Angiopoietin-like 4 Research Articles

Angiopoietin-like protein 2 deficiency promotes periodontal inflammation and alveolar bone loss.

Human periodontitis is a highly prevalent inflammatory disease that leads to connective tissue degradation, alveolar bone resorption, and tooth loss. Angiopoietin-like 2 (ANGPTL2) regulates chronic inflammation in various diseases and is functionally involved in maintaining tissue homeostasis and promoting tissue regeneration, but there is limited information about its function in periodontitis. Here we investigated the expression and explicit role of ANGPTL2 in periodontitis. Immunohistochemistry and quantitative real-time PCR (qRT-PCR) were used to detect the ANGPTL2 expression in periodontal tissues and periodontal ligament cells (PDLCs). A ligature-induced periodontitis model was generated in wild-type and ANGPTL2 knockout mice. qRT-PCR and enzyme-linked immunosorbent assay were used to assess the production of inflammatory cytokines and matrix metalloproteinases (MMPs) in cultured PDLCs. Western blot was performed to detect proteins in relevant signaling pathways. Increased ANGPTL2 expression was observed in inflamed periodontal tissues and PDLCs. ANGPTL2 deficiency promoted alveolar bone loss with enhanced osteoclastogenesis and inflammatory reactions in ligature-induced periodontitis. Downregulation of ANGPTL2 remarkably enhanced expression levels of interleukin (IL)-6, IL-8, MMP1, and MMP13 in Porphyromonas gingivalis lipopolysaccharide-induced PDLCs, whereas ANGPTL2-overexpressing PDLCs showed opposite trends. ANGPTL2 downregulation activated STAT3 and nuclear factor-κB pathways and blocked Akt signaling under inflammatory environment. Treatment with a STAT3 inhibitor partially suppressed the inflammatory reaction of PDLCs mediated by ANGPTL2 knockdown. Our study provides the first evidence of an anti-inflammatory effect of ANGPTL2 in murine periodontitis. The findings demonstrate the critical and protective role of ANGPTL2 in alveolar bone loss and periodontal inflammation.

Endothelial cell biomarkers in critically ill COVID-19 patients with encephalitis.

COVID-19 is associated with encephalitis in critically ill patients and endothelial dysfunction seems to contribute to this life-threatening complication. Our objective was to determine the hallmark of endothelial activation in COVID-19-related encephalitis. In an observational study in intensive care unit (ICU), we compared vascular biomarkers of critically ill COVID-19 patients with or without encephalitis. To be classified in the encephalitis group, patients had to have new onset of central neurologic symptom, and pathological findings on either brain magnetic resonance imaging (MRI) and/or electroencephalogram (EEG). Among the 32 critically ill COVID-19 consecutive patients, 21 were categorized in the control group and 11 in the encephalitis group. Encephalitis patients had a longer ICU stay than control patients (median length [25th-75th percentile] of 52 [16-79] vs. 20.5 [11-44] days, respectively, p=0.04). Nine-month overall follow-up mortality reached 21% (7/32 patients), with mortality rates in the encephalitis group and the control group of 27% and 19%, respectively. Encephalitis was associated with significant higher release of soluble endothelial activation markers (sE-selectin, tumor necrosis factor-α (TNF-α), interleukin 6, placental growth factor, and thrombomodulin), but these increases were correlated with TNF-α plasmatic levels. The hypoxia-inducible protein angiopoietin-like 4 (ANGPTL4) was at significantly higher levels in encephalitis patients compared to control patients (p=0.0099), and in contrary to the other increased factors, was not correlated with TNF-α levels (r=0.2832, p=0.1163). Our findings suggest that COVID-19-related encephalitis is a cytokine-associated acute brain dysfunction. ANGPTL4 was the only elevated marker found in encephalitis patients, which was not correlated with systemic inflammation, suggesting that ANGPTL4 might be a relevant factor to predict encephalitis in critically ill COVID-19 patients.

