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Frontiers in Endocrinology 2022() transgenic common carp ( L.) show desirable aquaculture traits. Their specific growth rate (SGR) and feed efficiency (FE) are approximately 12% and 17% higher than...
() transgenic common carp ( L.) show desirable aquaculture traits. Their specific growth rate (SGR) and feed efficiency (FE) are approximately 12% and 17% higher than the wild-type (WT) common carp, respectively. However, the mechanisms of lipid catabolism (lipolysis and fatty acid β-oxidation) and utilization in transgenic common carp are still unclear. In this study, we firstly compared the lipid metabolism of transgenic (initial weight 3.72 ± 0.32 g) and WT (initial weight 3.30 ± 0.28 g) common carp fed with a normal fat level diet (6% lipid, 33% protein) for two months, then compared the growth performance of transgenic (initial weight 3.65 ± 0.33 g) and WT (initial weight 3.27 ± 0.26 g) common carp fed with different fat levels diets (6% lipid and 12% lipid, 33% protein) for two months. We found that the lipid content in serum, liver and whole body was significantly reduced in transgenic common carp, the hepatic activities of the lipolytic enzymes hormone-sensitive lipase and adipose triglyceride lipase were enhanced, and the hepatic expression level of was upregulated. In addition, the mitochondrion numbers were increased, and the expression level of and was upregulated in the liver of transgenic common carp. transgenic common carp showed higher weight gain and SGR than that in WT carp when fed with a normal-fat diet as they did when fed with a high-fat diet, and transgenic common carp showed higher FE than that in WT carp when fed with a high-fat diet. These results suggested that the lipid catabolism and utilization was improved in the transgenic common carp liver through enhanced lipolytic and fatty acid β-oxidation pathways. Our study provides new insights into improving lipid utilization in some aquaculture fish species.
Topics: Animals; Animals, Genetically Modified; Carnitine O-Palmitoyltransferase; Carps; Fatty Acids; Growth Hormone; Human Growth Hormone; Lipase; Lipids; Lipolysis; Liver; Sterol Esterase
PubMed: 36171901
DOI: 10.3389/fendo.2022.982488 -
The American Journal of Pathology Feb 2021Utilization of proper preclinical models accelerates development of immunotherapeutics and the study of the interplay between human malignant cells and immune cells....
Utilization of proper preclinical models accelerates development of immunotherapeutics and the study of the interplay between human malignant cells and immune cells. Lysosomal acid lipase (LAL) is a critical lipid hydrolase that generates free fatty acids and cholesterol. Ablation of LAL suppresses immune rejection and allows growth of human lung cancer cells in lal mice. In the lal lymph nodes, the percentages of both T- and B-regulatory cells (Tregs and Bregs, respectively) are increased, with elevated expression of programmed death-ligand 1 and IL-10, and decreased expression of interferon-γ. Levels of enzymes in the glucose and glutamine metabolic pathways are elevated in Tregs and Bregs of the lal lymph nodes. Pharmacologic inhibitor of pyruvate dehydrogenase, which controls the transition from glycolysis to the citric acid cycle, effectively reduces Treg and Breg elevation in the lal lymph nodes. Blocking the mammalian target of rapamycin or reactivating peroxisome proliferator-activated receptor γ, an LAL downstream effector, reduces lal Treg and Breg elevation and PD-L1 expression in lal Tregs and Bregs, and improves human cancer cell rejection. Treatment with PD-L1 antibody also reduces Treg and Breg elevation in the lal lymph nodes and improves human cancer cell rejection. These observations conclude that LAL-regulated lipid metabolism is essential to maintain antitumor immunity.
Topics: Animals; B-Lymphocytes, Regulatory; Disease Models, Animal; Heterografts; Homeostasis; Humans; Lymph Nodes; Mice; Mice, Knockout; Neoplasm Transplantation; Neoplasms, Experimental; Sterol Esterase; T-Lymphocytes, Regulatory; Tumor Escape
PubMed: 33159889
DOI: 10.1016/j.ajpath.2020.10.007 -
American Journal of Physiology.... Jul 2020One of the primary metabolic functions of a mature adipocyte is to supply energy via lipolysis, or the catabolism of stored lipids. Adipose triacylglycerol lipase (ATGL)...
