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Trends in Endocrinology and Metabolism:... Nov 2014Non-alcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in Western countries, ranging from simple steatosis to steatohepatitis, cirrhosis,... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in Western countries, ranging from simple steatosis to steatohepatitis, cirrhosis, and hepatocellular cancer. Although the mechanisms underlying disease progression are incompletely understood, lipotoxic events in the liver resulting in inflammation and fibrosis appear to be central. Free fatty acids and their metabolites are potentially lipotoxic mediators triggering liver injury, suggesting a central role for metabolic lipases. These enzymes are major players in lipid partitioning between tissues and within cells, and provide ligands for nuclear receptors (NRs). We discuss the potential role of intracellular lipases and their lipolytic products in NAFLD. Because tissue-specific modulation of lipases is currently impossible, targeting NRs with ligands may open novel therapeutic perspectives.
Topics: Animals; Disease Progression; Humans; Lipase; Lipolysis; Liver; Non-alcoholic Fatty Liver Disease; Receptors, Cytoplasmic and Nuclear; Sterol Esterase
PubMed: 25183341
DOI: 10.1016/j.tem.2014.08.001 -
Expert Opinion on Drug Safety Feb 2022Lysosomal acid lipase deficiency is an autosomal recessive progressive lysosomal storage disease that mainly affects the liver, intestine growth, and causes... (Review)
Review
INTRODUCTION
Lysosomal acid lipase deficiency is an autosomal recessive progressive lysosomal storage disease that mainly affects the liver, intestine growth, and causes dyslipidemia. The disease presents as two major phenotypes: the severe early-onset and late-onset forms. Sebelipase alfa is a recombinant human enzyme-replacement therapy for lysosomal acid lipase deficiency, which has been approved for long-term treatment of early-onset and late-onset patients over five years.
AREAS COVERED
This review mainly focuses on the safety of sebelipase alfa based on the literature including studies, case reports, and reviews up to January 2021. The search was conducted on PubMed only by using the key word "sebelipase alfa." No restrictions were applied.
EXPERT OPINION
The documented adverse events related to sebelipase alfa almost always occurred as infusion reactions. The majority of these reactions were mild to moderate and were easily managed or prevented with antihistamines, antipyretics, and steroids. Rarely, these reactions occurred in the form of anaphylaxis but were treated successfully and the infusions were started again with desensitization without a need for stopping the treatment. Based on the scientific evidence until now, sebelipase alfa appears to be a safe treatment changing the natural history of lysosomal acid lipase deficiency.
Topics: Animals; Enzyme Replacement Therapy; Humans; Phenotype; Sterol Esterase; Wolman Disease
PubMed: 34664536
DOI: 10.1080/14740338.2022.1993186 -
Journal of Lipid Research Sep 2023Lysosomal acid lipase (LAL) is the sole lysosomal enzyme responsible for the degradation of cholesteryl esters and triacylglycerols at acidic pH. Impaired LAL activity...
Lysosomal acid lipase (LAL) is the sole lysosomal enzyme responsible for the degradation of cholesteryl esters and triacylglycerols at acidic pH. Impaired LAL activity leads to LAL deficiency (LAL-D), a severe and fatal disease characterized by ectopic lysosomal lipid accumulation. Reduced LAL activity also contributes to the development and progression of non-alcoholic fatty liver disease (NAFLD). To advance our understanding of LAL-related liver pathologies, we performed comprehensive proteomic profiling of livers from mice with systemic genetic loss of LAL (Lal-/-) and from mice with hepatocyte-specific LAL-D (hepLal-/-). Lal-/- mice exhibited drastic proteome alterations, including dysregulation of multiple proteins related to metabolism, inflammation, liver fibrosis, and cancer. Global loss of LAL activity impaired both acidic and neutral lipase activities and resulted in hepatic lipid accumulation, indicating a complete metabolic shift in Lal-/- livers. Hepatic inflammation and immune cell infiltration were evident, with numerous upregulated inflammation-related gene ontology biological process terms. In contrast, both young and mature hepLal-/- mice displayed only minor changes in the liver proteome, suggesting that loss of LAL solely in hepatocytes does not phenocopy metabolic alterations observed in mice globally lacking LAL. These findings provide valuable insights into the mechanisms underlying liver dysfunction in LAL-D and may help in understanding why decreased LAL activity contributes to NAFLD. Our study highlights the importance of LAL in maintaining liver homeostasis and demonstrates the drastic consequences of its global deficiency on the liver proteome and liver function.
