Role of lysosomal acid lipase in the intracellular metabolism of LDL-transported dehydroepiandrosterone-fatty acyl esters

2008 ◽  
Vol 295 (6) ◽  
pp. E1455-E1461 ◽  
Author(s):  
Feng Wang ◽  
Wei Wang ◽  
Kristiina Wähälä ◽  
Herman Adlercreutz ◽  
Elina Ikonen ◽  
...  
Keyword(s):  
Hela Cells ◽  
Ldl Receptor ◽  
Fatty Acyl ◽  
Biologically Active ◽  
Acid Lipase ◽  
Lysosomal Acid ◽  
Lysosomal Acid Lipase ◽  
Cellular Fraction ◽  
Hydrolysis Of

Dehydroepiandrosterone-fatty acyl esters (DHEA-FAE) belong to a unique family of naturally occurring hydrophobic steroid hormone derivatives that are transported in circulating lipoproteins and may act as a source of dehydroepiendrosterone (DHEA) and other biologically active steroid hormones in cells. Here, we studied the metabolic fate of low-density lipoprotein-associated [3H]DHEA-FAE ([3H]DHEA-FAE-LDL) and the possible role of lysosomal acid lipase (LAL) in the hydrolysis of DHEA-FAE in cultured human cells. When HeLa cells were incubated with [3H]DHEA-FAE-LDL, the accumulation of label in the cellular fraction increased with incubation time and could be inhibited by excess unlabeled LDL, suggesting LDL receptor or LDL receptor-related receptor-dependent uptake. During 48 h of chase, decreasing amounts of [3H]DHEA-FAE were found in the cellular fraction, while in the medium increasing amounts of unesterified [3H]DHEA and its two metabolites, [3H]-5α-androstanedione (5α-adione) and [3H]androstenedione (4-adione), appeared. As LDL-cholesteryl ester hydrolysis is dependent on LAL activity, we depleted LAL from HeLa cells using small interfering RNAs and compared the hydrolysis of [3H]DHEA-FAE-LDL and [3H]cholesteryl-FAE-LDL. The results demonstrated a more modest but significant reducing effect on the hydrolysis of [3H]DHEA-FAE compared with [3H]cholesteryl-FAE. Moreover, experiments in LAL-deficient human fibroblasts (Wolman disease patient cells) showed that [3H]DHEA-FAE hydrolysis was not completely dependent on LAL activity. In summary, LDL-transported [3H]DHEA-FAE entered cells via LDL receptor or LDL receptor-related receptor-mediated uptake, followed by intracellular hydrolysis and further metabolism into 5α-adione and 4-adione that were excreted from cells. Although LAL contributed to the deesterification of DHEA-FAE, it was not solely responsible for the hydrolysis.

Abstract 17868: Role of Lysosomal Acid Lipase in LDL-C Regulation in Familial Hypercholesterolemia and Metabolic Syndrome

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Atsushi Nohara ◽  
Masa-aki Kawashiri ◽  
Yoshikatsu Eto ◽  
Miwa Fujisaki ◽  
Hayato Tada ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
High Risk ◽  
Familial Hypercholesterolemia ◽  
Susceptibility Gene ◽  
Dried Blood Spots ◽  
Assay Method ◽  
Acid Lipase ◽  
Lysosomal Acid ◽  
Lysosomal Acid Lipase

