ANGPTL8 links inflammation and poor differentiation, which are characteristics of malignant renal cell carcinoma.

Inflammation is observed in many tumors, which affects metastasis, infiltration, and immune escape and causes poor differentiation of the cancer cells. However, the molecular basis underlying the relationship between inflammation and poor differentiation in tumors has not been identified. In this study, we demonstrate that angiopoietin-like protein-8 (ANGPTL8), which is induced by stress stimuli such as inflammation, is involved in the maintenance of the undifferentiated state of clear cell renal cell carcinoma (ccRCC) cells. ANGPTL8 is also involved in the production of chemokines that attract immune suppressor cells to the tumor microenvironment. ANGPTL8 sustains the continuous production of chemokines by activating the NF-κB signaling pathway and maintains the undifferentiated state of ccRCC cells. Finally, ANGPTL8 is induced by STAT3 signaling, which is activated by immune cells in the tumor microenvironment. These results support a role for ANGPTL8 in determining the properties of ccRCC by hampering tumor cell differentiation and establishing the tumor microenvironment.

Maternal and cord blood betatrophin (angiopoietin-like protein 8) in pregnant women with gestational diabetes and normoglycemic controls: A systematic review, meta-analysis, and meta-regression.

AIMS: This systematic review and meta-analysis examined maternal and cord blood betatrophin levels in pregnant women with gestational diabetes mellitus (GDM) and normoglycemic controls. MATERIAL AND METHODS: PubMed, Cochrane Library, Embase, LILACS, WangFang, and China National Knowledge Infrastructure were searched for literature from inception until May 2022. The primary outcomes were maternal and cord blood betatrophin levels. A random-effect meta-analysis was used to estimate the pooled results. The mean differences (MDs) or standardised MDs (SMD) and their 95% confidence intervals (CIs) were calculated. I2 tests were used to evaluate the heterogeneity. The quality of studies was evaluated using the Newcastle-Ottawa Scale. RESULTS: Betatrophin levels were reported in 22 studies with a total of 3034 pregnant women, and in seven studies including cord blood from 456 infants. Women with GDM display higher betatrophin levels than the normoglycemic controls (SMD = 0.85, 95% CI: 0.38-1.31) during the second half of the pregnancy. The sensitivity analysis indicated that no single study had significantly influenced the betatrophin overall outcomes. There was heterogeneity between the studies as evidenced by high I2 values. Meta-regression analysis indicated a significant regression coefficient for maternal betatrophin and glycosilated haemoglobin. There was no significant difference in cord blood betatrophin in infants from women with and without GDM (SMD = 0.34, 95% CI: -0.15-0.83). Women with GDM also had significantly higher insulin, glucose, glycosylated haemoglobin, HOMA-IR, LDL-cholesterol, HDL-cholesterol, triglycerides, and body mass index compared with the normoglycemic controls. CONCLUSIONS: Maternal betatrophin levels were higher in women with GDM than in the normoglycemic controls. There was no difference in cord blood betatrophin. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022311372.

ANGPTL8 deletion attenuates abdominal aortic aneurysm formation in ApoE-/- mice.

Angiopoietin-like protein 8 (ANGPTL8) plays important roles in lipid metabolism, glucose metabolism, inflammation, and cell proliferation and migration. Clinical studies have indicated that circulating ANGPTL8 levels are increased in patients with thoracic aortic dissection (TAD). TAD shares several risk factors with abdominal aortic aneurysm (AAA). However, the role of ANGPTL8 in AAA pathogenesis has never been investigated. Here, we investigated the effect of ANGPTL8 knockout on AAA in ApoE-/- mice. ApoE-/-ANGPTL8-/- mice were generated by crossing ANGPTL8-/- and ApoE-/- mice. AAA was induced in ApoE-/- using perfusion of angiotensin II (AngII). ANGPTL8 was significantly up-regulated in AAA tissues of human and experimental mice. Knockout of ANGPTL8 significantly reduced AngII-induced AAA formation, elastin breaks, aortic inflammatory cytokines, matrix metalloproteinase expression, and smooth muscle cell apoptosis in ApoE-/- mice. Similarly, ANGPTL8 sh-RNA significantly reduced AngII-induced AAA formation in ApoE-/- mice. ANGPTL8 deficiency inhibited AAA formation, and ANGPTL8 may therefore be a potential therapeutic target for AAA.

Gender-Dependent Associations between Serum Betatrophin Levels and Lipoprotein Subfractions in Diabetic and Nondiabetic Obese Patients.

