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Adipose triglyceride lipase (ATGL) was recently identified as a triglyceride (TG)-specific lipase. In this study, we first obtained from large yellow croaker fish a 1,820-bp (GenBank ID: HQ916211) ATGL cDNA fragment with a 141-bp 5′UTR, a 1,485-bp open reading frame, and a 194-bp 3′UTR. The predicted fish ATGL had 494 amino acids (GenBank ID: ADY89608) and a calculated molecular weight of 55.1 kDa. ATGL was highly expressed in liver and, to a lesser degree, in heart, muscle, and abdominal fat. ATGL gene expression was high at 4.5 g and then decreased at 157.9 g and increased again at 474.2 g. The effects of lipid levels and lipid sources on ATGL expression in vivo were also investigated. A high-lipid diet decreased ATGL expression in fish significantly (P?<?0.01). Fish in soybean oil group exhibited significantly lower ATGL expression than fish in the fish oil and beef tallow groups (P?<?0.01). These data enhance our understanding of ATGL in fish lipid metabolism. 相似文献
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Tomoaki Inoue Kunihisa Kobayashi Toyoshi Inoguchi Noriyuki Sonoda Yasutaka Maeda Eiichi Hirata Yoshinori Fujimura Daisuke Miura Ken-ichi Hirano Ryoichi Takayanagi 《Biochemical and biophysical research communications》2013
Adipose triglyceride lipase (ATGL) was recently identified as a rate-limiting triglyceride (TG) lipase and its activity is stimulated by comparative gene identification-58 (CGI-58). Mutations in the ATGL or CGI-58 genes are associated with neutral lipid storage diseases characterized by the accumulation of TG in multiple tissues. The cardiac phenotype, known as triglyceride deposit cardiomyovasculopathy, is characterized by TG accumulation in coronary atherosclerotic lesions and in the myocardium. Recent reports showed that myocardial TG accumulation is significantly higher in patients with diabetes and is associated with impaired left ventricular diastolic function. Therefore, we investigated the roles of ATGL and CGI-58 in the development of myocardial steatosis in the diabetic state. Histological examination with oil red O staining showed marked lipid deposition in the hearts of diabetic fatty db/db mice. Cardiac triglyceride and diglyceride contents were greater in db/db mice than in db/+ control mice. Next, we determined the expression of genes and proteins that affect lipid metabolism, and found that ATGL and CGI-58 expression levels were decreased in the hearts of db/db mice. We also found increased expression of genes regulating triglyceride synthesis (sterol regulatory element-binding protein 1c, monoacylglycerol acyltransferases, and diacylglycerol acyltransferases) in db/db mice. Regarding key modulators of apoptosis, PKC activity, and oxidative stress, we found that Bcl-2 levels were lower and that phosphorylated PKC and 8-hydroxy-2′-deoxyguanosine levels were higher in db/db hearts. These results suggest that reduced ATGL and CGI-58 expression and increased TG synthesis may exacerbate myocardial steatosis and oxidative stress, thereby promoting cardiac apoptosis in diabetic mice. 相似文献
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Katrine T.-B. G. Schjoldager Malene B. Vester-Christensen Eric Paul Bennett Steven B. Levery Tilo Schwientek Wu Yin Ola Blixt Henrik Clausen 《The Journal of biological chemistry》2010,285(47):36293-36303
The angiopoietin-like protein 3 (ANGPTL3) is an important inhibitor of the endothelial and lipoprotein lipases and a promising drug target. ANGPTL3 undergoes proprotein convertase processing (RAPR224↓TT) for activation, and the processing site contains two potential GalNAc O-glycosylation sites immediately C-terminal (TT226). We developed an in vivo model system in CHO ldlD cells that was used to show that O-glycosylation in the processing site blocked processing of ANGPTL3. Genome-wide SNP association studies have identified the polypeptide GalNAc-transferase gene, GALNT2, as a candidate gene for low HDL and high triglyceride blood