Topics: Mice; Animals; Sterol Esterase; Non-alcoholic Fatty Liver Disease; Proteome; Proteomics; Liver; Wolman Disease; Liver Cirrhosis; Triglycerides; Inflammation; Neoplasms
PubMed: 37595802
DOI: 10.1016/j.jlr.2023.100427 -
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 -
Frontiers in Endocrinology 2023Napping is a widespread practice worldwide and has in recent years been linked to increased abdominal adiposity. Lipase E or encodes the protein hormone-sensitive...
BACKGROUND AND PURPOSE
Napping is a widespread practice worldwide and has in recent years been linked to increased abdominal adiposity. Lipase E or encodes the protein hormone-sensitive lipase (HSL), an enzyme that plays an important role in lipid mobilization and exhibits a circadian expression rhythm in human adipose tissue. We hypothesized that habitual napping may impact the circadian expression pattern of , which in turn may attenuate lipid mobilization and induce abdominal fat accumulation.
METHODS
Abdominal adipose tissue explants from participants with obesity (n = 17) were cultured for a 24-h duration and analyzed every 4 h. Habitual nappers (n = 8) were selected to match non-nappers (n = 9) in age, sex, BMI, adiposity, and metabolic syndrome traits. Circadian expression rhythmicity was analyzed using the cosinor method.
RESULTS
Adipose tissue explants exhibited robust circadian rhythms in expression in non-nappers. In contrast, nappers had a flattened rhythm. amplitude was decreased in nappers as compared with non-nappers (71% lower). The decrease in amplitude among nappers was related to the frequency of napping (times per week) where a lower rhythm amplitude was associated with a higher napping frequency (r = -0.80; = 0.018). Confirmatory analyses in the activity of 's protein (i.e., HSL) also showed a significant rhythm in non-nappers, whereas significance in the activity of HSL was lost among nappers.
CONCLUSION
Our results suggest that nappers display dysregulated circadian expression as well as dysregulated circadian HSL activity, which may alter lipid mobilization and contribute to increased abdominal obesity in habitual nappers.
Topics: Humans; Abdominal Fat; Adipose Tissue; Circadian Rhythm; Obesity; Sterol Esterase; Lipase
PubMed: 37361522
DOI: 10.3389/fendo.2023.1166961 -
American Journal of Cardiovascular... Dec 2016Sebelipase alfa (Kanuma, Kanuma™), the first commercially available recombinant human lysosomal acid lipase (LAL), is approved in various countries worldwide,... (Review)
Review
Sebelipase alfa (Kanuma, Kanuma™), the first commercially available recombinant human lysosomal acid lipase (LAL), is approved in various countries worldwide, including those of the EU, the USA and Japan, as a long-term enzyme replacement therapy for patients diagnosed with LAL deficiency (LAL-D), an ultra-rare, autosomal recessive, progressive metabolic liver disease. In an ongoing study in nine infants presenting with early-onset LAL-D (Wolman disease), open-label treatment with sebelipase alfa significantly improved 1-year survival compared with historical controls. A substantial mortality benefit was maintained at 2 years of age, as was a reduction in disease-related activity. In an ongoing study of 66 children and adults with late-onset LAL-D (cholesteryl ester storage disease), 20 weeks' double-blind treatment with sebelipase alfa significantly reduced multiple disease-related hepatic and lipid abnormalities compared with placebo. Sustained improvements in markers of liver damage and dyslipidaemia were seen after 76 weeks' open-label treatment in an extension of this trial and, similarly, after 2 years' open-label treatment in an extension of another study in nine adults with late-onset LAL-D. Sebelipase alfa therapy has thus far been generally well tolerated, with signs and symptoms consistent with anaphylaxis being the most serious adverse reactions experienced by patients receiving the drug in clinical trials. Due to the rarity of the disease, these studies have enrolled a limited number of patients. Nonetheless, the available data indicate that sebelipase alfa is an effective disease-specific therapy for individuals with LAL-D who have historically been managed using supportive therapies (e.g. cholesterol reduction, hematopoietic stem cell transplantation, and liver transplantation).
