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Current Opinion in Lipidology Apr 2013Inherited diseases of lipoprotein metabolism may give rise to marked hypocholesterolemia with low or absent levels of LDL, depending on the gene involved and mode of... (Review)
Review
PURPOSE OF REVIEW
Inherited diseases of lipoprotein metabolism may give rise to marked hypocholesterolemia with low or absent levels of LDL, depending on the gene involved and mode of inheritance of the condition, together with the severity of the mutation or mutations present. In this review, we discuss the recent developments in the genetics of LDL deficiency.
RECENT FINDINGS
Carriers of a single loss-of-function variant in ANGPTL3 have reduced LDL-cholesterol and triglyceride concentrations, whereas homozygotes have markedly reduced LDL-cholesterol, triglyceride and HDL-cholesterol concentrations, a recessive form of hypocholesterolemia designated as familial combined hypolipidemia.
SUMMARY
The identification of loss-of-function ANGPTL3 mutations as a cause of familial combined hypolipidemia suggests a new mechanism for the regulation of LDL metabolism in humans, thereby making ANGPTL3 an attractive protein to target for therapeutics.
Topics: Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Angiopoietins; Animals; Biomarkers; Cholesterol, LDL; Genetic Predisposition to Disease; Heterozygote; Humans; Hypobetalipoproteinemias; Lipoprotein Lipase; Mice; Mutation; Triglycerides
PubMed: 23254474
DOI: 10.1097/MOL.0b013e32835ca0d9 -
Cell Reports Sep 2022Hepatic endoplasmic reticulum (ER) stress is a hallmark of obesity-induced liver steatosis and contributes to the progress of steatosis and insulin resistance in liver....
Hepatic endoplasmic reticulum (ER) stress is a hallmark of obesity-induced liver steatosis and contributes to the progress of steatosis and insulin resistance in liver. However, its influence on adipose function is still unclear. Here, we identify a hepatic ER stress-induced activating transcription factor 4 (ATF4)-cold-inducible RNA-binding protein (CIRP)-angiopoietin-related protein3 (ANGPTL3) cascade critical for the regulation of adipose browning. We find that obesity increases CIRP expression in liver through ER stress-induced ATF4. CIRP in turn binds to the 3' UTR and increases mRNA stability of ANGPTL3. ANGPTL3 secreted from liver suppresses uncoupling protein 1 expression through integrin αβ and c-Jun N-terminal kinase in adipose tissue. While hepatic expression of either ATF4, CIRP, or ANGPTL3 suppresses adipose browning, knockdown of CIRP and ANGPTL3 in liver or administration of integrin αβ inhibitor cilengitide increases adipose browning process. Taken together, we identify a communication mechanism to link hepatic ER stress and adipose browning that may imply a reciprocal regulation of obesity and liver steatosis.
Topics: 3' Untranslated Regions; Activating Transcription Factor 4; Adipose Tissue; Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Angiopoietins; Endoplasmic Reticulum Stress; Fatty Liver; Humans; Integrins; JNK Mitogen-Activated Protein Kinases; Liver; Obesity; RNA-Binding Proteins; Uncoupling Protein 1
PubMed: 36170814
DOI: 10.1016/j.celrep.2022.111422 -
PloS One 2017Minimal Change Disease (MCD) is the most common type of nephrotic syndrome in children. Angiopoietin-like-4 (Angplt4) has been proposed as mediator of proteinuria in...
BACKGROUND
Minimal Change Disease (MCD) is the most common type of nephrotic syndrome in children. Angiopoietin-like-4 (Angplt4) has been proposed as mediator of proteinuria in MCD. The aim of this study was to evaluate the role of Angptl4 as a biomarker in MCD.
METHODS
Patients with biopsy-proven primary MCD, focal segmental glomerulosclerosis, membranous nephropathy (60, 52 and 52 respectively) and 18 control subjects had urinary and serum Angptl4 measured by Elisa. Frozen kidney tissue sections were stained for Angptl4.