levels. We hypothesized that the GalNAc-T2 transferase performed critical O-glycosylation of proteins involved in lipid metabolism. Screening of a panel of proteins known to affect lipid metabolism for potential sites glycosylated by GalNAc-T2 led to identification of Thr226 adjacent to the proprotein convertase processing site in ANGPTL3. We demonstrated that GalNAc-T2 glycosylation of Thr226 in a peptide with the RAPR224↓TT processing site blocks in vitro furin cleavage. The study demonstrates that ANGPTL3 activation is modulated by O-glycosylation and that this step is probably controlled by GalNAc-T2. 相似文献
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E-Chiang Lee Urvi Desai Gennady Gololobov Seokjoo Hong Xiao Feng Xuan-Chuan Yu Jason Gay Nat Wilganowski Cuihua Gao Ling-Ling Du Joan Chen Yi Hu Sharon Zhao Laura Kirkpatrick Matthias Schneider Brian P. Zambrowicz Greg Landes David R. Powell William K. Sonnenburg 《The Journal of biological chemistry》2009,284(20):13735-13745
Angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4) are
secreted proteins that regulate triglyceride (TG) metabolism in part by
inhibiting lipoprotein lipase (LPL). Recently, we showed that treatment of
wild-type mice with monoclonal antibody (mAb) 14D12, specific for ANGPTL4,
recapitulated the Angptl4 knock-out (-/-) mouse phenotype of reduced
serum TG levels. In the present study, we mapped the region of mouse ANGPTL4
recognized by mAb 14D12 to amino acids
Gln29–His53, which we designate as specific
epitope 1 (SE1). The 14D12 mAb prevented binding of ANGPTL4 with LPL,
consistent with its ability to neutralize the LPL-inhibitory activity of
ANGPTL4. Alignment of all angiopoietin family members revealed that a sequence
similar to ANGPTL4 SE1 was present only in ANGPTL3, corresponding to amino
acids Glu32–His55. We produced a mouse mAb against
this SE1-like region in ANGPTL3. This mAb, designated 5.50.3, inhibited the
binding of ANGPTL3 to LPL and neutralized ANGPTL3-mediated inhibition of LPL
activity in vitro. Treatment of wild-type as well as hyperlipidemic
mice with mAb 5.50.3 resulted in reduced serum TG levels, recapitulating the
lipid phenotype found in Angptl3-/- mice. These results
show that the SE1 region of ANGPTL3 and ANGPTL4 functions as a domain
important for binding LPL and inhibiting its activity in vitro and
in vivo. Moreover, these results demonstrate that therapeutic
antibodies that neutralize ANGPTL4 and ANGPTL3 may be useful for treatment of
some forms of hyperlipidemia.Lipoprotein lipase
(LPL)5 plays a pivotal
role in lipid metabolism by catalyzing the hydrolysis of plasma triglycerides
(TGs). LPL is likely to be regulated by mechanisms that depend on nutritional
status and on the tissue in which it is expressed
(1–3).
Two secreted proteins, angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4
(ANGPTL4), play important roles in the regulation of LPL activity
(4,
5). ANGPTL3 and ANGPTL4 consist
of a signal peptide, an N-terminal segment containing coiled-coil domains, and
a C-terminal fibrinogen-like domain. The N-terminal segment as well as
full-length ANGPTL3 and ANGPTL4 have been shown to inhibit LPL activity, and
deletion of the N-terminal segment of ANGPTL3 and ANGPTL4 resulted in total
loss of LPL-inhibiting activity
(6,
7). These observations clearly
indicate that the N-terminal region of ANGPTL4 contains the functional domain
that inhibits LPL and affects plasma lipid levels. The coiled-coil domains
have been proposed to be responsible for oligomerization
(8); however, it is not known
whether the coiled-coil domains directly mediate the inhibition of LPL
activity.To define the physiological role of ANGPTL4 more clearly, we characterized
the pharmacological consequences of ANGPTL4 inhibition in mice treated with
the ANGPTL4-neutralizing monoclonal antibody (mAb) 14D12
(9). Injection of mAb 14D12
significantly lowered fasting TG levels in C57BL/6J mice relative to levels in
C57BL/6J mice treated with an isotype-matched anti-KLH control (KLH) mAb
