Angiopoietin-like protein 3 (ANGPTL3) deficiency and familial combined hypolipidemia

Three members of the angiopoietin-like(ANGPTL) protein family-ANGPTL3, ANGPTL4 and ANGPTL8-are important regulators of plasma lipoproteins. They inhibit the enzyme lipoprotein lipase, which plays a key role in the intravascular lipolysis of triglycerides present in some lipoprotein classes. This review focuses on the role of ANGPTL3 as emerged from the study of genetic variants of Angptl3 gene in mice and humans. Both loss of function genetic variants and inactivation of Angptl3 gene in mice are associated with a marked reduction of plasma levels of triglyceride and cholesterol and an increased activity of lipoprotein lipase and endothelial lipase. In humans with ANGPTL3 deficiency, caused by homozygous loss of function(LOF) variants of Angptl3 gene, the levels of all plasma lipoproteins are greatly reduced. This plasma lipid disorder referred to as familial combined hypolipidemia(FHBL2) does not appear to be associated with distinct pathological manifestations. Heterozygous carriers of LOF variants have reduced plasma levels of total cholesterol and triglycerides and are at lower risk of developing atherosclerotic cardiovascular disease, as compared to non-carriers. These observations have paved the way to the development of strategies to reduce the plasma level of atherogenic lipoproteins in man by the inactivation of ANGPTL3, using either a specific monoclonal antibody or anti-sense oligonucleotides.

冠心病不稳定型心绞痛合并冠脉狭窄患者CRP、Angptls 2、CTRP1水平变化及临床意义

目的探究冠心病不稳定型心绞痛合并冠脉狭窄患者C反应蛋白(CRP)、血管生成素样蛋白2(Angptls 2)、C1q TNF相关蛋白1(CTRP1)的水平变化及其临床意义。方法将西安国际医学中心医院心脏内科2018年2月至2019年2月间收治的53例冠心病不稳定型心绞痛合并冠脉狭窄患者作为观察组,同时选取同一时期入院体检的健康人群53例作为对照组,比较两组受检者的CRP、Angptls 2及CTRP1水平,以及不同冠脉病变支数患者的CRP、Angptls 2及CTRP1水平,并分析CRP、Angptls 2及CTRP1联合检测对患者的临床诊断价值。结果观察组和对照组患者的血清CRP[(5.35±1.83)mg/L vs(0.89±0.28)mg/L]、Angptls 2[(2.68±0.76)μg/L vs(0.91±0.24)μg/L]及CTRP1[(15.96±5.02)ng/mL vs(9.24±2.98)ng/mL]水平比较,观察组明显高于对照组,差异均有统计学意义(P<0.05);冠脉单支狭窄患者血清CRP水平、Angptls 2水平、CTRP1水平为(4.25±1.55)mg/L、(1.47±0.35)μg/L、(13.18±4.02)ng/mL,明显低于多支狭窄患者的(6.48±1.98)mg/L、(3.15±0.97)μg/L、(19.15±5.25)ng/mL,差异均有统计学意义(P<0.05);CRP、Angptls 2及CTRP1检测结果显示,三者联合检测准确率明显高于CRP+Angptls 2、CRP+CTRP1以及CTRP1+Angptls 2两者联合检测,差异均有统计学意义(P<0.05)。结论冠心病不稳定心绞痛合并冠脉狭窄患者CRP、Angptls 2及CTRP1水平明显升高,且多支狭窄患者CRP、Angptls 2及CTRP1水平明显高于单支狭窄患者,三项指标联合检测对患者临床诊断具有重要指导意义。

Leukocyte immunoglobulin-like receptor B2 overexpression as a promising therapeutic target and noninvasive screening biomarker for colorectal cancer