G protein-coupled estrogen receptor stimulates human trophoblast cell invasion via YAP-mediated ANGPTL4 expression

Insufficient invasion of trophoblast cells into the uterine decidua is associated with preeclampsia (PE). G protein-coupled estrogen receptor (GPER) is a membrane estrogen receptor involved in non-genomic estrogen signaling. GPER is expressed in human trophoblast cells and downregulated GPER levels are noted in PE. However, to date, the role of GPER in trophoblast cells remains largely unknown. Here, we applied RNA sequencing (RNA-seq) to HTR-8/SVneo human trophoblast cells in response to G1, an agonist of GPER, and identified angiopoietin-like 4 (ANGPTL4) as a target gene of GPER. Treatment of trophoblast cells with G1 or 17β-estradiol (E2) activated Yes-associated protein (YAP), the major downstream effector of the Hippo pathway, via GPER but in a mammalian STE20-like protein kinase 1 (MST1)-independent manner. Using pharmacological inhibitors as well as loss- and gain-of-function approaches, our results revealed that YAP activation was required for GPER-stimulated ANGPTL4 expression. Transwell invasion assays demonstrated that activation of GPER-induced ANGPTL4 promoted cell invasion. In addition, the expression levels of GPER, YAP, and ANGPTL4 were downregulated in the placenta of patients with PE. Our findings reveal a mechanism by which GPER exerts its stimulatory effect on human trophoblast cell invasion by upregulating YAP-mediated ANGPTL4 expression.

ANGPTL4-Mediated Promotion of Glycolysis Facilitates the Colonization of Fusobacterium nucleatum in Colorectal Cancer.

Colorectal cancer is a severe health problem worldwide, and accumulating evidence supports the contribution of Fusobacterium nucleatum (F. nucleatum) to colorectal cancer development, metastasis, and chemoresistance. However, the mechanisms underlying the colonization of F. nucleatum in colorectal cancer tissue are not yet clarified. Here we demonstrate that F. nucleatum infection mediated elevation of angiopoietin-like 4 (ANGPTL4) expression. Upregulated ANGPTL4 promoted glucose uptake and glycolysis activity in colorectal cancer cells in vitro and in vivo, which are necessary for the colonization of F. nucleatum. Furthermore, overall increased acetylation of histone H3 lysine 27 was observed in F. nucleatum-infected colorectal cancer cells and patient tumors, which was responsible for the corresponding transcriptional upregulation of ANGPTL4. These data indicate that the metabolic reprogramming of cancer cells induced by F. nucleatum is essential for its enrichment and persistence in colorectal cancer, providing a novel potential target for the clinical intervention of F. nucleatum-related colorectal cancer. SIGNIFICANCE: F. nucleatum colonization in colorectal cancer is regulated by ANGPTL4-mediated glycolysis, suggesting that this axis could be targeted for combined repression of F. nucleatum and cancer progression.

ANGPTL4 accelerates KRASG12D-Induced acinar to ductal metaplasia and pancreatic carcinogenesis.

Oncogenic KRASG12D induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN), and drives pancreatic ductal adenocarcinoma (PDAC). Angiopoietin-like 4 (ANGPTL4) is known to be involved in the regulation of cancer growth and metastasis. However, whether ANGPTL4 affects KRASG12D-mediated ADM and early PDAC intervention remains unknown. In the current study, we investigated the role of ANGPTL4 in KRASG12D-induced ADM, PanIN formation, and PDAC maintenance. We found that ANGPTL4 was highly expressed in human and mouse ADM lesions and contributed to the promotion of KRASG12D-driven ADM in mice. Consistently, ANGPTL4 rapidly induced ADM in three-dimensional culture of acinar cells with KRAS mutation and formed ductal cysts that silenced acinar genes and activated ductal genes, which are characteristic of in vivo ADM/PanIN lesions. We also found that periostin works as a downstream regulator of ANGPTL4-mediated ADM/PDAC. Genetic ablation of periostin diminished the ADM/PanIN phenotype induced by ANGPTL4. A high correlation between ANGPTL4 and periostin was confirmed in human samples. These results demonstrate that ANGPTL4 is critical for ADM/PanIN initiation and PDAC progression through the regulation of periostin. Thus, the ANGPTL4/periostin axis is considered a potential target for ADM-derived PDAC.

