbelliferyl-linked fatty acids are substrates. The acid lipase activity is probably localized in lysosomes (16) and is deficient in two human inherited diseases of neutral lipid metabolism, WD, and CESD (2,20). Although the clinical phenotype is quite different, both diseases are characterized by the intralysosomal accumulation of triacylglycerol and cholesterol esters (8).There is less certainty about the presence and relative amounts of other fibroblast lipases active with triacylglycerol and/or cholesterol esters. Several studies of acid lipase activity, in which the effects of pH on activity included the neutral range, have found very little or no detectable neutral activity (1, 3, 9). On the other hand, at least three studies have clearly demonstrated fibroblast l i p activities with pH optima in the neutral range. Lengle and Geyer (14) reported three pH optima (pH 4.5, 6.5, and 8.5) for lipase activities in mouse fibroblasts; 80% of the activity was at pH 6.5 and was localized in the cytosol. Oram et al. (19) also reported three pH optima (pH 4, 6, and 8) for lipase activities ...

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Section: Discussionmentioning

confidence: 99%

Abnormal Neutral Lipase Activity in Acid-Lipase-Deficient Cultured Human Fibroblasts

et al. 1983

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“…In most studies, less than 5% of control activity has been observed (4,6). Differences in residual activity that might account for the differing phenotypes in the two disorders have not been consistently demonstrated.…”

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confidence: 99%

“…In addition, the differences observed between the two disorders provide a biochemical explanation for the different phenotypes associated with the two disorders. (Pediatr Res 18:1242Res 18: -1245Res 18: ,1984 Abbreviations MEM, minimal essential medium LDL, low-density lipoprotein VLDL, very low-density lipoprotein CL, cholesteryl linoleate PBS, phosphate-buffered saline LPDS, lipoprotein-deficient serum Wolman's disease and cholesterol ester storage disease are genetically distinct inborn errors of metabolism associated with a deficiency of lysosomal acid lipase activity (6,15,19). Although both are characterized by accumulation of cholesterol esters and triglycerides in tissues, the clinical phenotypes are quite different.…”

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confidence: 99%

Cholesterol Ester and Triglyceride Metabolism in Intact Fibroblasts from Patients with Wolman's Disease and Cholesterol Ester Storage Disease

1984

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ABSTRACT. Cholesterol ester and triglyceride metabolism was examined in intact fibroblast monolayers from normal individuals and patients with Wolman's disease and cholesterol ester storage disease. Cholesterol esters were introduced into cells by incubation in medium containing [3H]cholesteryl linoleate (CL) bound to human low density lipoprotein. Triglycerides were introduced by incubation with glycerol tri[l-'4CJoleate (trjolein) bound to hunian very low-density lipoprotein. Both types of mutant cell lines accumulated the unhydrolyzed substrates to a greater extent than did normal cells with the greatest accumulation observed in Wolman's disease cells. Wolman's disease cells hydrolyzed CL at 10-22% and triolein at 11-19% the rate of normal cells; cholesterol ester storage disease cells hydrolyzed these substrates at 28-49 and 3047% the normal rate, respectively. In contrast, assays of acid lipase activity in cell lysates revealed less than 1% of control activity in both disorders. The data suggest that the mutant acid lipase present in Wolman's disease and cholesterol ester storage disease is more active in the intact cell than assays of cell lysates would indicate. In addition, the differences observed between the two disorders provide a biochemical explanation for the different phenotypes associated with the two disorders. (Pediatr Res 18:1242-1245,1984

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“…Acid lipase (AL) was assayed fluorometrically (8) in an Aminco-Bowman spectrophofluorometer (36) using Cmethylumbelliferyl oleate (MUO) as substrate (37) The adipocytes in culture gradually changed shape and assumed a stellate fibroblast-like appearance. At the same time, they gradually lost their stored lipids.…”

Section: Methodsmentioning

confidence: 99%

“…In adipose tissue, an acid lipase, which could be stimulated by lipolytic hormones (18,28) has been described as sedimenting with mitochondria (18,28). This is the class of lipases deficient in the tissues of patients with lipidoses such as Wolman's disease and cholesteryl ester storage disease (8).…”

Section: Speculationmentioning

confidence: 99%

Acid and Neutral Lipases of Cultured Adipocytes of Infants and Children

1978

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SummaryIn order to determine whether the mobilization of intracellular triglycerides observed in cultured human adipocytes is associated with changes in the activities of acid and neutral lipases, the activities of both enzymes were measured weekly on cultured adipocytes for several months. The activity of acid lipase was initially very low, but rose to levels 40 times the original activity within 3 months. The activity of neutral lipase decreased rapidly within the first 2-4 weeks and remained at approximately 25% of original levels thereafter. SpeculationThere is increasing evidence that the human adipocyte is highly specialized and that it is derived from a stromal precursor present in the adipose tissue. The cell has the capacity to acquire in culture the properties of the precursor, as evidenced by the appearance of acid lipase and disappearance of neutral lipase. We submit that the low level of acid lipase in the adipocyte is related to its lipid storage function. It remains to be proven that it is not primary to the differentiation of the adipocyte from its ~uhhermore, we speculate that a direct biochemical relations hi^ exists between the neutral lipase and intracellular triglyceride Aores in the adipocyte.Although lipid mobilization from adipose tissue appears to be under the control of a number of endogenous and exogenous influences, the final step in mobilization is hydrolysis of triglycerides by lipases. Neutral lipases have been characterized in the adipose and other tissues of a number of species (4-7, 11-17, 20, 21, 23, 27, 29-33). They are active at neutral pH, have affinity for long chain triglyceride esters, and sensitive to hormones such as epinephrine and insulin. Acid lipases are lysosoma1 in subcellular location (13,20,32). First described in the liver (13,28,32), acid lipases are active around pH 4.0 and appear to have a somewhat broader chain length preference. In adipose tissue, an acid lipase, which could be stimulated by lipolytic hormones (18, 28) has been described as sedimenting with mitochondria (18,28). This is the class of lipases deficient in the tissues of patients with lipidoses such as Wolman's disease and cholesteryl ester storage disease (8).Earlier, we showed that human adipose cells can be sustained in culture for long periods of time (1, 2) and have described some of the morphologic and enzymatic properties of these cells in culture (2). Other investigators (9, 24, 34) have also established presumptive "preadipose" or adipose cells in culture. In one study (24), cultured "preadipose cells" accumulated triglycerides and incorporated glucose into lipids, thus resembling adipose cells rather than skin fibroblasts. In a recent study, Van et al. (34) found measurable levels of lipoprotein lipase activity in cultured "adipocyte precursors" of human adipose tissue. These putative "preadipose cells" were also found to possess 15 times as much triglyceride synthetase activity as skin fibroblast from the same patients and twice the fatty acid synthetase activity. Dixon-Shanies ...

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Genetic Variation of Lysosomal Acid Lipase

Cited by 62 publications

References 4 publications

Abnormal Neutral Lipase Activity in Acid-Lipase-Deficient Cultured Human Fibroblasts

Abnormal Neutral Lipase Activity in Acid-Lipase-Deficient Cultured Human Fibroblasts

Cholesterol Ester and Triglyceride Metabolism in Intact Fibroblasts from Patients with Wolman's Disease and Cholesterol Ester Storage Disease

Acid and Neutral Lipases of Cultured Adipocytes of Infants and Children

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