RESULTS
Angptl4 was not identified in glomeruli of MCD patients in relapse. Urinary Angptl4 levels were elevated in MCD in relapse as well as in patients with massive proteinuria due to other glomerular diseases.
CONCLUSION
Neither serum nor urine Angptl4 appear to be good biomarkers in MCD. Elevated urinary Angptl4 n glomerular disease appears to reflect the degree of proteinuria rather than any specific disease.
Topics: Adolescent; Adult; Angiopoietin-Like Protein 4; Angiopoietins; Biomarkers; Child; Child, Preschool; Diagnosis, Differential; Female; Glomerulosclerosis, Focal Segmental; Humans; Kidney; Male; Middle Aged; Nephrosis, Lipoid; Nephrotic Syndrome; Young Adult
PubMed: 28441404
DOI: 10.1371/journal.pone.0176198 -
Molecular Medicine Reports Oct 2017Angiogenesis is the formation of new vessels starting from pre-existing vasculature. Tumour environment is characterized by 'aberrant angiogenesis', whose main features... (Review)
Review
Angiogenesis is the formation of new vessels starting from pre-existing vasculature. Tumour environment is characterized by 'aberrant angiogenesis', whose main features are tortuous and permeable blood vessels, heterogeneous both in their structure and in efficiency of perfusion and very different from normal vessels. Therapeutic strategies targeting the three pathways chiefly involved in tumour angiogenesis, VEGF, Notch and Ang signalling, have been identified to block the vascular supply to the tumour. However, phenomena of toxicity, development of primary and secondary resistance and hypoxia significantly blunted the effects of anti-angiogenic drugs in several tumour types. Thus, different strategies aimed to overcome these problems are imperative. The focus of the present review was some principal 'alternative' approaches to classic antiangiogenic therapies, including the cyclooxygenase-2 (COX-2) blockade, the use of oligonucleotide complementary to the miRNA to compete with the mRNA target (antimiRs) and the inhibition of matrix metalloproteinases (MMPs). The role of blood soluble VEGFA as a predictive biomarker during antiangiogenic therapy in gastric, ovarian and colorectal cancer was also examined.
Topics: Angiopoietins; Animals; Humans; Neoplasms; Neovascularization, Pathologic; Receptors, Notch; Signal Transduction; Vascular Endothelial Growth Factor A
PubMed: 28791360
DOI: 10.3892/mmr.2017.7179 -
The Journal of Clinical Investigation Oct 2018The M2 isoform of pyruvate kinase (PKM2) is highly expressed in most cancer cells, and has been studied extensively as a driver of oncogenic metabolism. In contrast, the...
The M2 isoform of pyruvate kinase (PKM2) is highly expressed in most cancer cells, and has been studied extensively as a driver of oncogenic metabolism. In contrast, the role of PKM2 in nontransformed cells is little studied, and nearly nothing is known of its role, if any, in quiescent cells. We show here that endothelial cells express PKM2 almost exclusively over PKM1. In proliferating endothelial cells, PKM2 is required to suppress p53 and maintain cell cycle progression. In sharp contrast, PKM2 has a strikingly different role in quiescent endothelial cells, where inhibition of PKM2 leads to degeneration of tight junctions and barrier function. Mechanistically, PKM2 regulates barrier function independently of its canonical activity as a pyruvate kinase. Instead, PKM2 suppresses NF-kB and its downstream target, the vascular permeability factor angiopoietin 2. As a consequence, loss of endothelial cell PKM2 in vivo predisposes mice to VEGF-induced vascular leak, and to severe bacteremia and death in response to sepsis. Together, these data demonstrate new roles of PKM2 in quiescent cells, and highlight the need for caution in developing cancer therapies that target PKM2.
Topics: Angiopoietin-2; Angiopoietins; Animals; Capillary Permeability; Cell Proliferation; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Mice; Mice, Mutant Strains; NF-kappa B; Pyruvate Kinase
PubMed: 30222136
DOI: 10.1172/JCI120912 -
Critical Care (London, England) Oct 2013Angiopoietins signal via the Tie-2 receptor and are essential molecules for vasculogenesis during development and in the adult state play roles in vascular stability as...
