Angiopoietin-like Protein Research Articles

Serum betatrophin levels and fatty acid profile in gestational diabetes mellitus: Correlation with insulin resistance

Introduction and Aim: Gestational diabetes mellitus (GDM) involves insulin resistance, altered levels of adipocytokines and inflammation. Interaction of various molecules in the pathogenesis of obesity and insulin resistance plays a major role in GDM. Angiopoietin-like protein 8, also named betatrophin is a hormone which is synthesized from liver and adipocytes. This molecule has beta cell-regenerating effect and is proposed to have therapeutic potential in obesity, insulin resistance and diabetes mellitus. The present study aimed to evaluate the role of betatrophin and free fatty acids (FFA) as markers of gestational diabetes mellitus (GDM). Materials and Methods: This study was conducted in Medical College Hospital on pregnant women with the normal body mass index. The study subjects were divided into 2 groups -one with healthy pregnant women and the other GDM and recruited for the study at 24 to 28 weeks of gestation. The levels of betatrophin, insulin and FFA were estimated in the serum and HOMA-IR was calculated. Results: Insulin resistance (IR), serum betatrophin level and plasma omega-6 fatty acid levels were higher, and plasma omega-3 fatty acid levels were lower among GDM subjects in comparison to healthy pregnant women. Fasting plasma glucose, serum betatrophin level and dihomo gamma linolenic acid level showed significant positive correlation with IR while omega 3 fatty acid %, levels of alpha linolenic acid, gamma linolenic acid and lauric acid showed negative correlation with IR in GDM women. Conclusion: Altered fatty acid profile in gestational diabetes mellitus indicated potential application of fatty acids as biomarkers of metabolic derangements which arise due to insulin resistance. The findings have diagnostic, prognostic, and therapeutic implications.

ANGPTL3 and Cardiovascular Outcomes in Patients With Acute Coronary Syndrome and Obstructive Sleep Apnea.

Background The aim of this prospective study was to determine the impact of elevated ANGPTL3 (angiopoietin-like protein 3) on cardiovascular events (CVEs) following acute coronary syndrome (ACS) in patients with or without obstructive sleep apnea (OSA). Methods and Results A total of 1174 patients with ACS underwent successful percutaneous coronary intervention were included in this prospective cohort study (NCT03362385). Patients were categorized according to the apnea-hypopnea index (≥15 events/h, OSA) and further classified by ANGPTL3 levels. We analyzed the incidence of CVEs in patients with ACS according to the status of OSA and ANGPTL3. During a median of 3.1 years of follow-up, 217 (18.48%) CVEs occurred. The patients with ACS with OSA had higher ANGPTL3 levels than those without OSA (30.4 [20.9-43.2] versus 27.80 [19.1-41.5]ng/mL; P<0.001). In all patients with ACS, 29≤ANGPTL3<42 mg/dL and ANGPTL3≥42 mg/dL were associated with an increased risk of CVEs with hazard ratios (HRs) of 1.555 (95% CI, 1.010-2.498) and 2.489 (95% CI 1.613-3.840), respectively. When the status of OSA or not was incorporated in stratifying factors, 29≤ANGPTL3<42 mg/dL and ANGPTL3≥42 mg/dL were associated with a significantly higher risk of CVEs in patients with ACS with OSA (HR, 1.916 [95% CI, 1.019-3.601] and HR, 2.692 [95% CI, 1.379-4.503]) but not without OSA. Moreover, adding ANGPTL3 to the Cox model increased C-statistic values by 0.035 and 0.029 in the OSA group and all patients with ACS, respectively, but was not statistically improved in patients with ACS without OSA. Conclusions In conclusion, our study demonstrates a predictive impact of plasma ANGPTL3 on cardiovascular risk in patients with ACS, especially in patients with ACS with OSA. It might be of clinical value in refining risk stratification and tailoring treatment of patients with ACS and OSA. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03362385.