(9). These reduced TG values
were similar to decreases in fasting plasma TG levels measured in
Angptl4 knock-out (-/-) mice. This study demonstrated that mAb 14D12
is a potent ANGPTL4-neutralizing antibody that is able to inhibit systemic
ANGPTL4 activity and thereby recapitulate the reduced lipid phenotype found in
Angptl4-/- mice. The readily apparent pharmacological
effect of mAb 14D12 prompted new questions about the epitope recognized by mAb
14D12 and how this antibody-antigen binding event affected ANGPTL4 function as
an LPL inhibitor.Although ANGPTL4 is able to interact directly with LPL
(10), it is not clear which
amino acids within ANGPTL4 mediate this interaction. Here we show that amino
acids Gln29–His53 of mANGPTL4 contain the epitope
for mAb 14D12. This region, hereby designated specific epitope 1 (SE1), also
defines a domain that mediates the interaction between ANGPTL4 and LPL and the
subsequent inactivation of LPL. With this information we present evidence that
ANGPTL3 also contains an SE1 region, and with antibodies specifically reactive
with ANGPTL3 SE1 we examine whether the ANGPTL3 SE1 region is involved in LPL
binding and inhibition. We also determined whether treatment of C57BL/6 mice
with an anti-ANGPTL3 SE1 mAb can recapitulate the phenotype of lower serum TG
and cholesterol levels found in Angptl3-/- mice. Finally
we tested the therapeutic potential of an anti-ANGPTL3 SE1 mAb for treatment
of hyperlipidemia in apolipoprotein E-/-
(ApoE-/-) or low density lipoprotein
receptor-/- (LDLr-/-) mice. 相似文献
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Anna Tikka Jarkko Soronen Pirkka-Pekka Laurila Jari Metso Christian Ehnholm Matti Jauhiainen 《Bioscience reports》2014,34(6)
Homozygosity of loss-of-function mutations in ANGPTL3 (angiopoietin-like protein 3)-gene results in FHBL2 (familial combined hypolipidaemia, OMIM #605019) characterized by the reduction of all major plasma lipoprotein classes, which includes VLDL (very-low-density lipoprotein), LDL (low-density lipoprotein), HDL (high-density lipoprotein) and low circulating NEFAs (non-esterified fatty acids), glucose and insulin levels. Thus complete lack of ANGPTL3 in humans not only affects lipid metabolism, but also affects whole-body insulin and glucose balance. We used wild-type and ANGPTL3-silenced IHHs (human immortalized hepatocytes) to investigate the effect of ANGPTL3 silencing on hepatocyte-specific VLDL secretion and glucose uptake. We demonstrate that both insulin and PPARγ (peroxisome-proliferator-activated receptor γ) agonist rosiglitazone down-regulate the secretion of ANGPTL3 and TAG (triacylglycerol)-enriched VLDL1-type particles in a dose-dependent manner. Silencing of ANGPTL3 improved glucose uptake in hepatocytes by 20–50% and influenced down-regulation of gluconeogenic genes, suggesting that silencing of ANGPTL3 improves insulin sensitivity. We further show that ANGPTL3-silenced cells display a more pronounced shift from the secretion of TAG-enriched VLDL1-type particles to secretion of lipid poor VLDL2-type particles during insulin stimulation. These data suggest liver-specific mechanisms involved in the reported insulin-sensitive phenotype of ANGPTL3-deficient humans, featuring lower plasma insulin and glucose levels. 相似文献
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Adipose triglyceride lipase (ATGL) catalyzes the initial step in the lipid lipolysis process, hydrolyzing triglyceride (TG) to produce diacylglycerol (DG) and free fatty acids (FFA). In addition, ATGL regulates lipid storage and release in adipocyte cells. However, its role in mammary gland tissue remains unclear. To assess the role of the ATGL gene in the goat mammary gland, this study analyzed the tissue distribution and expression of key genes together with lipid accumulation after knockdown of the ATGL gene. The mRNA of ATGL was highly expressed in subcutaneous adipose tissue, the lung and the mammary gland with a significant increase in expression during the lactation period compared with the dry