BACKGROUND Colorectal cancer(CRC)has become the second most deadly malignancy in the world,and the exploration of screening markers and precise therapeutic targets is urgent.Our previous research identified leukocyte immunoglobulin-like receptor B2(LILRB2)protein as a characteristic protein of CRC,but the association between LILRB2 expression and clinicopathological features,the internal mechanism related to CRC progression,and screening diagnostic efficacy are not clear.Therefore,we hypothesized that LILRB2 is significantly highly expressed in CRC tissues,correlated with advanced stage and a poor prognosis,and could be used as a therapeutic target and potential screening biomarker for CRC.AIM To explore whether LILRB2 can be used as a potential therapeutic target and noninvasive screening biomarker for CRC.METHODS Patients who underwent radical surgery for CRC at China-Japan Friendship Hospital between February 2021 and October 2022 were included.Cancer and paracancerous tissues were collected to verify LILRB2 expression,and the association between LILRB2 expression and clinicopathological features was analysed.Serum was collected from CRC patients,adenoma patients and healthy controls during the same period to assess the diagnostic value of LILRB2 as a noninvasive screening biomarker,and its diagnostic value was further compared with that of the traditional markers carcinoembryonic antigen(CEA)and carbohydrate antigen 19-9(CA19-9).RESULTS A total of 58 CRC patients were included,and LILRB2 protein was significantly overexpressed in cancer tissues compared with paracancerous tissues(P<0.001).Angiopoietin-like protein 2(ANGPTL2)protein,as the ligand of LILRB2,was synergistically overexpressed in CRC tissues(P<0.001),and overexpression of LILRB2 and ANGPTL2 protein was significantly correlated with poor to moderate differentiation,vascular involvement,lymph node metastasis,distant metastasis,advanced tumor-node-metastasis stage and a poor prognosis(P<0.05),which suggested that LILRB2 and ANGPTL2 are closely associated with CRC progression.In addition,serum LILRB2 concentrations increased stepwise in healthy individuals,adenoma patients and CRC patients with statistically significant differences.The sensitivity of serum LILRB2 for the diagnosis of CRC was 89.74%,the specificity was 88.89%,the area under the curve was 0.95,and the diagnostic efficacy was better than that of conventional CEA and CA19-9.CONCLUSION LILRB2 protein can be used as a potential novel therapeutic target and noninvasive screening biomarker for CRC,which is beneficial for early screening and precise treatment.

ANGPTL2 expression in gastric cancer tissues and cells and its biological behavior

AIM To explore expression of angiopoietin-like protein 2(ANGpT L2) and its effect on biological behavior such as proliferation and invasiveness in gastric cancer. METHODS Western blotting was used to detect expression of ANGp TL2 in 60 human normal gastric tissues, 60 human gastric cancer tissues and gastric cell lines including GES-1, N87, SGC7901, BGC823 and pA MC82. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) and Transwell assay were used to detect the proliferation and invasive ability of gastric cancer cells. RESULTS Compared to normal tissues, ANGp TL2 protein levels were significantly upregulated in gastric tissues, and this level was closely correlated with gastric tumor grade, clinical stage and lymph node metastasis. Compared to GES-1 cells, ANGpT L2 mR NA and protein levels were significantly increased in gastric cancer cells including N87, SGC7901, BGC823 and p AMC82. The expression of ANGpT L2 in highly malignant gastric cancer cell lines BGC823 and pA MC82 was significantly higher than in low malignancy gastric cancer cell lines N87 and SGC7901. MTT and Transwell experiments indicated that the proliferation rate and invasive ability of stable overexpressed gastric cancer cells was faster than in cells transfected with Lv-NC and blank controlcells, and the invasive ability of stable overexpressed gastric cancer cells was higher than that of cells transfected with Lv-NC and blank control cells.CONCLUSION ANGp TL2 contributed to proliferation and invasion of gastric cancer cells. In clinical treatment, ANGpT L2 may become a new target for treatment of gastric cancer.

Protective Effect of Irbesartan by Inhibiting ANGPTL2 Expression in Diabetic Kidney Disease

Angiopoietin-like protein 2(ANGPTL2)stimulates inflammation and is important in the pathogenesis of diabetic kidney disease(DKD).Irbesartan is helpful in reducing diabetes-induced renal damage.In this study,the effects of irbesartan on DKD and its renal protective role involving ANGPTL2 in DKD rats were examined.Wistar rats were divided into normal,DKD,and DKD+irbesartan groups.The DKD+irbesartan group was treated once daily for 8 weeks with 50 mg/kg irbesartan via intragastric gavage.The 24-h urinary albumin was determined each week,renal pathological changes were observed,and expression of ANGPTL2 and nuclear factor-kappa B(NF-κB)in rat renal tissue was assessed by immunohistochemistry.Mouse podocytes cultured in a high concentration of glucose were classified into four groups based on the irbesartan concentrations(0,25,50,and 75ºg/mL).Expression of ANGPTL2 and phosphorylated IκB-αwas assessed by Western blotting.The mRNA levels of ANGPTL2 and monocyte chemotactic protein 1(MCP-1)were assessed by real-time polymerase chain reaction.The DKD rats displayed proteinuria,podocyte injury,and increased ANGPTL2 and NF-κB expression.All were relieved by irbesartan treatment.In podocytes cultured in elevated glucose,ANGPTL2 and phosphorylated IκB-αwere overexpressed at the protein level,and ANGPTL2 and MCP-1 were highly expressed at the mRNA level.Irbesartan down-regulated ANGPTL2 and phosphorylated IκB-αexpression at the protein level and inhibited ANGPTL2 and MCP-1 expression at the mRNA level.The ameliorative effects of irbesartan against DKD involves podocyte protection and suppression of ANGPTL2.