A Review of free fatty acid-induced cell signaling, angiopoietin-like protein 4, and skeletal muscle differentiation

Postnatal skeletal muscle differentiation from quiescent satellite cells is a highly regulated process, although our understanding of the contribution of nutritional factors in myogenesis is limited. Free fatty acids (FFAs) are known to cause detrimental effects to differentiated skeletal muscle cells by increasing oxidative stress which leads to muscle wasting and insulin resistance in skeletal muscle. In addition, FFAs are thought to act as inhibitors of skeletal muscle differentiation. However, the precise molecular mechanisms underlying the effects of FFAs on skeletal muscle differentiation remains to be elucidated. There is a clear relationship between dietary FFAs and their ability to suppress myogenesis and we propose the hypothesis that the FFA-mediated increase in angiopoietin-like protein 4 (ANGPTL4) may play a role in the inhibition of differentiation. This review discusses the role of FFAs in skeletal muscle differentiation to-date and proposes potential mechanisms of FFA-induced ANGPTL4 mediated inhibition of skeletal muscle differentiation.

Effects of Fatty-Type and Lean-Type on Growth Performance and Lipid Droplet Metabolism in Pekin Ducks.

The reasons for differences in lipid depositions between fatty-type (F-T) and lean-type (L-T) ducks remain unknown. The present study aimed to compare the growth performance, lipid deposition, and gene expression related to lipid droplet formation in F-T and L-T Pekin ducks. One-day-old, 140 each L-T and F-T male ducks were selected and distributed separately into 20 replicate cages. All ducks were fed commercial diets up to 35 d of age. F-T ducks had a higher average daily gain from 21 to 28 d of age. On 35-day-old, F-T ducks had higher serum levels of high- and low-density lipoprotein cholesterol, cholesterol, albumin, and hydroxybutyrate dehydrogenase activity than L-T ducks. F-T ducks had higher abdominal fat and subcutaneous fat percentages than those in L-T ducks. Liver histological examination showed that L-T ducks contained more lipid droplets in the liver, which gradually decreased with increasing age. The average adipocyte area and diameter of abdominal fat and subcutaneous fat in the F-T and L-T ducks increased with age and were higher in F-T ducks than those in L-T ducks. Furthermore, the gene expression of perilipin 1, perilipin 2, angiopoietin-like protein 4, adipose triglyceride lipase, alpha/beta-hydrolase domain-containing protein 5 (ABHD5), and serine/threonine kinase 17a in the liver, abdominal fat, and subcutaneous fat of F-T ducks was higher than that in L-T ducks, and it increased with age. Compared to L-T ducks, F-T ducks had higher expression of ABHD5 in the abdominal fat and subcutaneous fat and lower expression in the liver. Thus, F-T ducks displayed lower hepatic lipid deposition and a higher percentage of abdominal fat and subcutaneous fat, suggesting that F-T ducks had higher lipid storage capacity due to increased gene expression related to lipid droplets.

Molecular characterisation, temporal expression and involvement of ANGPTL4 in fat deposition in Muscovy ducks

ABSTRACT 1. Angiopoietin-like protein 4 (ANGPTL4) plays a key role in promoting fat metabolism and reducing blood lipid. This study characterised the ANGPTL4 gene in Muscovy ducks (Cairina moschata) and investigated its potential functions in fat metabolism in Muscovy ducks. 2. The Muscovy duck ANGPTL4 cDNA was successfully cloned for the first time, showing a length of 2591 bp. After phylogenetic analysis by RT-qPCR analysis, it was found that the ANGPTL4 gene of Anas platyrhynchos shared the highest sequence similarity with that of Muscovy ducks. 3. The ANGPTL4 gene was commonly expressed in 23 different tissues with the highest expression in the abdominal fat in Muscovy ducks. A significant association was observed between abdominal fat percentage (AFP) and the mRNA expression of the ANGPTL4 gene. Moreover, Muscovy ducks showed a peak of ANGPTL4 expression in the liver and abdominal fat at 1–2 weeks old. 4. These findings suggest that the ANGPTL4 gene is related to fat deposition and regulation in Muscovy ducks.