period of the mammary gland. Knockdown of the ATGL gene in goat mammary epithelial cells (GMECs) using siRNA resulted in a significant decrease in both ATGL mRNA and protein levels. Silencing of the ATGL gene markedly increased lipid droplet accumulation and intracellular TG concentration (P < 0.05), while it reduced FFA levels in GMECs (P < 0.05). Additionally, the expression of HSL for lipolysis, FABP3 for fatty acid transport, PPARα for fatty acid oxidation, ADFP, BTN1A1, and XDH for milk fat formation and secretion was down-regulated (P < 0.05) after knockdown of the ATGL gene, with increased expression of CD36 for fatty acid uptake (P < 0.05). In conclusion, these data suggest that the ATGL gene plays an important role in triglyceride lipolysis in GMECs and provides the first experimental evidence that ATGL may be involved in lipid metabolism during lactation. 相似文献
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Methanol expression regulator 1 (Mxr1p) is a zinc finger protein that regulates the expression of genes encoding enzymes of the methanol utilization pathway in the methylotrophic yeast Pichia pastoris by binding to Mxr1p response elements (MXREs) present in their promoters. Here we demonstrate that Mxr1p is a key regulator of acetate metabolism as well. Mxr1p is cytosolic in cells cultured in minimal medium containing a yeast nitrogen base, ammonium sulfate, and acetate (YNBA) but localizes to the nucleus of cells cultured in YNBA supplemented with glutamate or casamino acids as well as nutrient-rich medium containing yeast extract, peptone, and acetate (YPA). Deletion of Mxr1 retards the growth of P. pastoris cultured in YNBA supplemented with casamino acids as well as YPA. Mxr1p is a key regulator of ACS1 encoding acetyl-CoA synthetase in cells cultured in YPA. A truncated Mxr1p comprising 400 N-terminal amino acids activates ACS1 expression and enhances growth, indicating a crucial role for the N-terminal activation domain during acetate metabolism. The serine 215 residue, which is known to regulate the expression of Mxr1p-activated genes in a carbon source-dependent manner, has no role in the Mxr1p-mediated activation of ACS1 expression. The ACS1 promoter contains an Mxr1p response unit (MxRU) comprising two MXREs separated by a 30-bp spacer. Mutations that abrogate MxRU function in vivo abolish Mxr1p binding to MxRU in vitro. Mxr1p-dependent activation of ACS1 expression is most efficient in cells cultured in YPA. The fact that MXREs are conserved in genes outside of the methanol utilization pathway suggests that Mxr1p may be a key regulator of multiple metabolic pathways in P. pastoris. 相似文献
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Ping-An Chang Ying-Jian Sun Fei-Fei Huang Wen-Zhen Qin Yu-Ying Chen Xin Zeng Yi-Jun Wu 《Molecular biology reports》2013,40(10):5597-5605
Recently members of mammalian patatin-like phospholipase domain containing (PNPLA) protein family have attracted attention for their critical roles in diverse aspects of lipid metabolism and signal pathway. Until now little has been known about the characteristics of PNPLA1. Here, the full length coding cDNA sequence of human PNPLA1 (hPNPLA1) was cloned for the first time, which encoded a polypeptide with 532 amino acids containing the whole patatin domain. Tissue expression profiles analysis showed that low mRNA levels of hPNPLA1 existed in various tissues, except high expression in the digestive system, bone marrow and spleen. Subcellular distribution of hPNPLA1 tagged with green fluorescence protein mainly localized to lipid droplets. Furthermore, a nonsense mutation of PNPLA1 in human cervical cancer HeLa cells was identified. The hPNPLA1 mutant encoded a protein of 412 amino acids without the C-terminal domain and did not colocalize to lipid droplets, which suggested that the C-terminal region of hPNPLA1 affected lipid droplet binding. These results identified hPNPLA1 and a mutant in HeLa cells, and provided insights into the structure and function of PNPLA1. 相似文献
13.