Excipient of paclitaxel induces metabolic dysregulation and unfolded protein response

SummaryTaxane-based reagents, such as Taxol, Taxotere, and Abraxane, are popular anti-cancer drugs that can differ in their clinical efficacy. This difference is generally attributed to their active pharmaceutical ingredients. Here, we report a serendipitous discovery that Taxol induces metabolic dysregulation and unfolded protein response. Surprisingly, these effects of Taxol are entirely dependent on its excipient, Cremophor EL (CrEL). We show that CrEL promotes aerobic glycolysis and in turn results in drastic upregulation of angiopoietin like 4 (ANGPTL4), a major regulator of human blood lipid profile. Notably, premedication with dexamethasone further enhances the expression of ANGPTL4. Consistently, we find that the amplitude and frequency of increase in triglycerides is more prominent in Taxol-treated patients with breast cancer. In addition, we find that CrEL activates the unfolded protein response pathway to trigger proinflammatory gene expression and caspase/gasdermin E-dependent pyroptosis. Finally, we discuss the implications of these results in anti-cancer therapies.

Oleic and palmitic acids induce hepatic angiopoietin-like 4 expression predominantly via PPAR-γ in Larimichthys crocea.

Angiopoietin-like 4 (ANGPTL4) is a potent regulator of TAG metabolism, but knowledge of the mechanisms underlying ANGPTL4 transcription in response to fatty acids is still limited in teleost. In the current study, we explored the molecular characterisation of ANGPTL4 and regulatory mechanisms of ANGPTL4 in response to fatty acids in large yellow croaker (Larimichthys crocea). Here, croaker angptl4 contained a 1416 bp open reading frame encoding a protein of 471 amino acids with highly conserved 12-amino acid consensus motif. Angptl4 was widely expressed in croaker, with the highest expression in the liver. In vitro, oleic and palmitic acids (OA and PA) treatments strongly increased angptl4 mRNA expression in croaker hepatocytes. Moreover, angptl4 expression was positively regulated by PPAR family (PPAR-α, β and γ), and expression of PPARγ was also significantly increased in response to OA and PA. Moreover, inhibition of PPARγ abrogated OA- or PA-induced angptl4 mRNA expression. Beyond that, PA might increase angptl4 expression partly via the insulin signalling. Overall, the expression of ANGPTL4 is strongly upregulated by OA and PA via PPARγ in the liver of croaker, which contributes to improve the understanding of the regulatory mechanisms of ANGPTL4 in fish.

Weighted Gene Co-Expression Network Analysis Identifies ANGPTL4 as a Key Regulator in Diabetic Cardiomyopathy via FAK/SIRT3/ROS Pathway in Cardiomyocyte.

BackgroundDiabetic cardiomyopathy (DbCM) is characterized by initial impairment of left ventricular relaxation followed by contractile dysfunction. Despite intensive research, the exact mechanism remains so far unsolved.MethodsWe constructed weighted gene co-expression network analysis (WGCNA) to screen gene modules that were closely related with DbCM based on the GSE5606 dataset, which contained expression data of the cardiac left ventricle in a rodent model of streptozotocin (STZ)-induced DbCM. Then, the most related hub gene, angiopoietin-like 4 (ANGPTL4), was selected for functional ex vivo and in vitro assays. In our experiments, STZ-induced diabetic mice (C57BL/6J) and human cardiomyocytes (AC16) were used to study the functional roles and potential mechanisms of ANGPTL4 in DbCM.ResultsWGCNA analysis revealed the yellow and green modules were most correlated with DbCM, and identified ANGPTL4 as one of the most significantly upregulated hub genes (ANGPTL4, ACOT1, DECR1, HMGCS2, and PDK4). Consistent with the bioinformatic analysis, the amount of ANGPTL4 was significantly upregulated in diabetic mouse heart. DbCM group, compared with the control group, had increased phosphorylation of focal adhesion kinase (FAK), reduced SIRT3 expression, increased SOD2 acetylation, upregulated NADPH oxidase activation, elevated reactive oxygen species (ROS) produciton, and enhanced apoptosis in the diabetic mouse heart. Moreover, ANGPTL4 induced apoptosis via FAK/SIRT3/ROS pathway in human cardiomyocytes (AC16) under high glucose condition in vitro.These effects were abrogated by treatment of two independent siRNA for ANGPTL4, whereas exogenous recombinant ANGPLT4 protein treatment exacerbated those effects in AC16.ConclusionWe found ANGPTL4, ACOT1, DECR1, HMGCS2, and PDK4 were significantly increased in diabetic heart. ANGPTL4 could promote cardiac apoptosis via a FAK/SIRT3/ROS dependent signaling pathway in DbCM.

Hepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice.

Hepatic uptake and biosynthesis of fatty acids (FA), as well as the partitioning of FA into oxidative, storage, and secretory pathways are tightly regulated processes. Dysregulation of one or more of these processes can promote excess hepatic lipid accumulation, ultimately leading to systemic metabolic dysfunction. Angiopoietin-like-4 (ANGPTL4) is a secretory protein that inhibits lipoprotein lipase (LPL) and modulates triacylglycerol (TAG) homeostasis. To understand the role of ANGPTL4 in liver lipid metabolism under normal and high-fat fed conditions, we generated hepatocyte specific Angptl4 mutant mice (Hmut). Using metabolic turnover studies, we demonstrate that hepatic Angptl4 deficiency facilitates catabolism of TAG-rich lipoprotein (TRL) remnants in the liver via increased hepatic lipase (HL) activity, which results in a significant reduction in circulating TAG and cholesterol levels. Consequently, depletion of hepatocyte Angptl4 protects against diet-induce obesity, glucose intolerance, liver steatosis, and atherogenesis. Mechanistically, we demonstrate that loss of Angptl4 in hepatocytes promotes FA uptake which results in increased FA oxidation, ROS production, and AMPK activation. Finally, we demonstrate the utility of a targeted pharmacologic therapy that specifically inhibits Angptl4 gene expression in the liver and protects against diet-induced obesity, dyslipidemia, glucose intolerance, and liver damage, which likely occurs via increased HL activity. Notably, this novel inhibition strategy does not cause any of the deleterious effects previously observed with neutralizing antibodies.

Overexpressed Neuropilin-1 in Endothelial Cells Promotes Endothelial Permeability through Interaction with ANGPTL4 and VEGF in Kawasaki Disease.

Disrupted endothelial permeability plays a crucial role in the vasculitis pathogenesis of Kawasaki disease (KD), which leads to pathological vascular leak and facilitates inflammatory cell infiltration in vascular lesions; however, the mechanisms involved in the development of endothelial barrier dysfunction during KD vasculitis are still largely unclear. Here, we found that sera from patients with KD can induce endothelial cell (EC) hyperpermeability compared to sera from healthy controls. We observed that serum vascular endothelial growth factor (VEGF) levels were increased in KD patients and sera from KD patients upregulated the expression of VEGF receptor 2 (VEGFR2) and neuropilin-1 (NRP1) in human coronary artery endothelial cells (HCAECs). Intriguingly, compared with silence of VEGFR2 in HCAECs, NRP1 silence resulted in a marked decrease in EC permeability. Furthermore, soluble NRP1 (sNRP1) remarkably reduced the stimulation of EC permeability by sera from KD patients compared with bevacizumab treatment. Importantly, we showed that besides VEGF, angiopoietin-like-4 (ANGPTL4), a NRP1-binding vasoactive factor, was also increased in KD and contributed to the EC permeability in KD conditions. In addition, levels of both ANGPTL4 and VEGF were inversely correlated with albumin levels in the serum of KD patients. Collectively, the data demonstrated that overexpressed NRP1, along with upregulated VEGFR2, in HCAECs treated with KD sera promotes endothelial permeability via interaction with the increased ANGPTL4 and VEGF in KD. Neutralization of hyperpermeability factors by sNRP1 may be a novel therapeutic strategy for KD vasculitis.