Angiopoietins signal via the Tie-2 receptor and are essential molecules for vasculogenesis during development and in the adult state play roles in vascular stability as well as inflammation and appear to be involved in the dysregulation of the endothelium in illness. Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are, respectively, agonists and competitive partial agonists, which have been found to undergo alterations in individuals with sepsis. In sepsis, Ang-2 levels are elevated and Ang-1 is decreased. In the previous issue of Critical Care, Fiusa and colleagues measure circulating Ang-1 and Ang-2 along with other growth factors in humans with febrile neutropenia. The authors found that an increased Ang-2/Ang-1 ratio, or an elevated Ang-2 level, at the time of an initial fever, is associated with subsequent development of septic shock and death. These findings validate that the Ang-2/Ang-1 balance, which is thought to reflect overall signaling via the Tie-2 receptor, is relevant to outcomes in patients with sepsis. Importantly, the specimens were obtained far in advance of the development of septic shock, suggesting that detectable alterations in this pathway may provide early clues regarding outcomes. This study adds to the evidence that angiopoietins are early markers of endothelial dysfunction in sepsis and provide prognostic information regarding outcomes.
Topics: Angiopoietin-1; Angiopoietin-2; Febrile Neutropenia; Female; Humans; Male; Shock, Septic
PubMed: 24131798
DOI: 10.1186/cc13066 -
World Journal of Gastroenterology Jul 2006To investigate the significance of angiopoietins, Tie2 and vascular endothelial growth factor (VEGF) expression in the angiogenesis and progress of hepatocellular...
AIM
To investigate the significance of angiopoietins, Tie2 and vascular endothelial growth factor (VEGF) expression in the angiogenesis and progress of hepatocellular carcinoma (HCC).
METHODS
Fresh surgically resected specimens of HCC and noncancerous liver (NCL) tissue from 38 patients with HCC were obtained, and expression of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), Tie2, and VEGF messenger RNA (mRNA) was examined by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). Expression pattern of each gene in HCC and NCL tissue specimens was compared and the potential role and interaction in angiogenesis of HCC were analyzed. Genes' expression level and its relationship with tumor's clinicopathological parameters were also investigated. Immunohistochemical staining of CD34 was performed to determine the microvessel density (MVD) and Ang-2/Ang-1 ratio was calculated. Relationships between Ang-2/Ang-1 ratio, VEGF and MVD and clinicopathological features were also tested so as to evaluate their significance in the progression of HCC.
RESULTS
Ang-2 and VEGF mRNAs in HCC were significantly higher than those in NCL tissue (P < 0.05), whereas the Ang-1 and Tie2 mRNAs showed no statistical significance (P > 0.05), though slightly lower level of Ang-1 mRNA in HCC was observed. Ang-2/Ang-1 ratio and VEGF were both positively correlated to MVD. The Ang-2/ Ang-1 ratio, Ang-2 and VEGF were all associated with tumor's clinicopathological parameters (P < 0.05) except for histological grades (P > 0.05). Ang-1 and Tie2 levels in different clinicopathological groups were not significantly different (P > 0.05).
CONCLUSION
Dominant Ang-2 expression against Ang-1 through Tie2 receptor in the presence of VEGF plays a critical role in initiating early neovascularization and transformation of noncancerous liver to hepatocellular carcinoma. Its consequently constant operation in formed HCC induces further angiogenesis and progression of HCC.
Topics: Adult; Aged; Angiopoietin-1; Angiopoietin-2; Angiopoietins; Antigens, CD34; Carcinoma, Hepatocellular; Disease Progression; Female; Gene Expression Regulation; Humans; Liver; Liver Neoplasms; Male; Middle Aged; Neovascularization, Pathologic; RNA, Messenger; Receptor, TIE-2; Vascular Endothelial Growth Factor A
PubMed: 16830384
DOI: 10.3748/wjg.v12.i26.4241 -
European Heart Journal Dec 2013
Topics: Angiopoietin-Like Protein 4; Angiopoietins; Animals; Brain Ischemia; Humans; Male; Nootropic Agents; Stroke
PubMed: 23729690
DOI: 10.1093/eurheartj/eht183 -
Diabetologia Jun 2018Three members of the angiopoietin-like (ANGPTL) family of proteins, ANGPTL3, ANGPTL4 and ANGPTL8, are known regulators of plasma triacylglycerol levels. Recently, these...