Increased Levels of ANGPTL3 and CTRP9 in Patients With Obstructive Sleep Apnea and Their Relation to Insulin Resistance and Lipid Metabolism and Markers of Endothelial Dysfunction.

Obstructive sleep apnea (OSA) has a close relation with obesity and perturbation in adipokines and hepatokines, which are linked to OSA consequences such as insulin resistance, dyslipidemia, and endothelial dysfunction. This study aimed to assess the relation of C1q/TNF-related protein 9 (CTRP9) and angiopoietin-like protein 3 (ANGPTL3) with OSA and biochemical measurements. Serum levels of ANGPTL3, CTRP9, adiponectin, leptin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion protein 1 (VCAM-1) were determined in 74 OSA patients and 27 controls using enzyme-linked immunosorbent assay kits. Levels of ANGPTL3, CTRP9, leptin, ICAM-1, and VCAM-1 were increased in the patients compared to the controls, whereas adiponectin levels decreased. ANGPTL3 had a positive correlation with total cholesterol, triglyceride, low-density lipoprotein cholesterol, ICAM-1, and VCAM-1 and was inversely correlated with leptin. CTRP9 showed a positive correlation with body mass index, insulin resistance, ICAM-1, and VCAM-1. The results indicated the relation of ANGLTP3 and CTRP9 with OSA and its complications, which suggested a possible role for these factors in the consequences of OSA.

The predictive diagnosis for ANGPTL8 level in women with T2DM

Background: The metabolic syndrome including type 2 diabetes mellitus(T2DM), insulin resistance(IR), obese, hypertension, and dyslipidemia, is an increasing health burden. In the last decade, various metabolic hormones have been noticed to significantly role obese and associated complications. for example of this, the adipokines or hepatokines secreted proteins from hepatocyte and adipocyteare correlate with metabolic syndrome. Angiopoietin-like protein 8 (ANGPTL8) has a novel hepatokine or adipokine, which is mostly expressed in the adipose tissue, and liver stimulates the β-cell proliferation as a pancreatic in an insulin resistance state. It's a recently discovered the endocrine regulator associated with glucose homeostasis, IR, and metabolism of lipid. Materials and Methods: Ninety women participated in this study, comprising sixty patients with diabetes mellitus type-2 and thirty healthy (sex and age - matched) as a control group. Enzyme linked immune sorbent assay (ELISA) was used to assess ANGPTL8 and insulin. Standard procedures were used to measure fasting blood glucose, lipid profile, and glycated hemoglobin (HBA1c) in a certified laboratory. Results: Diabetes patients had higher levels of ANGPTL8 than the control group. The blood ANGPTL8 level in the Type-2 diabetes group varied from 4432.89±1171.09 pg/ml, while the control group's level was 2892.11±537.91pg/dl (p&lt;0.0001).

ANGPTL8 promotes adipogenic differentiation of mesenchymal stem cells: potential role in ectopic lipid deposition.

