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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 -
Cell Aug 2020Fatty acid binding proteins (FABPs) serve as intracellular chaperones for fatty acids and other hydrophobic ligands inside cells. Recent studies have demonstrated new...
Fatty acid binding proteins (FABPs) serve as intracellular chaperones for fatty acids and other hydrophobic ligands inside cells. Recent studies have demonstrated new functions of individual members of the FABP family. This Snapshot describes the overall functions of FABPs in health and disease and highlights emerging roles of adipose FABP (A-FABP) and epidermal FABP (E-FABP) in the fields of obesity, chronic inflammation, and cancer development. To view this SnapShot, open or download the PDF.
Topics: Adipocytes; Fatty Acid-Binding Proteins; Humans; Macrophages; Models, Biological; Neoplasms; Obesity; Peroxisome Proliferator-Activated Receptors; Signal Transduction; Skin Diseases; Sterol Esterase
PubMed: 32822569
DOI: 10.1016/j.cell.2020.07.027 -
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 -
Nature Oct 2017Catecholamine-induced lipolysis, the first step in the generation of energy substrates by the hydrolysis of triglycerides, declines with age. The defect in the...
Catecholamine-induced lipolysis, the first step in the generation of energy substrates by the hydrolysis of triglycerides, declines with age. The defect in the mobilization of free fatty acids in the elderly is accompanied by increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. Although catecholamine signalling in adipocytes is normal in the elderly, how lipolysis is impaired in ageing remains unknown. Here we show that adipose tissue macrophages regulate the age-related reduction in adipocyte lipolysis in mice by lowering the bioavailability of noradrenaline. Unexpectedly, unbiased whole-transcriptome analyses of adipose macrophages revealed that ageing upregulates genes that control catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in ageing restored catecholamine-induced lipolysis by downregulating growth differentiation factor-3 (GDF3) and monoamine oxidase A (MAOA) that is known to degrade noradrenaline. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing levels of MAOA and caspase-1. Furthermore, inhibition of MAOA reversed the age-related reduction in noradrenaline concentration in adipose tissue, and restored lipolysis with increased levels of the key lipolytic enzymes adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-immunometabolic signalling between the sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.
Topics: Adipocytes; Adipose Tissue; Aging; Animals; Caspase 1; Catecholamines; Gene Expression Profiling; Gene Expression Regulation; Growth Differentiation Factor 3; Inflammasomes; Lipase; Lipolysis; Macrophages; Mice; Monoamine Oxidase; Monoamine Oxidase Inhibitors; NLR Family, Pyrin Domain-Containing 3 Protein; Norepinephrine; Sterol Esterase
PubMed: 28953873
DOI: 10.1038/nature24022 -
Nature Immunology Sep 2014Alternative (M2) activation of macrophages driven via the α-chain of the receptor for interleukin 4 (IL-4Rα) is important for immunity to parasites, wound healing, the...
Alternative (M2) activation of macrophages driven via the α-chain of the receptor for interleukin 4 (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of the fatty acids that support this metabolic program has not been clear. We found that the uptake of triacylglycerol substrates via the scavenger receptor CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation, enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth and blocked protective responses to this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation.
Topics: Animals; CD36 Antigens; Cell Respiration; Fatty Acids; Helminthiasis, Animal; Humans; Interleukin-4; Lipolysis; Lysosomes; Macrophage Activation; Macrophages; Mice; Oxidative Phosphorylation; Oxygen Consumption; Receptors, Interleukin-4; Signal Transduction; Sterol Esterase; Transcriptome
PubMed: 25086775
DOI: 10.1038/ni.2956 -
Autophagy Jul 2017Excess triglyceride (TG) accumulation in the liver underlies fatty liver disease, a highly prevalent ailment. TG occurs in the liver sequestered in lipid droplets, the...
Excess triglyceride (TG) accumulation in the liver underlies fatty liver disease, a highly prevalent ailment. TG occurs in the liver sequestered in lipid droplets, the major lipid storage organelle. Lipid droplets are home to the lipid droplet proteins, the most abundant of which are the perilipins (PLINs), encoded by 5 different genes, Plin1 to Plin5. Of the corresponding gene products, PLIN2 is the only constitutive and ubiquitously expressed lipid droplet protein that has been used as a protein marker for lipid droplets. We and others reported that plin2 mice have an ∼60% reduction in TG content, and are protected against fatty liver disease. Here we show that PLIN2 overexpression protects lipid droplets against macroautophagy/autophagy, whereas PLIN2 deficiency enhances autophagy and depletes hepatic TG. The enhanced autophagy in plin2 mice protects against severe ER stress-induced hepatosteatosis and hepatocyte apoptosis. In contrast, hepatic TG depletion resulting from other genetic and pharmacological manipulations has no effect on autophagy. Importantly, PLIN2 deficiency lowers cellular TG content in wild-type mouse embryonic fibroblasts (MEFs) via enhanced autophagy, but does not affect cellular TG content in atg7 MEFs that are devoid of autophagic function. Conversely, adenovirus-shAtg7-mediated hepatic Atg7 knockdown per se does not alter the hepatic TG level, suggesting a more complex regulation in vivo. In sum, PLIN2 guards its own house, the lipid droplet. PLIN2 overexpression protects against autophagy, and its downregulation stimulates TG catabolism via autophagy.
Topics: Animals; Autophagy; Autophagy-Related Protein 7; Carrier Proteins; Cells, Cultured; Endoplasmic Reticulum Stress; Hepatocytes; Liver; Mice; Mice, Knockout; Mitophagy; Perilipin-2; Sterol Esterase; Triglycerides
PubMed: 28548876
DOI: 10.1080/15548627.2017.1319544 -
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 -
Biomolecules Nov 2019This review addresses the contribution of some genes to the phenotype of familial hypercholesterolemia. At present, it is known that the pathogenesis of this disease... (Review)
Review
This review addresses the contribution of some genes to the phenotype of familial hypercholesterolemia. At present, it is known that the pathogenesis of this disease involves not only a pathological variant of low-density lipoprotein receptor and its ligands (apolipoprotein B, proprotein convertase subtilisin/kexin type 9 or low-density lipoprotein receptor adaptor protein 1), but also lipids, including sphingolipids, fatty acids, and sterols. The genetic cause of familial hypercholesterolemia is unknown in 20%-40% of the cases. The genes (signal transducing adaptor family member 1), (cytochrome P450 family 7 subfamily A member 1), (lipase A, lysosomal acid type), (ATP binding cassette subfamily G member 5), (ATP binding cassette subfamily G member 8), and (patatin like phospholipase domain containing 5), which can cause aberrations of lipid metabolism, are being evaluated as new targets for the diagnosis and personalized management of familial hypercholesterolemia.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; Adaptor Proteins, Signal Transducing; Animals; Cholesterol 7-alpha-Hydroxylase; Genetic Predisposition to Disease; Humans; Hyperlipoproteinemia Type II; Lipase; Lipoproteins; Sterol Esterase
PubMed: 31795497
DOI: 10.3390/biom9120807 -
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