ANGPTL4 Attenuates Ang II-Induced Atrial Fibrillation and Fibrosis in Mice via PPAR Pathway.

Atrial fibrillation (AF) is the more significant portion of arrhythmia in clinical practice, with inflammation and fibrosis as its central pathological mechanisms. This study aimed to investigate angiopoietin-like 4 (ANGPTL4) effects on angiotensin II- (Ang II-) induced AF and its related pathophysiological mechanisms. C57BL/6J mice were randomized and divided into three groups: the control group, the Ang II group, and the ANGPTL4 group (Ang II with ANGPTL4 treatment). Mice were infused with Ang II (2000 ng/kg/min) and were administrated with recombinant human ANGPTL4 (rhANGPTL4, 20 μg/kg/day) for 3 weeks. The fibrosis was evaluated with Masson's trichrome staining in the atrial myocardium. mRNA levels of IL-1β, IL-6, collagen I, and collagen III were measured using real-time qRT-PCR. Protein levels of PPARα, PPARγ, CPT-1, and SIRT3 were measured using Western blotting. Compared to the control group, the mice infused with Ang II showed electrocardiogram characteristics of AF, and this effect was markedly attenuated in ANGPTL4-treated mice. ANGPTL4 also reversed the increase in cardiomyocyte apoptosis, inflammation, interstitial collagen fraction, and collagen gene expression in mice with Ang II. Mechanistically, ANGPTL4 inhibited the activation of several fatty acid metabolism-related proteins, including PPARα, PPARγ, and CPT-1, and the expression of SIRT3 protein in atrial tissues. In conclusion, ANGPTL4 attenuates Ang II-induced AF and atrial fibrosis by modulation in the SIRT3, PPARα, and PPARγ signaling pathways.

The Regulation of Circulating Hepatokines by Fructose Ingestion in Humans.

ContextFibroblast growth factor 21 (FGF21), follistatin, angiopoietin-like 4 (ANGPTL4), and growth differential factor 15 (GDF15) are regulated by energy metabolism. Recent findings in humans demonstrate that fructose ingestion increases circulating FGF21, with increased response in conditions of insulin resistance.ObjectiveThis study examines the acute effect of fructose and somatostatin on circulating FGF21, follistatin, ANGPTL4, and GDF15 in humans.MethodsPlasma FGF21, follistatin, ANGPTL4, and GDF15 concentrations were measured in response to oral ingestion of 75 g of fructose in 10 young healthy males with and without a 15-minute infusion of somatostatin to block insulin secretion. A control infusion of somatostatin was also performed in the same subjects.ResultsFollowing fructose ingestion, plasma FGF21 peaked at 3.7-fold higher than basal concentration (P < 0.05), and it increased 4.9-fold compared with basal concentration (P < 0.05) when somatostatin was infused. Plasma follistatin increased 1.8-fold after fructose ingestion (P < 0.05), but this increase was blunted by concomitant somatostatin infusion. For plasma ANGPTL4 and GDF15, no increases were obtained following fructose ingestion. Infusion of somatostatin alone slightly increased plasma FGF21 and follistatin.ConclusionHere we show that in humans (1) the fructose-induced increase in plasma FGF21 was enhanced when somatostatin was infused, suggesting an inhibitory role of insulin on the fructose-induced FGF21 increase; (2) fructose ingestion also increased plasma follistatin, but somatostatin infusion blunted the increase; and (3) fructose ingestion had no stimulating effect on ANGPTL4 and GDF15 levels, demonstrating differences in the hepatokine response to fructose ingestion.

Long-term physical activity modulates adipsin and ANGPTL4 serum levels, a potential link to exercise-induced metabolic changes.