BackgroundEctopic lipid deposition plays a promoting role in many chronic metabolic diseases. Abnormal adipogenic differentiation of mesenchymal stem cells (MSCs) is an important cause of lipid deposition in organs. Studies have shown that serum angiopoietin-like protein 8 (ANGPTL8) levels are increased in patients with many chronic metabolic diseases (such as type 2 diabetes, obesity, and hepatic steatosis), while the role of ANGPTL8 in ectopic lipid accumulation has not been reported.MethodsWe used the Gene Expression Omnibus (GEO) database to analyze the expression of ANGPTL8 in subcutaneous adipose tissue of obese patients and qPCR to analyze the expression of ANGPTL8 in the liver of high-fat diet (HFD)-induced obese mice. To explore the potential roles of ANGPTL8 in the progression of ectopic lipid deposition, ANGPTL8 knockout (KO) mice were constructed, and obesity models were induced by diet and ovariectomy (OVX). We analyzed lipid deposition (TG) in the liver, kidney, and heart tissues of different groups of mice by Oil Red O, Sudan black B staining, and the single reagent GPO-PAP method. We isolated and characterized MSCs to analyze the regulatory effect of ANGPTL8 on Wnt/β-Catenin, a key pathway in adipogenic differentiation. Finally, we used the pathway activator LiCl and a GSK3β inhibitor (i.e., CHIR99021) to analyze the regulatory mechanism of this pathway by ANGPTL8.ResultsANGPTL8 is highly expressed in the subcutaneous adipose tissue of obese patients and the liver of HFD-induced obese mice. Both normal chow diet (NCD)- and HFD-treated ANGPTL8 KO male mice gained significantly less weight than wild-type (WT) male mice and reduced ectopic lipid deposition in organs. However, the female mice of ANGPTL8 KO, especially the HFD group, did not show differences in body weight or ectopic lipid deposition because HFD could induce estrogen overexpression and then downregulate ANGPTL8 expression, thereby counteracting the reduction in HFD-induced ectopic lipid deposition by ANGPTL8 deletion, and this result was also further proven by the OVX model. Mechanistic studies demonstrated that ANGPTL8 could promote the differentiation of MSCs into adipocytes by inhibiting the Wnt/β-Catenin pathway and upregulating PPARγ and c/EBPα mRNA expression.ConclusionsANGPTL8 promotes the differentiation of MSCs into adipocytes, suggesting that ANGPTL8 may be a new target for the prevention and treatment of ectopic lipid deposition in males.

Free-cell therapeutics and mechanism of exosomes from adipose-derived stem cells in promoting wound healing: current understanding and future applications.

Free-cell therapeutics and mechanism of exosomes from adipose-derived stem cells in promoting wound healing: current understanding and future applications.

Abstract P3010: Angptl4 Reduces Atherosclerosis And Promotes Fibrous Cap Stability By Targeting Klf4 In Vascular Smooth Muscle Cells

Background: Atherosclerosis is vascular disease of chronic inflammation, and we recently showed that angiopoietin-like 4 (ANGPTL4) promote cardiac repair by suppressing pathological inflammation. Given the contribution of inflammation to atherosclerosis, we assessed the effect of ANGPTL4 on atherosclerosis development. Methods: We injected recombinant ANGPTL4 protein or PBS to atherosclerotic Apoe-/- mice twice a week fed a high-fat diet for 8 weeks, and analyzed atherosclerotic lesion size, inflammation, and plaque stability. The effect of ANGPTL4 on vascular smooth muscle cells (VSMCs) was studied, and plasma levels of ANGPTL4 in patients were measured. Results: ANGPTL4 treatment reduced the atherosclerotic plaque size and vascular inflammation. In the atherosclerotic lesions, the number of α-SMA(+)MYH11(+) cells was higher, while the number of CD68(+)cells was lower in the ANGPTL4 group than in the vehicle-treated group. Moreover, α-SMA-expressing fibrous cap was significantly thicker in the ANGPTL4 group than in the PBS group. Then, we isolated VSMCs from atherosclerotic aortas, and found that CD68 and Krüppel-like factor 4 (KLF4) were significantly upregulated in the PBS group. As KLF4 is a phenotypic modulator and an inducer of NADP oxidase 1 (Nox1) in VSMCs, the effect of ANGPTL4 on VSMCs was assessed. Cholesterol-induced upregulations of Nox1 and KLF4 were substantially inhibited by ANGPTL4 treatment. Then, we analyzed the circulating ANGPTL4 levels of the cardiovascular disease patients, and found the positive correlation between high ANGPTL4 and low incidence of vascular events. Conclusions: Our results showed that ANGPTL4 inhibited atherogenesis by increasing the fibrous cap thickness. KLF4 and Nox1 were suggested as targets of ANGPTL4 in VSMCs to confer plaque stability by attenuating phenotypic changes of VSMCs toward inflammatory macrophage-like cells. Taken together, circulating ANGPTL4 may be associated with regulation of vascular events.

