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Biomolecules Dec 2020Since the lipid profile is altered by physical activity, the study of lipid metabolism is a remarkable element in understanding if and how physical activity affects the... (Review)
Review
Since the lipid profile is altered by physical activity, the study of lipid metabolism is a remarkable element in understanding if and how physical activity affects the health of both professional athletes and sedentary subjects. Although not fully defined, it has become clear that resistance exercise uses fat as an energy source. The fatty acid oxidation rate is the result of the following processes: (a) triglycerides lipolysis, most abundant in fat adipocytes and intramuscular triacylglycerol (IMTG) stores, (b) fatty acid transport from blood plasma to muscle sarcoplasm, (c) availability and hydrolysis rate of intramuscular triglycerides, and (d) transport of fatty acids through the mitochondrial membrane. In this review, we report some studies concerning the relationship between exercise and the aforementioned processes also in light of hormonal controls and molecular regulations within fat and skeletal muscle cells.
Topics: Adipose Tissue; Blood Glucose; Endocrine System; Exercise; Fatty Acids; Humans; Lipid Metabolism; Lipolysis; Mitochondrial Membranes; Muscle, Skeletal; Oxygen; Sterol Esterase; Temperature; Triglycerides
PubMed: 33371437
DOI: 10.3390/biom10121699 -
Trends in Molecular Medicine Jun 2023Lysosomal acid lipase (LAL) is the sole enzyme known to degrade neutral lipids in the lysosome. Mutations in the LAL-encoding LIPA gene lead to rare lysosomal lipid... (Review)
Review
Lysosomal acid lipase (LAL) is the sole enzyme known to degrade neutral lipids in the lysosome. Mutations in the LAL-encoding LIPA gene lead to rare lysosomal lipid storage disorders with complete or partial absence of LAL activity. This review discusses the consequences of defective LAL-mediated lipid hydrolysis on cellular lipid homeostasis, epidemiology, and clinical presentation. Early detection of LAL deficiency (LAL-D) is essential for disease management and survival. LAL-D must be considered in patients with dyslipidemia and elevated aminotransferase concentrations of unknown etiology. Enzyme replacement therapy, sometimes in combination with hematopoietic stem cell transplantation (HSCT), is currently the only therapy for LAL-D. New technologies based on mRNA and viral vector gene transfer are recent efforts to provide other effective therapeutic strategies.
Topics: Humans; Wolman Disease; Sterol Esterase; Hematopoietic Stem Cell Transplantation; Lipids
PubMed: 37028992
DOI: 10.1016/j.molmed.2023.03.001 -
TheScientificWorldJournal 2022Hormone-sensitive lipase (HSL) is a pivotal enzyme that mediates triglyceride hydrolysis to provide free fatty acids and glycerol in adipocytes in a hormonally... (Review)
Review
Hormone-sensitive lipase (HSL) is a pivotal enzyme that mediates triglyceride hydrolysis to provide free fatty acids and glycerol in adipocytes in a hormonally controlled lipolysis process. Elevated plasma-free fatty acids were accompanied by insulin resistance, type-2 diabetes, and obesity. Inhibition of lipolysis through HSL inhibition may provide a mechanism to prevent the accumulation of free fatty acids and to improve the affectability of insulin and blood glucose handling in type II diabetes. The published studies that examine the structure, regulation, and function of HSL and major inhibitors were reviewed in this paper.