One of the primary metabolic functions of a mature adipocyte is to supply energy via lipolysis, or the catabolism of stored lipids. Adipose triacylglycerol lipase (ATGL) and hormone-sensitive lipase (HSL) are critical lipolytic enzymes, and their phosphorylation generates phospho-binding sites for 14-3-3 proteins, a ubiquitously expressed family of molecular scaffolds. Although we previously identified essential roles of the 14-3-3ζ isoform in murine adipogenesis, the presence of 14-3-3 protein binding sites on ATGL and HSL suggests that 14-3-3ζ could also influence mature adipocyte processes like lipolysis. Here we demonstrate that 14-3-3ζ is necessary for lipolysis in male mice and fully differentiated 3T3-L1 adipocytes, as depletion of 14-3-3ζ significantly impaired glycerol and free fatty acid (FFA) release. Unexpectedly, reducing 14-3-3ζ expression was found to significantly impact adipocyte maturity, as observed by reduced abundance of peroxisome proliferator-activated receptor (PPAR)γ2 protein and expression of mature adipocyte genes and those associated with de novo triglyceride synthesis and lipolysis. The impact of 14-3-3ζ depletion on adipocyte maturity was further examined with untargeted lipidomics, which revealed that reductions in 14-3-3ζ abundance promoted the acquisition of a lipidomic signature that resembled undifferentiated preadipocytes. Collectively, these findings reveal a novel aspect of 14-3-3ζ in adipocytes, as reducing 14-3-3ζ was found to have a negative effect on adipocyte maturity and adipocyte-specific processes like lipolysis.
Topics: 14-3-3 Proteins; 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; Cell Differentiation; Fatty Acids, Nonesterified; Glycerol; Lipase; Lipidomics; Lipolysis; Male; Mice; PPAR gamma; RNA, Messenger; Sterol Esterase
PubMed: 32369418
DOI: 10.1152/ajpendo.00093.2020 -
Cell Death & Disease Nov 2021Recent studies demonstrated reduced blood lysosomal acid lipase (LAL) activity in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to verify hepatic LAL...
Recent studies demonstrated reduced blood lysosomal acid lipase (LAL) activity in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to verify hepatic LAL protein content and activity in in vitro and in vivo models of fat overload and in NAFLD patients. LAL protein content and activity were firstly evaluated in Huh7 cells exposed to high-glucose/high-lipid (HGHL) medium and in the liver of C57BL/6 mice fed with high-fat diet (HFD) for 4 and 8 months. LAL protein was also evaluated by immunohistochemistry in liver biopsies from 87 NAFLD patients and 10 controls, and correlated with hepatic histology. Huh7 cells treated with HGHL medium showed a significant reduction of LAL activity, which was consistent with reduced LAL protein levels by western blotting using an antibody towards the N-term of the enzyme. Conversely, antibodies towards the C-term of the enzyme evidenced LAL accumulation, suggesting a post-translational modification that masks the LAL N-term epitope and affects enzymatic activity. Indeed, we found a high rate of ubiquitination and extra-lysosomal localization of LAL protein in cells treated with HGHL medium. Consistent with these findings, inhibition of proteasome triggered dysfunctional LAL accumulation and affected LAL activity. Accumulation of ubiquitinated/dysfunctional LAL was also found in the liver of HFD fed mice. In NAFLD patients, hepatic levels of non-ubiquitinated/functional LAL were lower than in controls and inversely correlated with disease activity and some of the hallmarks of reduced LAL. Fat overload leads to LAL ubiquitination and impairs its function, possibly reducing hepatic fat disposal and promoting NAFLD activity.
Topics: Animals; Disease Models, Animal; Humans; Lipid Metabolism; Male; Mice; Non-alcoholic Fatty Liver Disease; Sterol Esterase; Transfection
PubMed: 34795230
DOI: 10.1038/s41419-021-04382-4 -
Journal of Microbiology and... Nov 2017Lipases are important enzymes with biotechnological applications in dairy, detergent, food, fine chemicals, and pharmaceutical industries. Specifically,... (Review)
Review
Lipases are important enzymes with biotechnological applications in dairy, detergent, food, fine chemicals, and pharmaceutical industries. Specifically, hormone-sensitive lipase (HSL) is an intracellular lipase that can be stimulated by several hormones, such as catecholamine, glucagon, and adrenocorticotropic hormone. Bacterial hormone-sensitive lipases (bHSLs), which are homologous to the C-terminal domain of HSL, have α/β-hydrolase fold with a catalytic triad composed of His, Asp, and Ser. These bHSLs could be used for a wide variety of industrial applications because of their high activity, broad substrate specificity, and remarkable stability. In this review, the relationships among HSLs, the microbiological origins, the crystal structures, and the biotechnological properties of bHSLs are summarized.