Association between Maternal Serum Concentrations of Angiopoietin-like Protein 2 in Early Pregnancy and Subsequent Risk of Gestational Diabetes Mellitus

Background：A recent study reported a positive association between elevated serum levels of angiopoietin-like protein 2 （ANGPTL2） and the development of type 2 diabetes in a general population.However,the relationship of serum ANGPTL2 levels with the risk of developing gestational diabetes mellitus （GDM） has not been reported to date.The aim of this study was to investigate the change of maternal serum ANGPTL2 concentrations in the first trimester of pregnancy and to determine whether ANGPTL2 is a biomarker for subsequent GDM development.Methods：We conducted a prospective,nested case-control study in a pregnancy cohort.First-trimester ANGPTL2 levels were measured using a high-resolution assay in 89 women who subsequently developed GDM and in a random sample of 177 women who remained euglycemic throughout the pregnancy.Median ANGPTL2 levels were compared using Mann-Whitney U-test.Logistic regression was used to compute unadjusted and multivariable-adjusted odds ratios for developing GDM among ANGPTL2 quartiles.Results：The serum levels of ANGPTL2 was higher in women with GDM than that in women without GDM （3.06 [2.59,3.65] ng/ml vs.2.46 [2.05,2.96] ng/ml,P =0.003）.Fasting blood glucose was higher in women with GDM than that in women without GDM （5.0 ± 0.9 mmol/L vs.4.4 ± 0.6 mmol/L,P 〈 0.001）.Glucose challenge test showed that the blood glucose was higher in women with GDM than that in women without GDM （9.1 ± 3.5 mmol/L vs.6.2 ± 1.2 mmol/L,P 〈 0.001）.A multivariate model adjusted for baseline characteristics,medical complications,and gestational characteristics revealed that the risk of developing GDM among women in Q4 compared with Q1 was 2.90-fold more likely to develop GDM later in pregnancy.Conclusions：At 1 1-13 weeks in pregnancies that develop GDM,the serum concentration of ANGPTL2 is increased,and it can be combined with maternal factors to provide effective early screening for GDM.

Leptin-mediated suppression of lipoprotein lipase cleavage enhances lipid uptake and facilitates lymph node metastasis in gastric cancer

Background:Lymph node metastasis(LNM)is the primary mode of metastasis in gastric cancer(GC).However,the precise mechanisms underlying this process remain elusive.Tumor cells necessitate lipid metabolic reprogramming to facilitate metastasis,yet the role of lipoprotein lipase(LPL),a pivotal enzyme involved in exogenous lipid uptake,remains uncertain in tumor metastasis.Therefore,the aim of this study was to investigate the presence of lipid metabolic reprogramming during LNM of GC as well as the role of LPL in this process.Methods:Intracellular lipid levels were quantified using oil red O staining,BODIPY 493/503 staining,and flow cytometry.Lipidomics analysis was employed to identify alterations in intracellular lipid composition following LPL knockdown.Protein expression levels were assessed through immunohistochemistry,Western blotting,and enzyme-linked immunosorbent assays.The mouse popliteal LNM model was utilized to investigate differences in LNM.Immunoprecipitation and mass spectrometry were employed to examine protein associations.In vitro phosphorylation assays and Phos-tag sodium dodecyl-sulfate polyacrylamide gel electrophoresis assays were conducted to detect angiopoietin-like protein 4(ANGPTL4)phosphorylation.Results:We identified that an elevated intracellular lipid level represents a crucial characteristic of node-positive(N+)GC and further demonstrated that a high-fat diet can expedite LNM.LPL was found to be significantly overexpressed in N+GC tissues and shown to facilitate LNM by mediating dietary lipid uptake within GC cells.Leptin,an obesity-related hormone,intercepted the effect exerted by ANGPTL4/Furin on LPL cleavage.Circulating leptin binding to the leptin receptor could induce the activation of inositol-requiring enzyme-1(IRE1)kinase,leading to the phosphorylation of ANGPTL4 at the serine 30 residue and subsequently reducing its binding affinity with LPL.Moreover,our research revealed that LPL disrupted lipid homeostasis by elevating intracellular levels of arachidonic acid,which then triggered the cyclooxygenase-2/prostaglandin E2(PGE2)pathway,thereby promoting tumor lymphangiogenesis.Conclusions:Leptin-induced phosphorylation of ANGPTL4 facilitates LPLmediated lipid uptake and consequently stimulates the production of PGE2,ultimately facilitating LNM in GC.