A first-in-human single ascending dose study of a monoclonal antibody against the ANGPTL3/8 complex in subjects with mixed hyperlipidemia

Background and Aims : Angiopoietin-like protein 3 (ANGPTL3) inhibition reduces LDL-cholesterol (LDL-C), triglycerides (TG) and HDL-C in patients with hyperlipidemia. Post-prandially, ANGPTL8 forms a complex with ANGPTL3; the ANGPTL3/8 complex inhibits lipoprotein lipase 100-fold more potently and circulates at much lower levels than ANGPTL3 alone. This phase 1 study assessed the safety and pharmacology of single ascending doses of LY3475766 (LY), a monoclonal antibody against the ANGPTL3/8 complex.

Recent Updates in Hypertriglyceridemia Management for Cardiovascular Disease Prevention.

Mounting evidence continues to support the causal role of triglyceride-rich lipoproteins (TRL) in the development of atherosclerotic cardiovascular disease (ASCVD). Substantial residual ASCVD risk remains among high-risk patients who have elevated triglycerides despite reduction in low-density lipoprotein cholesterol (LDL-C) with statin therapy. Ongoing research efforts have focused on evaluating triglyceride-lowering therapies among patients with hypertriglyceridemia. The REDUCE-IT trial showed that the addition of icosapent ethyl, a highly purified form of eicosapentaenoic acid (EPA), can reduce vascular events among statin-treated individuals with elevated triglycerides who have either clinical ASCVD or diabetes plus another risk factor. Although additional evidence for EPA has emerged from other trials, conflicting results have been reported by subsequent trials that tested different omega-3 fatty acid formulations. Randomized clinical trials have not demonstrated incremental ASCVD benefit of fibrates on background of statin therapy, but fibrates are used to help prevent pancreatitis in patients with severe hypertriglyceridemia. Selective inhibitors of apolipoprotein C-III (apoC3) and angiopoietin-like protein 3 (ANGPTL3), proteins that are involved in metabolism of TRLs by regulating lipoprotein lipase, have been tested in selected patient populations and showed significant reduction in triglyceride and LDL-C levels. Statin therapy continues to be the cornerstone of pharmacologic reduction of cardiovascular risk. High-dose EPA in the form of icosapent ethyl has been demonstrated to have cardiovascular benefit on top of statins in persons with elevated triglycerides at high ASCVD risk. Ongoing clinical trials are evaluating novel selective therapies such as apoC3 and ANGPTL3 inhibitors.

Relationship of ANGPTL6 With Neonatal Glucose Homeostasis and Fat Mass Is Disrupted in Gestational Diabetic Pregnancies.

Angiopoietin-like protein 6 (ANGPTL6) is a hepatokine, which, in animal studies, improves insulin sensitivity and increases energy expenditure to counteract insulin resistance. Evaluate in a human population, the role of serum ANGPTL6 in gestational diabetes mellitus (GDM) or its presence in fetal circulation. A total of 190 women (115 controls and 75 GDM) and their offspring were studied. Insulin, glucose, ANGPTL6, retinol binding protein 4 (RBP4), and retinol, as well as leptin and adiponectin, were determined in maternal serum obtained at term and from umbilical artery blood at delivery. At term, pregnant women with GDM showed higher serum concentrations of ANGPTL6, insulin, homeostatic model assessment, and apo-RBP4 (free RBP4) than controls but not of glucose, which remained similar in both groups. Also, in arterial cord serum, ANGPTL6 concentration was increased in GDM neonates with respect to the control group (201 ± 12 ng/mL vs 119 ± 8 ng/mL, respectively). No effect of maternal insulin treatment of some GDM mothers in neonates of either sex on ANGPTL6 levels was observed. In GDM, circulating ANGPTL6 showed no correlation with glucose or insulin concentration or with neonatal adiposity. However, in control pregnancies, the variation in glucose concentration was positively correlated with ANGPTL6 concentration, both in maternal and in cord samples, and cord ANGPTL6 was negatively correlated with neonatal fat mass. Furthermore, in control pregnant women, serum concentrations of ANGPTL6 and apo-RBP4 were negatively correlated. Serum ANGPTL6 levels are associated with maternal glucose homeostasis and fetal adiposity in normal pregnancy. ANGPTL6 levels in maternal and cord serum GDM pregnancy at term are increased, although its mechanism and physiological role are unknown yet.