Topics: Adrenocorticotropic Hormone; Amino Acid Sequence; Bacteria; Bacterial Proteins; Biotechnology; Catalytic Domain; Catecholamines; Enzyme Stability; Glucagon; Industrial Microbiology; Models, Molecular; Protein Conformation; Sterol Esterase; Substrate Specificity
PubMed: 29032653
DOI: 10.4014/jmb.1708.08004 -
American Journal of Physiology.... Oct 2020Obesity and type 2 diabetes are frequently complicated by excess fat accumulation in the liver, which is known as nonalcoholic fatty liver disease (NAFLD). In this... (Review)
Review
Obesity and type 2 diabetes are frequently complicated by excess fat accumulation in the liver, which is known as nonalcoholic fatty liver disease (NAFLD). In this context, liver steatosis develops as a result of the deregulation of pathways controlling de novo lipogenesis and fat catabolism. Recent evidences suggest the clinical relevance of a reduction in the activity of lysosomal acid lipase (LAL), which is a key enzyme for intracellular fat disposal, in patients with NAFLD. In this review, we provided a comprehensive overview of the critical steps in hepatic fat metabolism and alterations in these pathways in NAFLD, with a special focus on lipophagy and LAL activity. During NAFLD, hepatic fat metabolism is impaired at several levels, which is significantly contributed to by impaired lipophagy, in which reduced LAL activity may play an important role. For further research and intervention in NAFLD, targeting LAL activity may provide interesting perspectives.
Topics: Autophagy; Humans; Lipid Metabolism; Lipolysis; Liver; Lysosomes; Non-alcoholic Fatty Liver Disease; Sterol Esterase
PubMed: 32812776
DOI: 10.1152/ajpgi.00049.2020 -
International Journal of Molecular... Nov 2015Lysosomal Acid Lipase (LAL) is a key enzyme involved in lipid metabolism, responsible for hydrolysing the cholesteryl esters and triglycerides. Wolman Disease represents... (Review)
Review
Lysosomal Acid Lipase (LAL) is a key enzyme involved in lipid metabolism, responsible for hydrolysing the cholesteryl esters and triglycerides. Wolman Disease represents the early onset phenotype of LAL deficiency rapidly leading to death. Cholesterol Ester Storage Disease is a late onset phenotype that occurs with fatty liver, elevated aminotransferase levels, hepatomegaly and dyslipidaemia, the latter characterized by elevated LDL-C and low HDL-C. The natural history and the clinical manifestations of the LAL deficiency in adults are not well defined, and the diagnosis is often incidental. LAL deficiency has been suggested as an under-recognized cause of dyslipidaemia and fatty liver. Therefore, LAL activity may be reduced also in non-obese patients presenting non-alcoholic fatty liver disease (NAFLD), unexplained persistently elevated liver transaminases or with elevation in LDL cholesterol. In these patients, it could be indicated to test LAL activity. So far, very few studies have been performed to assess LAL activity in representative samples of normal subjects or patients with NAFLD. Moreover, no large study has been carried out in adult subjects with NAFLD or cryptogenic cirrhosis.
Topics: Adult; Atherosclerosis; Biomarkers; Cardiovascular Diseases; Enzyme Activation; Humans; Lipid Metabolism; Liver; Non-alcoholic Fatty Liver Disease; Sterol Esterase; Wolman Disease
PubMed: 26602919
DOI: 10.3390/ijms161226085 -
Journal of Lipid Research May 2022Lipid droplets (LDs) are multifunctional organelles that regulate energy storage and cellular homeostasis. The first step of triacylglycerol hydrolysis in LDs is...
Lipid droplets (LDs) are multifunctional organelles that regulate energy storage and cellular homeostasis. The first step of triacylglycerol hydrolysis in LDs is catalyzed by adipose triglyceride lipase (ATGL), deficiency of which results in lethal cardiac steatosis. Although hormone-sensitive lipase (HSL) functions as a diacylglycerol lipase in the heart, we hypothesized that activation of HSL might compensate for ATGL deficiency. To test this hypothesis, we crossed ATGL-KO (AKO) mice and cardiac-specific HSL-overexpressing mice (cHSL) to establish homozygous AKO mice and AKO mice with cardiac-specific HSL overexpression (AKO+cHSL). We found that cardiac triacylglycerol content was 160-fold higher in AKO relative to Wt mice, whereas that of AKO+cHSL mice was comparable to the latter. In addition, AKO cardiac tissues exhibited reduced mRNA expression of PPARα-regulated genes and upregulation of genes involved in inflammation, fibrosis, and cardiac stress. In contrast, AKO+cHSL cardiac tissues exhibited expression levels similar to those observed in Wt mice. AKO cardiac tissues also exhibited macrophage infiltration, apoptosis, interstitial fibrosis, impaired systolic function, and marked increases in ceramide and diacylglycerol contents, whereas no such pathological alterations were observed in AKO+cHSL tissues. Furthermore, electron microscopy revealed considerable LDs, damaged mitochondria, and disrupted intercalated discs in AKO cardiomyocytes, none of which were noted in AKO+cHSL cardiomyocytes. Importantly, the life span of AKO+cHSL mice was comparable to that of Wt mice. HSL overexpression normalizes lipotoxic cardiomyopathy in AKO mice and the findings highlight the applicability of cardiac HSL activation as a therapeutic strategy for ATGL deficiency-associated lipotoxic cardiomyopathies.