Topics: Humans; Sterol Esterase; Fatty Acids, Nonesterified; Diabetes Mellitus, Type 2; Lipase; Lipolysis
PubMed: 36530555
DOI: 10.1155/2022/1964684 -
Drug Design, Development and Therapy 2020Lysosomal acid lipase (LAL) deficiency is a metabolic (storage) disorder, encompassing a severe (Wolman disease) and attenuated (Cholesterol ester storage disease)... (Review)
Review
Lysosomal acid lipase (LAL) deficiency is a metabolic (storage) disorder, encompassing a severe (Wolman disease) and attenuated (Cholesterol ester storage disease) subtype; both inherited as autosomal recessive traits. Cardinal clinical features include the combination of hepatic dysfunction and dyslipidemia, as a consequence of cholesteryl esters and triglyceride accumulation, predominately in the liver and vascular and reticuloendothelial system. Significant morbidity can arise, due to liver failure and/or atherosclerosis; in part related to the severity of the underlying gene defect and corresponding enzyme deficiency. Diagnosis is based on demonstration of decreased LAL enzyme activity, complemented by analysis of the cognate gene defects. Therapeutic options include dietary manipulation and the use of lipid-lowering drugs. Sebelipase alfa, a recombinant enzyme replacement therapy, has garnered regulatory approval, following demonstration of improvements in disease-relevant markers and clinical benefit in clinical trials, which included increased survival in the most severe cases.
Topics: Animals; Atherosclerosis; Cholesterol Ester Storage Disease; Humans; Hypolipidemic Agents; Liver Failure; Severity of Illness Index; Sterol Esterase; Wolman Disease
PubMed: 32103901
DOI: 10.2147/DDDT.S149264 -
Trends in Pharmacological Sciences Feb 2019Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters (CEs) and triglycerides (TGs) to free cholesterol (FC) and free fatty acids (FFAs), which are then used for... (Review)
Review
Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters (CEs) and triglycerides (TGs) to free cholesterol (FC) and free fatty acids (FFAs), which are then used for metabolic purposes in the cell. The process also occurs in immune cells that adapt their metabolic machinery to cope with the different energetic requirements associated with cell activation, proliferation, and polarization. LAL deficiency (LALD) causes severe lipid accumulation and affects the immunometabolic signature in animal models. In humans, LAL deficiency is associated with a peculiar clinical immune phenotype, secondary hemophagocytic lymphohistiocytosis. These observations suggest that LAL might play an important role in cellular immunometabolic modulation, and availability of an effective enzyme replacement strategy makes LAL an attractive target to rewire the metabolic machinery of immune cells beyond its role in controlling cellular lipid metabolism.
Topics: Animals; Humans; Immune System; Lipid Metabolism; Liver; Sterol Esterase; Wolman Disease
PubMed: 30665623
DOI: 10.1016/j.tips.2018.12.006 -
Jornal de Pediatria 2022Lysosomal acid lipase deficiency (LAL-D) is an underdiagnosed autosomal recessive disease with onset between the first years of life and adulthood. Early diagnosis is... (Review)
Review
OBJECTIVE
Lysosomal acid lipase deficiency (LAL-D) is an underdiagnosed autosomal recessive disease with onset between the first years of life and adulthood. Early diagnosis is crucial for effective therapy and long-term survival. The objective of this article is to recognize warning signs among the clinical and laboratory characteristics of LAL-D in pediatric patients through a scope review.
SOURCES
Electronic searches in the Embase, PubMed, Livivo, LILACS, Web of Science, Scopus, Google Scholar, Open Gray, and ProQuest Dissertations and Theses databases. The dataset included observational studies with clinical and laboratory characteristics of infants, children and adolescents diagnosed with lysosomal acid lipase deficiency by enzyme activity testing or analysis of mutations in the lysosomal acid lipase gene (LIPA). The reference selection process was performed in two stages. The references were selected by two authors, and the data were extracted in June 2020.
SUMMARY OF THE FINDINGS
The initial search returned 1593 studies, and the final selection included 108 studies from 30 countries encompassing 206 patients, including individuals with Wolman disease and cholesteryl ester storage disease (CESD). The most prevalent manifestations in both spectra of the disease were hepatomegaly, splenomegaly, anemia, dyslipidemia, and elevated transaminases.