ANGPTL4 attenuates palmitic acid-induced endothelial cell injury by increasing autophagy

ANGPTL4, a member of the angiopoietin-like protein family, is reported to be involved in angiogenesis regulation, lipid metabolism, glucose metabolism and redox reactions, among others. Our previous study showed that the plasma ANGPTL4 level was lower in coronary atherosclerotic heart disease (CAHD) and could be a useful predictor of coronary atherosclerosis. However, the molecular mechanism underlying the function of ANGPTL4 in atherosclerosis is poorly understood. In this study, we found that overexpression of ANGPTL4 in HUVECs enhanced cell proliferation and clone-forming ability in vitro, whereas knockdown of ANGPTL4 resulted in the opposite. The expression of ANGPTL4 was upregulated in palmitic acid (PA)-treated HUVECs. Overexpression of ANGPTL4 protected against PA-induced endothelial injury. Knockdown of ANGPTL4 exacerbated the effects of PA on HUVECs. Mechanistically, we demonstrated that ANGPTL4 promoted endothelial cell proliferation through the regulation of autophagy. Knockdown of ATG7 or 3-MA (an autophagy inhibitor) attenuated the effects of ANGPTL4 on endothelial cells. The serum level of ANGPTL4 was downregulated in atherosclerosis mice. Furthermore, the expression of ANGPTL4 was correlated with autophagy-related proteins in aortic tissues of atherosclerotic mice. ANGPTL4 promotes endothelial cell proliferation and suppresses PA-induced endothelial cell injury by increasing autophagy, which may protect against the development of atherosclerosis.

Tumor cell-derived ANGPTL2 promotes β-catenin-driven intestinal tumorigenesis.

Uncontrolled proliferation of intestinal epithelial cells caused by mutations in genes of the WNT/β-catenin pathway is associated with development of intestinal cancers. We previously reported that intestinal stromal cell-derived angiopoietin-like protein 2 (ANGPTL2) controls epithelial regeneration and intestinal immune responses. However, the role of tumor cell-derived ANGPTL2 in intestinal tumorigenesis remained unclear. Here, we show that tumor cell-derived ANGPTL2 promotes β-catenin-driven intestinal tumorigenesis. ANGPTL2 deficiency suppressed intestinal tumor development in an experimental mouse model of sporadic colon cancer. We also found that increased ANGPTL2 expression in colorectal cancer (CRC) cells augments β-catenin pathway signaling and promotes tumor cell proliferation. Relevant to mechanism, our findings suggest that tumor cell-derived ANGPTL2 upregulates expression of OB-cadherin, which then interacts with β-catenin, blocking destruction complex-independent proteasomal degradation of β-catenin proteins. Moreover, our observations support a model whereby ANGPTL2-induced OB-cadherin expression in CRC cells is accompanied by decreased cell surface integrin α5β1 expression. These findings overall provide novel insight into mechanisms of β-catenin-driven intestinal tumorigenesis.

Dual roles of ANGPTL4 in multiple inflammatory responses in stomatitis mice.