Within the presented prospective study, we aimed to illuminate the effect of long-term physical exercise on serum levels of adipsin (complement factor D) and angiopoietin-like 4 (ANGPTL4). Although past studies already outlined the effects of acute exercise, our trial design aimed to depict the development under long-term physical activity conditions. Ninety-eight participants were included in the study and were asked to perform eight months of moderate physical activity for at least 150 minutes/week and/or vigorous-intensity exercise for at least 75 minutes/week. According to initial performance and performance gain throughout the study period, four groups were formed and subsequently compared. Blood sampling for the determination of routine laboratory parameters was done at baseline, after 2, 6, and 8 months. Additionally, adipsin and ANGPTL4 serum levels were concurrently quantified using commercially available ELISA kits. The study cohort consisted of 61.2% male participants with an average age of 49.3±6.7 years. Adipsin and ANGPTL4 were found to be strongly increased by long-term physical exercise. Participants displaying a performance gain of >2.9% throughout the study showed significantly increased serum levels of both biomarkers. Serum levels of adipsin and ANGPTL4 were closely tied to the individual performance gain of the participating probands. An association of adipsin levels, initial performance, and serum triglycerides was found at baseline. Interestingly, this interrelationship was not detectable after eight months of physical training. This finding might indicate adipsin's involvement in linking triglyceride-balance to individual performance and energy demands in a homeostatic state.

A graphene oxide-based aptasensor for ANGPTL4 biomarker detection

In this study, aptamers targeting angiopoietin-like 4 (ANGPTL4) with high affinity and specificity were first obtained by SELEX technology. Subsequently, through the optimization strategy of mutation and truncation, a core sequence was generated, with the binding affinity increased by 4–5 times. The improvement after optimization is attributed to the reduction in steric hindrance of targeted binding and the conversion of the aptamer's folding structure, which results in sufficient exposure of the binding site. Finally, a graphene oxide-based aptasensor was developed using the fluorescence on/off switching mechanism, with the detection limit of ANGPTL4 determined as 0.12 nM. The aptasensor showed good reproducibility and stability in the analysis of ANGPTL4 in serum samples. The developed aptasensor may come to be a robust, convenient, and cost-effective approach for practical detection of ANGPTL4 in the future.

ANGPTL4 regulates CD163 expression and Kuppfer cell polarization induced cirrhosis via TLR4/NF-κB pathway

Angiopoietin like 4 (ANGPTL4) has been proved to play an important role in lipid and glucose metabolism disorders and related cardiovascular diseases, but its role in the formation of cirrhosis still needs to be further explored. Therefore, the aim of this study was to investigate the role of ANGPTL4 in the development of liver cirrhosis and its mechanism, as well as its effect on Kupffer cell polarization and hepatic stellate cell activation. The ELISA and RT-qPCR assay were used to detect the content of ANGPTL4 in serum and mRNA expression in cells and tissues respectively. The expression of ANGPTL4, Arg1 and Mrc2 in Kupffer cells was measured by Western blot. The percentage of CD163+ and CD206+ cells was measured by flow cytometry. Mice cirrhosis model was established, and the expression of ANGPTL4 was interfered by injecting sh-ANGPTL4 lentiviral vector into caudal vein. The results revealed that ANGPTL4 was significantly up-regulated in liver cirrhosis patients and HBV induced liver injury cell models. Further studies found that interference with ANGPTL4 regulated CD163 and inhibited the polarization and proinflammatory effects of KCs，as well as inhibited the activation of hepatic stellate cells (HSCs) and fibrosis. More importantly, Interference with ANGPTL4 inhibits the progression of liver cirrhosis in mice. What's more, TLR4/NF-κB pathway was involved in the molecular mechanism of ANGPTL4 on Kupffer cells and hepatic stellate cells. It is suggested that the mechanism of sh-ANGPTL4 suppressing the polarization of KCs and the activation of hepatic stellate cells (HSCs) is to regulate the TLR4/NF-κB signaling pathways.