Inoue T Kobayashi K Inoguchi T Sonoda N Fujii M Maeda Y Fujimura Y Miura D Hirano K Takayanagi R 《The Journal of biological chemistry》2011,286(37):32045-32053
We examined the effects of adipose triglyceride lipase (ATGL) on the initiation of atherosclerosis. ATGL was recently identified as a rate-limiting triglyceride (TG) lipase. Mutations in the human ATGL gene are associated with neutral lipid storage disease with myopathy, a rare genetic disease characterized by excessive accumulation of TG in multiple tissues. The cardiac phenotype, known as triglyceride deposit cardiomyovasculopathy, shows massive TG accumulation in both coronary atherosclerotic lesions and the myocardium. Recent reports show that myocardial triglyceride content is significantly higher in patients with prediabetes or diabetes and that ATGL expression is decreased in the obese insulin-resistant state. Therefore, we investigated the effect of decreased ATGL activity on the development of atherosclerosis using human aortic endothelial cells. We found that ATGL knockdown enhanced monocyte adhesion via increased expression of TNFα-induced intercellular adhesion molecule-1 (ICAM-1). Next, we determined the pathways (MAPK, PKC, or NFκB) involved in ICAM-1 up-regulation induced by ATGL knockdown. Both phosphorylation of PKC and degradation of IκBα were increased in ATGL knockdown human aortic endothelial cells. In addition, intracellular diacylglycerol levels and free fatty acid uptake via CD36 were significantly increased in these cells. Inhibition of the PKC pathway using calphostin C and GF109203X suppressed TNFα-induced ICAM-1 expression. In conclusion, we showed that ATGL knockdown increased monocyte adhesion to the endothelium through enhanced TNFα-induced ICAM-1 expression via activation of NFκB and PKC. These results suggest that reduced ATGL expression may influence the atherogenic process in neutral lipid storage diseases and in the insulin-resistant state. 相似文献
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Franz P. W. Radner Ingo E. Streith Gabriele Schoiswohl Martina Schweiger Manju Kumari Thomas O. Eichmann Gerald Rechberger Harald C. Koefeler Sandra Eder Silvia Schauer H. Christian Theussl Karina Preiss-Landl Achim Lass Robert Zimmermann Gerald Hoefler Rudolf Zechner Guenter Haemmerle 《The Journal of biological chemistry》2010,285(10):7300-7311
Comparative gene identification-58 (CGI-58), also designated as α/β-hydrolase domain containing-5 (ABHD-5), is a lipid droplet-associated protein that activates adipose triglyceride lipase (ATGL) and acylates lysophosphatidic acid. Activation of ATGL initiates the hydrolytic catabolism of cellular triacylglycerol (TG) stores to glycerol and nonesterified fatty acids. Mutations in both ATGL and CGI-58 cause “neutral lipid storage disease” characterized by massive accumulation of TG in various tissues. The analysis of CGI-58-deficient (Cgi-58−/−) mice, presented in this study, reveals a dual function of CGI-58 in lipid metabolism. First, systemic TG accumulation and severe hepatic steatosis in newborn Cgi-58−/− mice establish a limiting role for CGI-58 in ATGL-mediated TG hydrolysis and supply of nonesterified fatty acids as energy substrate. Second, a severe skin permeability barrier defect uncovers an essential ATGL-independent role of CGI-58 in skin lipid metabolism. The neonatal lethal skin barrier defect is linked to an impaired hydrolysis of epidermal TG. As a consequence, sequestration of fatty acids in TG prevents the synthesis of acylceramides, which are essential lipid precursors for the formation of a functional skin permeability barrier. This mechanism may also underlie the pathogenesis of ichthyosis in neutral lipid storage disease patients lacking functional CGI-58. 相似文献
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《生物化学与生物物理学报:疾病的分子基础》2023,1869(2):166619