Topics: Clinical Trials as Topic; Double-Blind Method; Humans; Liver; Liver Diseases; Sterol Esterase; Wolman Disease
PubMed: 27878737
DOI: 10.1007/s40256-016-0203-2 -
Food Chemistry Jan 2022Cow (CwC) and camel casein (CaC) hydrolysates were generated using Alcalase™ (CwCA and CaCA) and Pronase-E (CwCP and CaCP) each for 3 and 6 h, and investigated for... (Comparative Study)
Comparative Study
A comparative investigation into novel cholesterol esterase and pancreatic lipase inhibitory peptides from cow and camel casein hydrolysates generated upon enzymatic hydrolysis and in-vitro digestion.
Cow (CwC) and camel casein (CaC) hydrolysates were generated using Alcalase™ (CwCA and CaCA) and Pronase-E (CwCP and CaCP) each for 3 and 6 h, and investigated for their potential to inhibit key lipid digesting enzymes i.e., pancreatic lipase (PL) and cholesteryl esterase (CE). Results revealed stronger PL and CE inhibition by CaC hydrolysates compared to CwC. Potent hydrolysates (CwCP-3 h and CaCA-6 h) upon simulated gastrointestinal digestion (SGID) showed significant improvement in inhibition of both PL and CE. However, both the SGID hydrolysates showed similar extent of PL and CE inhibition and were further sequenced for peptide identification. Peptides MMML, FDML, HLPGRG from CwC and AAGF, MSNYF, FLWPEYGAL from CaC hydrolysates were predicted to be most active PL inhibitory peptides. Peptide LP found in both CwC and CaC hydrolysates was predicted as active CE inhibitor. Thus, CwC and CaC could be potential source of peptides with promising CE and PL inhibitory properties.
Topics: Animals; Camelus; Caseins; Cattle; Digestion; Female; Hydrolysis; Lipase; Peptides; Protein Hydrolysates; Sterol Esterase
PubMed: 34348197
DOI: 10.1016/j.foodchem.2021.130661 -
Journal of Structural Biology Sep 2014Sterol esterases are able to efficiently hydrolyze both sterol esters and triglycerides and to carry out synthesis reactions in the presence of organic solvents. Their...
Sterol esterases are able to efficiently hydrolyze both sterol esters and triglycerides and to carry out synthesis reactions in the presence of organic solvents. Their high versatility makes them excellent candidates for biotechnological purposes. Sterol esterase from fungus Ophiostoma piceae (OPE) belongs to the family abH03.01 of the Candida rugosa lipase-like proteins. Crystal structures of OPE were solved in this study for the closed and open conformations. Enzyme activation involves a large displacement of the conserved lid, structural rearrangements of loop α16-α17, and formation of a dimer with a large opening. Three PEG molecules are placed in the active site, mimicking chains of the triglyceride substrate, demonstrating the position of the oxyanion hole and the three pockets that accommodate the sn-1, sn-2 and sn-3 fatty acids chains. One of them is an internal tunnel, connecting the active center with the outer surface of the enzyme 30 Å far from the catalytic Ser220. Based on our structural and biochemical results we propose a mechanism by which a great variety of different substrates can be hydrolyzed in OPE paving the way for the construction of new variants to improve the catalytic properties of these enzymes and their biotechnological applications.