CONCLUSIONS
Vomiting, diarrhea, jaundice, and splenomegaly may be correlated, and may serve as a starting point for investigating LAL-D. Familial lymphohistiocytosis should be part of the differential diagnosis with LAL-D, and all patients undergoing upper gastrointestinal endoscopy should be submitted to intestinal biopsy.
Topics: Adolescent; Adult; Child; Cholesterol Ester Storage Disease; Hepatomegaly; Humans; Infant; Sterol Esterase; Wolman Disease
PubMed: 33964214
DOI: 10.1016/j.jped.2021.03.003 -
Journal of Atherosclerosis and... 2011Cholesterol ester-laden macrophage foam cells are a hallmark of atherosclerosis. The cycle of esterification and hydrolysis of cholesterol esters is one of the key steps... (Review)
Review
Cholesterol ester-laden macrophage foam cells are a hallmark of atherosclerosis. The cycle of esterification and hydrolysis of cholesterol esters is one of the key steps in macrophage cholesterol trafficking. In the process of foam cell formation, excess free cholesterol undergoes esterification by acyl coenzyme A: acylcholesterol transferase 1 (ACAT-1), and fatty acid sterol esters are stored in cytoplasmic lipid droplets. The actions of ACAT-1 are opposed by neutral cholesterol ester hydrolase (nCEH), which generates free cholesterol and fatty acids. The resulting free cholesterol is a preferential source for cholesterol efflux into the extracellular space. Despite the important role of nCEH in protection against foam cell formation and atherosclerosis, the molecular identity of nCEH has long been debated. Although hormone-sensitive lipase (LIPE) has been proposed to be the nCEH in macrophages, recent evidence suggested the existence of other nCEH(s). We have recently identified a novel nCEH, neutral cholesterol ester hydrolase 1 (NCEH1), and demonstrated that NCEH1, in addition to LIPE, primarily mediates the hydrolysis of CE in macrophages. This review focuses on the protective roles of nCEHs in atherosclerosis, with special emphasis on the role of NCEH1.
Topics: Animals; Atherosclerosis; Cholesterol Esters; Foam Cells; Humans; Hydrolysis; Sterol Esterase
PubMed: 21467808
DOI: 10.5551/jat.7013 -
ELife Feb 2021Triacylglycerol (TG) and steryl ester (SE) lipid storage is a universal strategy to maintain organismal energy and membrane homeostasis. Cycles of building and...
Triacylglycerol (TG) and steryl ester (SE) lipid storage is a universal strategy to maintain organismal energy and membrane homeostasis. Cycles of building and mobilizing storage fat are fundamental in (re)distributing lipid substrates between tissues or to progress ontogenetic transitions. In this study, we show that Hormone-sensitive lipase (Hsl) specifically controls SE mobilization to initiate intergenerational sterol transfer in . Tissue-autonomous Hsl functions in the maternal fat body and germline coordinately prevent adult SE overstorage and maximize sterol allocation to embryos. While Hsl-deficiency is largely dispensable for normal development on sterol-rich diets, animals depend on adipocyte Hsl for optimal fecundity when dietary sterol becomes limiting. Notably, accumulation of SE but not of TG is a characteristic of Hsl-deficient cells across phyla including murine white adipocytes. In summary, we identified Hsl as an ancestral regulator of SE degradation, which improves intergenerational sterol transfer and reproductive success in flies.
Topics: Animals; Drosophila Proteins; Drosophila melanogaster; Reproduction; Sterol Esterase; Sterols
PubMed: 33538247
DOI: 10.7554/eLife.63252 -
BioMed Research International 2022The present study investigated the effect of the leaves extracts and fractions of on the inhibition of pancreatic lipase, cholesterol esterase, adipocytes lipid uptake,...
OBJECTIVE
The present study investigated the effect of the leaves extracts and fractions of on the inhibition of pancreatic lipase, cholesterol esterase, adipocytes lipid uptake, and antithrombotic activity which may be important in atherosclerosis development.
