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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 -
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 -
International Journal of Molecular... Dec 2022Lysosomal acid lipase (LAL) is a lysosomal enzyme essential for the degradation of cholesteryl esters through the endocytic pathway. Deficiency of the LAL enzyme encoded... (Review)
Review
Lysosomal acid lipase (LAL) is a lysosomal enzyme essential for the degradation of cholesteryl esters through the endocytic pathway. Deficiency of the LAL enzyme encoded by the gene leads to LAL deficiency (LAL-D) (OMIM 278000), one of the lysosomal storage disorders involving 50-60 genes. Among the two disease subtypes, the severe disease subtype of LAL-D is known as Wolman disease, with typical manifestations involving hepatomegaly, splenomegaly, vomiting, diarrhea, and hematopoietic abnormalities, such as anemia. In contrast, the mild disease subtype of this disorder is known as cholesteryl ester storage disease, with hypercholesterolemia, hypertriglyceridemia, and high-density lipoprotein disappearance. The prevalence of LAL-D is rare, but several treatment options, including enzyme replacement therapy, are available. Accordingly, a number of screening methodologies have been developed for this disorder. This review summarizes the current discussion on LAL-D, covering genetics, screening, and the tertiary structure of human LAL enzyme and preclinical study for the future development of a novel therapy.
Topics: Humans; Wolman Disease; Cholesterol Ester Storage Disease; Sterol Esterase; Hepatomegaly
PubMed: 36555187
DOI: 10.3390/ijms232415549 -
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 -
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 -
Nature Communications Mar 2021Increased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are...
Increased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.
Topics: Adipocytes; Adiponectin; Adipose Tissue; Adiposity; Animals; Diet, High-Fat; Fatty Acids; Fatty Liver; Gene Expression Regulation; Glucose; Homeostasis; Humans; Insulin Resistance; Lipid Metabolism; Lipolysis; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; PPAR alpha; Phosphoprotein Phosphatases; Phosphorylation; Signal Transduction; Sterol Esterase
PubMed: 33758172
DOI: 10.1038/s41467-021-22106-2