Stomatitis is inflammation of the oral mucosa. Angiopoietin-like protein 4 (ANGPTL4) has pleiotropic functions both anti-inflammatory and pro-inflammatory properties. In the present study, we tested whether there is a correlation between increased ANGPTL4 expression and inflammation in stomatitis mice and the mechanisms involved. In this study, the oral mucosa of mice was burned with 90% phenol and intraperitoneal injection of 5-fluorouracil to establish the model of stomatitis mice. The pathological changes of stomatitis mice were observed by H&E staining of paraffin section. The expressions of cytokines and ANGPTL4 were detected by fluorescence quantitative PCR, and the protein levels of ANGPTL4 were detected by western blot. Compared with control group, the oral mucosal structure of model mice was damaged. The expression of ANGPTL4 were significantly increased concomitantly with elevated production of anti-inflammatory cytokine (peroxisome proliferator-activated receptoralpha) and pro-inflammatory cytokines [nuclear transcription factor-kappaB, interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α] in mice with stomatitis. This study suggests that ANGPTL4 may be a double-edged sword in multiple inflammatory responses in stomatitis mice.

Antisense Oligonucleotides and Small Interfering RNA for the Treatment of Dyslipidemias

The burden of atherosclerotic disease worldwide necessitates implementing the treatment of its risk factors. Among them, hypercholesterolemia has a central role. In addition to conventional small organic compounds and the recently introduced monoclonal antibodies, new technologies are arising such as the antisense oligonucleotides and small interfering RNAs (siRNAs) that operate upstream, blocking the mRNA translation of the proteins specifically involved in lipid metabolism. In this review, we briefly explain the mechanisms of action of these molecules and discuss the difficulties related to their in vivo use as therapeutical agents. We go over the oligonucleotides tested in clinical trials that could potentially revolutionize the care of patients by acting on proteins involved in the lipoprotein metabolism and regulation, namely: angiopoietin-like protein 3 (ANGPTL3); lipoprotein a (Lp(a)); apolipoprotein B (Apo B); apolipoprotein C III (Apo C-III); and proprotein convertase subtilisin–kexin type 9 (PCSK9). Finally, the differences between ASOs and siRNAs, their future possible clinical applications, and the role of Inclisiran, a siRNA direct against PCSK9 to reduce LDL-C, were reviewed in detail.

ANGPTL4 Regulates Psoriasis via Modulating Hyperproliferation and Inflammation of Keratinocytes.

Background: Psoriasis is characterized by keratinocyte proliferation and massive inflammatory leukocytes infiltration, affecting 0.14%–1.99% of the world’s population. Our aim was to identify novel potential therapeutic strategies for psoriasis. Methods: Weighted gene co-expression network analysis (WGCNA) was performed to identify gene modules that were closely related to psoriasis based on the GSE30999 dataset, which contained expression data from 85 patients with moderate-to-severe psoriasis. Then, angiopoietin-like 4 (ANGPTL4), one of the most related hub genes, was selected for in vitro and in vivo functional assays. In our experiments, imiquimod (IMQ)-induced psoriasiform dermatitis in mice and human keratinocytes (HaCaT) cells were used to study the potential roles and mechanisms of ANGPTL4 in psoriasis. Results: WGCNA analysis revealed the turquoise module was most correlated with psoriasis, and ANGPTL4 is one of the most related hub genes that significantly upregulated in psoriasis lesions compared with non-lesional skin. Consistent with the bioinformatic analysis, the expression of ANGPTL4 was significantly upregulated in IMQ-induced psoriasiform skin of mice. Exogenous recombinant ANGPLT4 protein treatment could promote the proliferation and induce the expression of inflammatory cytokines in HaCaTs, whereas silencing of ANGPTL4 effectively inhibited these effects. Then we demonstrated that recombinant ANGPTL4 protein exacerbated psoriasiform inflammation and epidermal hyperproliferation in vivo. Mechanismly, extracellular signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) pathways were involved in ANGPTL4-mediated regulation of proliferation and inflammation. Conclusion: We found ANGPTL4 was significantly increased in IMQ-induced psoriasiform skin of mice. ANGPTL4 could promote keratinocyte proliferation and inflammatory response via ERK1/2 and STAT3 dependent signaling pathways in psoriasis.