Topics: Animals; Cardiomyopathies; Fibrosis; Lipase; Lipolysis; Mice; Myocytes, Cardiac; Sterol Esterase; Triglycerides
PubMed: 35283217
DOI: 10.1016/j.jlr.2022.100194 -
World Journal of Gastroenterology Aug 2019Lysosomal acid lipase (LAL) plays a key role in intracellular lipid metabolism. Reduced LAL activity promotes increased multi-organ lysosomal cholesterol ester storage,... (Review)
Review
Lysosomal acid lipase (LAL) plays a key role in intracellular lipid metabolism. Reduced LAL activity promotes increased multi-organ lysosomal cholesterol ester storage, as observed in two recessive autosomal genetic diseases, Wolman disease and Cholesterol ester storage disease. Severe liver steatosis and accelerated liver fibrosis are common features in patients with genetic LAL deficiency. By contrast, few reliable data are available on the modulation of LAL activity and on the epigenetic and metabolic factors capable of regulating its activity in subjects without homozygous mutations of the Lipase A gene. In the last few years, a less severe and non-genetic reduction of LAL activity was reported in children and adults with non-alcoholic fatty liver disease (NAFLD), suggesting a possible role of LAL reduction in the pathogenesis and progression of the disease. Patients with NAFLD show a significant, progressive reduction of LAL activity from simple steatosis to non-alcoholic steatohepatitis and cryptogenic cirrhosis. Among cirrhosis of different etiologies, those with cryptogenic cirrhosis show the most significant reductions of LAL activity. These findings suggest that the modulation of LAL activity may become a possible new therapeutic target for patients with more advanced forms of NAFLD. Moreover, the measurement of LAL activity may represent a possible new marker of disease severity in this clinical setting.
Topics: Biomarkers; Cholesterol Esters; Disease Progression; Dried Blood Spot Testing; Enzyme Replacement Therapy; Humans; Lipid Metabolism; Liver; Liver Cirrhosis; Liver Function Tests; Lysosomes; Non-alcoholic Fatty Liver Disease; Severity of Illness Index; Sterol Esterase; Triglycerides; Wolman Disease
PubMed: 31435171
DOI: 10.3748/wjg.v25.i30.4172 -
International Journal of Molecular... Aug 2023Obesity is associated with high risk of mortality globally because obesity is associated with development of diseases such as diabetes, dyslipidemia, fatty liver...
Obesity is associated with high risk of mortality globally because obesity is associated with development of diseases such as diabetes, dyslipidemia, fatty liver disease, hypertension, and cancer. The present study aimed to identify the mechanism of action related to the anti‑obesity activity of root (PLR) based on its effects on lipid droplet accumulation. The inhibitory activity on lipid accumulation was analyzed through Oil‑Red O staining, and the changes in levels of lipid accumulation‑related proteins were analyzed using Western blot analysis. And the contents of triacylglycerol and free glycerol were analyzed using an ELISA Kit. PLR significantly inhibited the accumulation of lipid droplets and triacylglycerol in differentiating 3T3‑L1 cells. PLR increased phosphorylated‑hormone sensitive lipase (HSL), HSL and adipose triglyceride lipase (ATGL) and decreases perilipin‑1 in differentiating and fully differentiated 3T3‑L1 cells. Furthermore, treatment of fully differentiated 3T3‑L1 cells with PLR resulted in increased free glycerol levels. PLR treatment increased levels of peroxisome proliferator‑activated receptor‑gamma coactivator‑1 alpha (PGC‑1α), PR domain containing 16 (PRDM16) and uncoupling protein 1 (UCP‑1) in both differentiating and fully differentiated 3T3‑L1 cells. However, the PLR‑mediated increase in lipolytic, such as ATGL and HSL, and thermogenic factors, such as PGC‑1a and UCP‑1, were decreased by inhibition of AMP‑activated protein kinase (AMPK) with Compound C. Taken together, these results suggest that PLR exerted anti‑obesity effects by regulating lipolytic and thermogenic factors via AMPK activation. Therefore, the present study provided evidence that PLR is a potential natural agent for the development of drugs to control obesity.
Topics: Mice; Animals; Humans; Lipolysis; AMP-Activated Protein Kinases; Paeonia; 3T3-L1 Cells; Glycerol; Lipase; Sterol Esterase; Triglycerides; Obesity; Thermogenesis
PubMed: 37326061
DOI: 10.3892/ijmm.2023.5268