Topics: Binding Sites; Catalytic Domain; Crystallography, X-Ray; Enzyme Activation; Fungal Proteins; Glycosylation; Hydrolysis; Hydrophobic and Hydrophilic Interactions; Models, Molecular; Mutation; Ophiostoma; Polysaccharides; Protein Binding; Protein Conformation; Protein Multimerization; Protein Structure, Tertiary; Serine; Sterol Esterase; Substrate Specificity; Triglycerides
PubMed: 25108239
DOI: 10.1016/j.jsb.2014.07.007 -
Biochimica Et Biophysica Acta.... Sep 2022There is an inverse relationship between the differentiation of mesenchymal stem cells (MSCs) along either an adipocyte or osteoblast lineage, with lineage...
There is an inverse relationship between the differentiation of mesenchymal stem cells (MSCs) along either an adipocyte or osteoblast lineage, with lineage differentiation known to be mediated by transcription factors PPARγ and Runx2, respectively. Endogenous ligands for PPARγ are generated during the hydrolysis of triacylglycerols to fatty acids through the actions of lipases such as hormone sensitive lipase (HSL). To examine whether reduced production of endogenous PPARγ ligands would influence bone regeneration, we examined the effects of HSL knockout on fracture repair in mice using a tibial mono-cortical defect as a model. We found an improved rate of fracture repair in HSL-ko mice documented by serial μCT and bone histomorphometry compared to wild-type (WT) mice. Similarly, accelerated rates of bone regeneration were observed with a calvarial model where implantation of bone grafts from HSL-ko mice accelerated bone regeneration at the injury site. Further analysis revealed improved MSC differentiation down osteoblast and chondrocyte lineage with inhibition of HSL. MSC recruitment to the injury site was greater in HSL-ko mice than WT. Finally, we used single cell RNAseq to understand the osteoimmunological differences between WT and HSL-ko mice and found changes in the pre-osteoclast population. Our study shows HSL-ko mice as an interesting model to study improvements to bone injury repair. Furthermore, our study highlights the potential importance of pre-osteoclasts and osteoclasts in bone repair.
Topics: Animals; Bone Regeneration; Ligands; Mice; Mice, Knockout; PPAR gamma; Sterol Esterase
PubMed: 35618183
DOI: 10.1016/j.bbadis.2022.166449 -
Journal of Biomolecular Structure &... Jul 2022In this work, Combining coumarin and thiazole with 3-tertiary butyl salicylaldehyde into in a single molecule, new Schiff base (CTS), and its metal complexes with...
Synthesis, characterization, molecular docking and in vitro screening of new metal complexes with coumarin Schiff base as anticholine esterase and antipancreatic cholesterol esterase agents.
In this work, Combining coumarin and thiazole with 3-tertiary butyl salicylaldehyde into in a single molecule, new Schiff base (CTS), and its metal complexes with palladium and platinum were synthesized and characterized by using well-known spectroscopic techniques such as H-NMR, C-NMR, FT-IR and LC-MS. And also, the formation of these complexes were confirmed by magnetic moment and conductivity measurements. The photophysical properties of CTS were studied and it was observed that the Schiff base has a sensitivity to CN, F, and AcO anions. The quantum chemical calculations based on density functional theory (DFT) were done for explaining some experimental, structural, and spectroscopic data of the dyes. Also, to evaluate the binding interactions between the ligand (CTS) and its metal complexes and enzymes, molecular docking studies were performed and all the compounds tested to determine its inhibition potential against the cholinesterase (AChE and BChE) and pancreatic cholesterol esterase (CEase) enzymes. Both and the results showed that all of the compounds could act as potent inhibitors of AChE, BChE, and CEase. The Pt (II) complex showed the most potent inhibitory property against all of the enzymes with IC values of 12 µM for AChE, 23 µM for BChE, and 21 µM for CEase.Communicated by Ramaswamy H. Sarma.
Topics: Coordination Complexes; Coumarins; Esterases; Molecular Docking Simulation; Schiff Bases; Spectroscopy, Fourier Transform Infrared; Sterol Esterase
PubMed: 33480334
DOI: 10.1080/07391102.2020.1858163