METHODS
Aqueous, ethanolic, and hydroethanolic extracts of were prepared by maceration. The hydroethanolic extract was fractionated into -hexane, ethylacetate, and butanol fractions and their inhibition of pancreatic lipase, cholesterol esterase, adipocytes lipid uptake, and antithrombotic activities measured. Liquid chromatography-high resolution mass spectrometry (LC-HRMS) analysis was carried out to determine phytochemical constituents present in the extracts.
RESULTS
The standard orlistat exhibited a higher inhibitory activity on pancreatic lipase and cholesterol esterase (16.31 g/mL and 15.75 g/mL, respectively) compared to ethyl acetate fraction (IC, 17.70 g/mL and IC, 24.8 g/mL, respectively). Among crude extract, hydroethanolic extract showed a better inhibition against pancreatic lipase (IC, 21.06 g/mL) and cholesterol esterase (IC, 25.14 g/mL) though not comparable to the effect of orlistat. The best lipid uptake inhibition was observed in the hydroethanolic extract (IC, 45.42 g/mL) followed by the ethyl acetate fraction (IC, 47.77 g/mL). A better antithrombolytic activity was exhibited by the ethyl acetate fraction at all concentrations (50-800 /mL), while hydroethanolic extract exhibited the best activity among crude extract. However, these were not comparable to the standard aspirin. The LC-HRMS analysis revealed the presence of 7--methyl luteolin 5---D-glucopyranoside, chrysoeriol 5---D-glucopyranoside, 5,7-dihydroxy-3,2',4'-trimethoxyflavone, and plectranmicin as major compounds in both hydroethanolic extract and ethyl acetate fraction.
CONCLUSION
Thus, our finding supports the traditional use of this plant, which might provide a potential source for future antiatherosclerotic drug discovery.
Topics: Antioxidants; Fibrinolytic Agents; Lamiaceae; Lipase; Lipids; Orlistat; Plant Extracts; Plant Leaves; Plectranthus; Sterol Esterase
PubMed: 35178447
DOI: 10.1155/2022/4145659 -
Current Opinion in Lipidology Jun 2018Lysosomal acid lipase (LAL), encoded by the LIPA gene, is an essential lysosomal enzyme that hydrolyzes cholesteryl ester and triglyceride delivered to the lysosome.... (Review)
Review
PURPOSE OF REVIEW
Lysosomal acid lipase (LAL), encoded by the LIPA gene, is an essential lysosomal enzyme that hydrolyzes cholesteryl ester and triglyceride delivered to the lysosome. This review highlights the novel pathophysiological role of LAL, the functional genomic discoveries of LIPA as a risk locus for coronary heart diseases (CHD), and the clinical advance in therapies for LAL deficiency.
RECENT FINDINGS
The essential role of LAL in lipid metabolism has been confirmed in human and mice with LAL deficiency. In humans, loss-of-function mutations of LIPA cause rare lysosomal disorders, Wolman disease, and cholesteryl ester storage disease, in which LAL enzyme replacement therapy has shown significant benefits in a phase 3 clinical trial. Recent studies have revealed the role of LAL-mediated lysosomal lipolysis in regulating macrophage M2 polarization, lipid mediator production, VLDL secretion, lysosomal function and autophagy, extracellular degradation of aggregated-LDL, and adipose tissue lipolysis. Genome-wide association studies and functional genomic studies have identified LIPA as a risk locus for CHD, but the causal variants and mechanisms remain to be determined.
SUMMARY
Despite years of research, our understanding of LAL is incomplete. Future studies will continue to focus on the key pathophysiological functions of LAL in health and diseases including CHD.
Topics: Adipose Tissue; Animals; Humans; Lipid Metabolism; Lipoproteins, VLDL; Lysosomes; Mice; Sterol Esterase; Wolman Disease
PubMed: 29547398
DOI: 10.1097/MOL.0000000000000507