1229-P: Decreased Circulating Zonulin in Obese Adults as a Marker of Leaky Gut: Preliminary Results

Leaky gut contributes to metabolic syndrome. Zonulin is an intestinal protein that is involved in gut permeability. We aimed to assess the relationships between circulating zonulin and lipopolysaccharide (LPS), body composition, liver characteristics, and cytokines involved in obesity or liver disease. Forty seven nondiabetic, euthyreotic adults were included: 12 with BMI 29 kg/m2. Basic clinical parameters, total and visceral fat (bioimpedance; Tanita), liver steatosis and fibrosis (transient elastography; Fibroscan), as well as serum Sirtuin-1, Fetuin-A, Fatty Acid-Binding Protein 1 (FABP-1), Angiopoietin-like 4 (ANGPTL4) (all Fine Biotech Co.), Zonulin (DRG International), and LPS (Qayee Biotechnology Co.) were analyzed. “Obese” subjects presented insulin resistance and liver injury. In the “Obese” serum zonulin was ~50% lower, whilst serum CRP and LPS significantly higher than in the “Lean. Serum zonulin was correlated inversely with BMI, total fat, liver fibrosis, serum CRP and LPS, but no studied cytokine (table 1). Our data point to decreased circulating zonulin in obese subjects, indicative of leaky gut as implied by its associations with endotoxemia, microinflammation, fat accumulation, and fibrotic liver damage. Disclosure G. Wystrychowski: Other Relationship; Self; Roche Pharma. W. Grzeszczak: Other Relationship; Self; Berlin-Chemie AG, Roche Pharma. A. Witkowska: None. E. Wojtyna: None. A. Golda: Other Relationship; Self; Servier Laboratories. M. Wrobel: None. K. Bochenek: None. W. Trautsolt: None. S. Gorczynska-kosiorz: None. N. Szweda-gandor: None. Funding Medical University of Silesia (KNW-1-178/N/7/K, KNW-1-008/K/8/K)

Circadian Angiopoietin-Like-4 as a Novel Therapy in Cardiovascular Disease

Angiopoietin-like 4 (ANGPTL4) is critical for regulating plasma lipids, and thus an attractive therapeutic target for cardiovascular diseases. Unfortunately, targeting ANGPTL4 results in a proinflammatory and ultimately lethal phenotype in animals. The serendipitous discovery of cardiac ANGPTL4 as a circadian protein reveals novel mechanistic insight and a solution for this therapeutic dilemma.

Regulation of fat partitioning by ANGPTL4

Altered triglyceride metabolism and changes in fatty acid partitioning are major contributors to metabolic diseases including metabolic syndrome, diabetes, and atherosclerosis. The triglycerides in plasma lipoproteins are hydrolyzed by lipoprotein lipase (LPL), and the levels of LPL activity in the capillary beds of peripheral tissues such as heart, skeletal muscle, and adipose serve as the primary determinant dietary fat delivery to those tissues. LPL activity is regulated by a variety of extracellular proteins including angiopoietin-like 4 (ANGPTL4). ANGPTL4 regulates plasma triglyceride metabolism by inactivating LPL. ANGPTL4 is most highly expressed in adipose tissue and liver, but it is also expressed at lower levels in muscle, heart, kidney, and intestine. It also circulates in plasma. Using whole-body and tissue-specific ANGPTL4 knockout mice we sought to determine where and when ANGPTL4 acts on LPL, and how the action of ANGPTL4 alters lipid partitioning. We found that ANGPTL4-deficiency specifically increases the uptake of triglyceride-derived fatty acids into adipose tissue, and that is effect is observed most prominently in the fasted state. Adipose-specific knockout of ANGPTL4 could wholly recapitulate the plasma triglyceride and fat partitioning phenotypes of whole-body ANGPTL4 knockouts, supporting the idea that adipose-derived ANGPTL4 is the primary driver of ANGPTL4’s effect on plasma triglycerides. Our data also suggest that ANGPTL4 expressed in adipose primarily acts locally to suppress LPL activity in the fasted state. Consistent with other reports, we also found that adipose-specific deletion of ANGPTL4 leads to short-term improvement in glucose tolerance in mice fed a high fat diet. However, we found that this improvement disappears with age. Moreover, we found that in wild-type mice LPL activity, ANGPTL4 expression, and lipid portioning are all altered with age. As age is also an important risk factor for metabolic disease, these finding suggest that age-induced changes in triglyceride metabolism may contribute to the increased risk of metabolic disease associated with aging.