Thoracic aortic aneurysm/dissection (TAAD) is a life-threatening cardiovascular disorder. Endoplasmic reticulum stress (ERS) and vascular smooth muscle cell (VSMC) apoptosis are involved in TAAD progression. The Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) pathway is associated with VSMC apoptosis. Serum Angiopoietin-Like Protein 8 (ANGPTL8) levels are associated with aortic diameter and rupture rate of TAAD. However, a direct role of ANGPTL8 in TAAD has not been determined. β-Aminopropionitrile monofumarate (BAPN) was used to induce TAAD in C57BL/6 mice. ANGPTL8 knockout mice were used to detect the effects of ANGPTL8 on TAAD development. ANGPTL8knockdown in vitro was used to analyze the role of ANGPTL8 in VSMCs and ERS. In addition, over-expression of ANGPTL8 in VSMCs and a PERK inhibitor were used to assess the effect of ANGPTL8 on the PERK pathway. ANGPTL8 levels were increased in the aortic wall and VSMCs of BAPN-induced TAAD mice. Compared with BAPN-treated wild-type mice, ANGPTL8 knockout significantly reduced the rupture rate of TAAD to 0 %. In addition, the protein levels of proinflammatory cytokines and matrix metalloproteinase 9 (MMP9) and ERS proteins were decreased in the aorta wall. Angptl8 shRNA decreased MMP9 and ERS protein levels in VSMCs in vitro. Overexpression of ANGPTL8 significantly increased the levels of ERS proteins and MMPs, while a PERK inhibitor significantly decreased the effects of ANGPTL8 in VSMCs. ANGPTL8 contributed to TAAD development by inducing ERS activation and degradation of extracellular matrix in the aorta wall. Inhibition of ANGPTL8 may therefore represent a new strategy for TAAD therapy. 相似文献
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LKB1 plays important roles in governing energy homeostasis by regulating AMP-activated protein kinase (AMPK) and other AMPK-related kinases, including the salt-inducible kinases (SIKs). However, the roles and regulation of LKB1 in lipid metabolism are poorly understood. Here we show that Drosophila LKB1 mutants display decreased lipid storage and increased gene expression of brummer, the Drosophila homolog of adipose triglyceride lipase (ATGL). These phenotypes are consistent with those of SIK3 mutants and are rescued by expression of constitutively active SIK3 in the fat body, suggesting that SIK3 is a key downstream kinase of LKB1. Using genetic and biochemical analyses, we identify HDAC4, a class IIa histone deacetylase, as a lipolytic target of the LKB1-SIK3 pathway. Interestingly, we found that the LKB1-SIK3-HDAC4 signaling axis is modulated by dietary conditions. In short-term fasting, the adipokinetic hormone (AKH) pathway, related to the mammalian glucagon pathway, inhibits the kinase activity of LKB1 as shown by decreased SIK3 Thr196 phosphorylation, and consequently induces HDAC4 nuclear localization and brummer gene expression. However, under prolonged fasting conditions, AKH-independent signaling decreases the activity of the LKB1-SIK3 pathway to induce lipolytic responses. We also identify that the Drosophila insulin-like peptides (DILPs) pathway, related to mammalian insulin pathway, regulates SIK3 activity in feeding conditions independently of increasing LKB1 kinase activity. Overall, these data suggest that fasting stimuli specifically control the kinase activity of LKB1 and establish the LKB1-SIK3 pathway as a converging point between feeding and fasting signals to control lipid homeostasis in Drosophila. 相似文献
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Chakrabarti P English T Karki S Qiang L Tao R Kim J Luo Z Farmer SR Kandror KV 《Journal of lipid research》2011,52(9):1693-1701
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Thyroid-stimulating hormone (TSH) has been shown to play an important role in the regulation of triglyceride (TG) metabolism in adipose tissue. Adipose triglyceride lipase (ATGL) is a rate-limiting enzyme controlling the hydrolysis of TG. Thus far, it is unclear whether TSH has a direct effect on the expression of ATGL. Because TSH function is mediated through the TSH receptor (TSHR), TSHR knockout mice (Tshr-/- mice) (supplemented with thyroxine) were used in this study to determine the effects of TSHR deletion on ATGL expression. These effects were verified in 3T3-L1 adipocytes and potential underlying mechanisms were explored. In the Tshr-/- mice, ATGL expression in epididymal adipose tissue was significantly increased compared with that in Tshr+/+ mice. ATGL expression was observed to increase with the differentiation process of 3T3-L1 preadipocytes. In mature 3T3-L1 adipocytes, TSH significantly suppressed ATGL expression at both the protein and mRNA levels in a dose-dependent manner. Forskolin, which is an activator of adenylate cyclase, suppressed the expression of ATGL in 3T3-L1 adipocytes. The inhibitory effects of TSH on ATGL expression were abolished by H89, which is a protein kinase A (PKA) inhibitor. These results indicate that TSH has an inhibitory effect on ATGL expression in mature adipocytes. The associated mechanism is related to PKA activation. 相似文献