ANGPTL8 is a negative regulator in pathological cardiac hypertrophy

Pathological cardiac hypertrophy is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the role of angiopoietin-like protein 8 (ANGPTL8) in pathological cardiac hypertrophy. We found that serum ANGPTL8 levels were significantly increased in hypertensive patients with cardiac hypertrophy and in mice with cardiac hypertrophy induced by Ang II or TAC. Furthermore, the secretion of ANGPTL8 from the liver was increased during hypertrophic processes, which were triggered by Ang II. In the Ang II- and transverse aortic constriction (TAC)-induced mouse cardiac hypertrophy model, ANGPTL8 deficiency remarkably accelerated cardiac hypertrophy and fibrosis with deteriorating cardiac dysfunction. Accordingly, both recombinant human full-length ANGPTL8 (rANGPTL8) protein and ANGPTL8 overexpression significantly mitigated Ang II-induced cell enlargement in primary neonatal rat cardiomyocytes (NRCMs) and H9c2 cells. Mechanistically, the antihypertrophic effects of ANGPTL8 depended on inhibiting Akt and GSK-3β activation, and the Akt activator SC-79 abolished the antihypertrophic effects of rANGPTL8 in vitro. Moreover, we demonstrated that ANGPTL8 directly bound to the paired Ig-like receptor PIRB (LILRB3) by RNA-seq and immunoprecipitation-mass screening. Remarkably, the antihypertrophic effects of ANGPTL8 were largely blocked by anti-LILRB3 and siRNA-LILRB3. Our study indicated that ANGPTL8 served as a novel negative regulator of pathological cardiac hypertrophy by binding to LILRB3 (PIRB) and inhibiting Akt/GSK3β activation, suggesting that ANGPTL8 may provide synergistic effects in combination with AT1 blockers and become a therapeutic target for cardiac hypertrophy and heart failure.

Angiopoietin-Like Protein 3 (ANGPTL3) Inhibitors in the Management of Refractory Hypercholesterolemia.

Cardiovascular disease (CVD) is the most common cause of death in a global scale and significantly depends on the elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and the subsequent formation of atherosclerotic plaques. While physicians have several LDL-C-lowering agents with diverse mechanisms of action, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and inclisiran, angiopoietin-like protein 3 (ANGPTL3) inhibitors have recently emerged as a powerful addition in the armamentarium of lipid-lowering strategies, especially for patients with refractory hypercholesterolemia, as in the case of patients with homozygous familial hypercholesterolemia (HoFH). ANGPTL3 protein is a glycoprotein secreted by liver cells that is implicated in the metabolism of lipids along with other ANGPTL proteins. These proteins inhibit lipoprotein lipase (LPL) and endothelial lipase (EL) in tissues. Loss-of-function mutations affecting the gene encoding ANGPTL3 are linked with lower total cholesterol, LDL-C, and triglyceride (TG) levels. Evinacumab is a monoclonal antibody that targets, binds to, and pharmacologically inhibits ANGPTL3, which was recently approved by the United States Food and Drug Administration (FDA) as a complementary agent to other LDL-C lowering regimens for patients aged 12 or older with HoFH, based on clinical trial evidence that confirmed its safety and efficacy in those patients. Antisense oligonucleotides (ASOs) also represent an interesting class of agents that target and inhibit the mRNA derived from the transcription of ANGPTL3 gene. This review aims to present and discuss the current clinical and scientific data pertaining to the role of ANGPTL3 inhibitors, a novel lipid-modifying class of agents capable of reducing LDL-C levels via a mechanism independent of LDL receptors.