Age‐dependent Decline in Angiogenesis and Repair from Influenza

Aging is associated with impaired repair of lung injury, while influenza and pneumonia are one of the leading causes of death in aged adults. Angiogenesis – the formation of new capillaries –plays key roles in repair from injury. Angiogenesis is impaired in aging animals. Thus, in order to develop more efficient strategies for lung injury in aged people, we need to understand the mechanism by which aging inhibits angiogenesis and how the signaling contributes to impairment of repair from injury. It has been reported that angiopoietin like4 (ANGPTL4) contributes to influenza infection. However, it remains unknown whether ANGPTL4 mediates age-dependent impairment of repair from influenza infection. Here we find that the levels of ANGPTL4 are higher in aged endothelial cells (ECs) compared to young ECs. Survival rate of PR8 influenza infection is lower in aged mice. The mRNA levels of ANGPTL4 peak at 7 days post influenza infection (dpi) in young mice, while the levels remain high at 14 dpi in aged mouse lungs. These results suggestthat repair from influenza infection is inhibited in aged lung through ANGPTL4. Modulation of ANGPTL4 may reverse the impairment of angiogenesis and improves recovery from influenza infection in aged lungs.

PPARs and Tumor Microenvironment: The Emerging Roles of the Metabolic Master Regulators in Tumor Stromal-Epithelial Crosstalk and Carcinogenesis.

Simple SummaryThe roles of peroxisome proliferator-activated receptors (PPARs) in carcinogenesis are increasingly appreciated. With the growing interest in tumor stromal-epithelial crosstalk, we aim to provide an up-to-date overview of the implications of PPARs in the tumor microenvironment. In the tumor stromal cells, the nuclear receptors exhibit critical, but functionally diverse activities, rendering it hard to ascribe either an exclusive pro- or anti-tumorigenic role for different PPAR isotypes. Based on the existing evidence, we also highlight the knowledge gaps and future prospects of targeting PPARs in the tumor microenvironment. Essentially, a PPAR-based anticancer approach holds a great deal of untapped potential, but its success relies on innovative strategies for cell-specific or tumor microenvironment-triggered drug delivery systems.Peroxisome proliferator-activated receptors (PPARs) have been extensively studied for more than three decades. Consisting of three isotypes, PPARα, γ, and β/δ, these nuclear receptors are regarded as the master metabolic regulators which govern many aspects of the body energy homeostasis and cell fate. Their roles in malignancy are also increasingly recognized. With the growing interest in crosstalk between tumor stroma and epithelium, this review aims to highlight the current knowledge on the implications of PPARs in the tumor microenvironment. PPARγ plays a crucial role in the metabolic reprogramming of cancer-associated fibroblasts and adipocytes, coercing the two stromal cells to become substrate donors for cancer growth. Fibroblast PPARβ/δ can modify the risk of tumor initiation and cancer susceptibility. In endothelial cells, PPARβ/δ and PPARα are pro- and anti-angiogenic, respectively. Although the angiogenic role of PPARγ remains ambiguous, it is a crucial regulator in autocrine and paracrine signaling of cancer-associated fibroblasts and tumor-associated macrophages/immune cells. Of note, angiopoietin-like 4 (ANGPTL4), a secretory protein encoded by a target gene of PPARs, triggers critical oncogenic processes such as inflammatory signaling, extracellular matrix derangement, anoikis resistance and metastasis, making it a potential drug target for cancer treatment. To conclude, PPARs in the tumor microenvironment exhibit oncogenic activities which are highly controversial and dependent on many factors such as stromal cell types, cancer types, and oncogenesis stages. Thus, the success of PPAR-based anticancer treatment potentially relies on innovative strategies to modulate PPAR activity in a cell type-specific manner.