Three members of the angiopoietin-like (ANGPTL) family of proteins, ANGPTL3, ANGPTL4 and ANGPTL8, are known regulators of plasma triacylglycerol levels. Recently, these three proteins have garnered considerable interest as potential targets for therapeutically reducing plasma triacylglycerol levels and improving cardiovascular outcomes. In this issue of Diabetologia, Janssen et al ( https://doi.org/10.1007/s00125-018-4583-5 ) and Vatner et al ( https://doi.org/10.1007/s00125-018-4579-1 ) show that reducing levels of ANGPTL4 and ANGPTL8, respectively, could have the added benefit of improving glucose tolerance. Interestingly, the improvements in glucose tolerance observed in both studies, both done in rodents, were coupled with increased fat mass. These findings suggest that funnelling lipids to adipose tissue and away from ectopic sites could be beneficial and strengthen the argument for pursuing the therapeutic targeting of ANGPTL proteins.
Topics: Angiopoietin-like Proteins; Angiopoietins; Animals; Diet; Glucose; Insulin Resistance; Lipid Metabolism; Non-alcoholic Fatty Liver Disease; Oligonucleotides, Antisense; Rodentia
PubMed: 29619530
DOI: 10.1007/s00125-018-4604-4 -
Malaria Journal Jul 2022Malaria related mortality is associated with significant deregulation of host inflammatory factors such as interferon-inducible protein 10, a member of the CXC or...
BACKGROUND
Malaria related mortality is associated with significant deregulation of host inflammatory factors such as interferon-inducible protein 10, a member of the CXC or α-subfamily (CXCL10), and host angiogenic factors such as angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2). However, detection of these factors in malaria patients requires the drawing of blood, which is invasive and increases the risk of accidental blood-borne infections. There has been an increased interest in the use of saliva as the body fluid of choice for the diagnosis of many infectious diseases including malaria. Here, saliva levels of CXCL10, Ang-1, and Ang-2 previously shown to be predictive of severe malaria in malaria patients in Ghana were assessed in malaria patients.
METHODS
This study was conducted in the Shai-Osudoku District Hospital in Dodowa, Accra, Ghana and the study population comprised 119 malaria patients and 94 non-malaria subjects. The non-malaria subjects are healthy community participants with no malaria infection. Plasma and saliva levels of CXCL10, Ang-1 and Ang-2 of the study participants were measured using an enzyme-linked immunoassay. Complete blood counts of each participant were measured with a haematology autoanalyzer. Pearson correlation was used to evaluate the correlation between plasma and saliva levels of each biomarker in malaria patients. A p-value of < 0.05 was considered significant. Box plots of median biomarker concentrations were plotted. SPSS version 14.2 software was used for statistical analysis.
RESULTS
The non-malaria subjects had a median age of 29 years compared to 23 years for malaria patients (p = 0.001). Among the malaria patients, there was a strong significant relationship between CXCL10 (R = 0.7, p < 0.0001) and Ang-1 (R = 0.7, p < 0.0001). Malaria patients had lower saliva levels of Ang-1 (p = 0.009) and higher saliva levels of CXCL10 (p = 0.004) and Ang-2 (p = 0.001) compared to non-malaria subjects.
CONCLUSIONS
This study provides the first evidence of elevated levels of CXCL10 and Ang-2 in the saliva of malaria patients. Detection of CXCL10, Ang-1 and Ang-2 in saliva may have a potential application for non-invasive malaria diagnosis.
Topics: Adult; Angiopoietin-1; Angiopoietin-2; Biomarkers; Ghana; Humans; Malaria; Saliva
PubMed: 35836234
DOI: 10.1186/s12936-022-04221-7