Lysosomal acid lipase (LAL), coded by LIPA gene, is key role player of LDL receptor pathway, and LIPA is a susceptibility gene for CAD in many GWAS studies. LAL hydrolyzes cholesterol-ester in hepatocytes, and is essential for M2 activation of macrophages. Furthermore, LAL-deficiency, with increased LDL-C and premature CAD, has been focused as underdiagnosed disease similar to familial hypercholesterolemia (FH). On the other hand, little is known about the role of physiological LAL activity on atherosclerosis. We investigated LIPA gene as genetic cause of FH, and LAL activity in CAD high-risk group. Methods: This study consisted of two parts. First part was genetic analysis of LIPA gene. From 940 clinically diagnosed hetero-FH patients in Japan, pathogenic mutations were identified in 788 patients through screening in LDLR, PCSK9, and APOB genes. All coding regions of LIPA gene were investigated in 143 hetero-FH patients without pathogenic mutation in those genes. Identified variants were also evaluated in 200 genetically confirmed hetero-FH, 200 non-FH dyslipidemia, and 250 general population samples. Second part was LAL acclivity measurement with very recently developed fluorometric assay method using dried blood spots. A total of 122 CAD high-risk patients (M/F: 67/55, age: 65 ± 15 yrs, established CAD: 34%, DM: 46%, hetero-FH: 25%) were investigated their LAL activity. Results: Analysis in LIPA gene revealed no patients with LAL-deficiency among FH without confirmed mutations. All variants identified were considered as benign. Intriguingly, common LIPA T16P carriers showed lower pre-treatment LDL-C in genetically confirmed hetero-FH (LDL-C 215±61 vs. 242±70 mg/dL, p <0.05). In activity analysis, LAL activity correlated positively with BMI (R 2 : 10%, p <0.0005), γGTP (R 2 : 11%, p <0.0005), and HbA1c (R 2 : 5%, p <0.05), and negatively with LDL-C (R 2 : 4%, p <0.05). Exclusion of FH did not change these results. LAL might have a protective role in obesity, like metabolic syndrome does not necessarily reveal high LDL-C. Conclusion: LAL-deficiency was not common genetic cause of FH in Japan. LAL activity increased with obesity, and negatively correlated with LDL-C. Further study will clarify the role of LAL in atherosclerosis.

scholarly journals Effect of Phospholipids on the Hydrolysis of Cholesterol Oleate Liquid Crystals by Lysosomal Acid Lipase

1986 ◽  
Vol 14 (2) ◽  
pp. 443-445
Author(s):  
Ruka TAKEUCHI ◽  
Tsuneo IMANAKA ◽  
Masayasu ENOMOTO ◽  
Shod OHKUMA ◽  
Tatsuya TAKANO
Keyword(s):  
Liquid Crystals ◽  
Acid Lipase ◽  
Lysosomal Acid ◽  
Lysosomal Acid Lipase ◽  
Hydrolysis Of

scholarly journals Long-term survival with sebelipase alfa enzyme replacement therapy in infants with rapidly progressive lysosomal acid lipase deficiency: final results from 2 open-label studies

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Suresh Vijay ◽  
Anais Brassier ◽  
Arunabha Ghosh ◽  
Simona Fecarotta ◽  
Florian Abel ◽  
...  
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Phase 2 ◽  
Free Hemoglobin ◽  
Acid Lipase ◽  
Short Term ◽  
Open Label ◽  
Lysosomal Acid ◽  
Enzyme Replacement ◽  
Lysosomal Acid Lipase

Abstract Background If symptomatic in infants, the autosomal recessive disease lysosomal acid lipase deficiency (LAL-D; sometimes called Wolman disease or LAL-D/Wolman phenotype) is characterized by complete loss of LAL enzyme activity. This very rare, rapidly progressive form of LAL-D results in severe manifestations leading to failure to thrive and death, usually by 6 months of age. We report results from 2 open-label studies of enzyme replacement therapy with sebelipase alfa, a recombinant human LAL, in infants with LAL-D: the phase 2/3 Survival of LAL-D Infants Treated With Sebelipase Alfa (VITAL) study (NCT01371825) and a phase 2 dose-escalation study (LAL-CL08 [CL08]; NCT02193867). In both, infants received once-weekly intravenous infusions of sebelipase alfa. Results The analysis population contained 19 patients (9 in VITAL; 10 in CL08). Kaplan–Meier estimates of survival to 12 months and 5 years of age were 79% and 68%, respectively, in the combined population, and the median age of surviving patients was 5.2 years in VITAL and 3.2 years in CL08. In both studies, median weight-for-age, length-for-age, and mid-upper arm circumference-for-age z scores increased from baseline to end of study. Decreases in median liver and spleen volume over time were noted in both studies. Short-term transfusion-free hemoglobin normalization was achieved by 100% of patients eligible for assessment in VITAL, in an estimated median (95% confidence interval [CI]) time of 4.6 (0.3–16.6) months. In CL08, short-term transfusion-free hemoglobin normalization was achieved by 70% of patients eligible for assessment, in an estimated median (95% CI) time of 5.5 (3.7–19.6) months. No patient discontinued treatment because of treatment-emergent adverse events. Most infusion-associated reactions (94% in VITAL and 88% in CL08) were mild or moderate in severity. Conclusions The findings of these 2 studies of infants with rapidly progressive LAL-D demonstrated that enzyme replacement therapy with sebelipase alfa prolonged survival with normal psychomotor development, improved growth, hematologic parameters, and liver parameters, and was generally well tolerated, with an acceptable safety profile.

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