Betatrophin, also known as angiopoietin-like protein 8 (ANGPTL8), mainly plays a role in lipid metabolism. To date, associations between betatrophin and lipoprotein subfractions are poorly investigated. For this study, 50 obese patients with type 2 diabetes (T2D) and 70 nondiabetic obese (NDO) subjects matched in gender, age, and body mass index (BMI) as well as 49 gender- and age-matched healthy, normal-weight controls were enrolled. Serum betatrophin levels were measured with ELISA, and lipoprotein subfractions were analyzed using Lipoprint gel electrophoresis. Betatrophin concentrations were found to be significantly higher in the T2D and NDO groups compared to the controls in all subjects and in females, but not in males. We found significant positive correlations between triglyceride, very low density lipoprotein (VLDL), large LDL (low density lipoprotein), small LDL, high density lipoprotein (HDL) -6-10 subfractions, and betatrophin, while negative correlations were detected between betatrophin and IDL, mean LDL size, and HDL-1-5. Proportion of small HDL was the best predictor of betatrophin in all subjects. Small LDL and large HDL subfractions were found to be the best predictors in females, while in males, VLDL was found to be the best predictor of betatrophin. Our results underline the significance of serum betatrophin measurement in the cardiovascular risk assessment of obese patients with and without T2D, but gender differences might be taken into consideration.

Circulating angiopoietin-like proteins in metabolic-associated fatty liver disease: a systematic review and meta-analysis.

BACKGROUND: Angiopoietin-like proteins (ANGPTLs) are closely related to insulin resistance and lipid metabolism, and may be a key in metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD) (newly named metabolic-associated fatty liver disease (MAFLD)) is based on metabolic dysfunction. There may be some correlation between ANGPTLs and MAFLD, but the specific correlation is unclear. This study aims to explore the predictive role of ANGPTLs in MAFLD and its progression. METHODS: Seven databases (PubMed, EMBASE, Cochrane Library, CNKI, WANFANG, CBM and Clinicaltrials.gov ) were searched with free terms and MeSH terms. The random-effects model was used to pool the data, and Standardized Mean Difference (SMD) and 95% confidence intervals (CI) were taken as the overall outcome. No language restrictions existed in the article selection. RevMan 5.3, Stata 16 and MetaXL software were applied to analyse the data and the GRADE system was utilized to assess the certainty of evidence. RESULTS: After reviewing 823 related articles, 13 studies (854 cases and 610 controls) met the inclusion criteria, and contributed to this meta-analysis. The results showed that circulating ANGPTL8 level was significantly elevated in the MAFLD group than in the healthy control group (SMD = 0.97 pg/mL, 95%CI: 0.77, 1.18). Conversely, there was no significant difference in the ANGPTL4 (SMD = 0.11 ng/mL, 95%CI: - 0.32, 0.54) and ANGPTL3 (SMD = - 0.95 ng/mL, 95%CI: - 4.38, 2.48) between the two groups. Subgroup analysis showed that: 1) the MAFLD group had significantly higher ANGPTL8 levels than the healthy control group in Asian and other races; 2) the ANGPTL8 levels in Body Mass Index (BMI) > 25 kg/m2 patients with MAFLD were higher than those in the healthy control group; 3) the higher ANGPTL8 levels were observed in moderate to severe MAFLD group than the healthy control group. Meta-regression demonstrated that BMI might effectively explain the high heterogeneity. No significant publication bias existed (P > 0.05). The certainty of evidence was assessed as very low by the GRADE system. CONCLUSIONS: The ANGPTLs may be related to MAFLD. The increased ANGPTL8 level may be positively correlated with different situations of MAFLD, which may act as a potential indicator to monitor the development trends.

Role of ANGPTL8 in NAFLD Improvement after Bariatric Surgery in Experimental and Human Obesity.

Angiopoietin-like protein 8 (ANGPTL8) is an hepatokine altered in several metabolic conditions, such as obesity, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease (NAFLD). We sought to explore whether ANGPTL8 is involved in NAFLD amelioration after bariatric surgery in experimental models and patients with severe obesity. Plasma ANGPTL8 was measured in 170 individuals before and 6 months after bariatric surgery. Hepatic ANGPTL8 expression was evaluated in liver biopsies of patients with severe obesity undergoing bariatric surgery with available liver pathology analysis (n = 75), as well as in male Wistar rats with diet-induced obesity subjected to sham operation, sleeve gastrectomy or Roux-en-Y gastric bypass (RYGB) (n = 65). The effect of ANGPTL8 on lipogenesis was assessed in human HepG2 hepatocytes under palmitate-induced lipotoxic conditions. Plasma concentrations and hepatic expression of ANGPTL8 were increased in patients with obesity-associated NAFLD in relation to the degree of hepatic steatosis. Sleeve gastrectomy and RYGB improved hepatosteatosis and reduced the hepatic ANGPTL8 expression in the preclinical model of NAFLD. Interestingly, ANGPTL8 inhibited steatosis and expression of lipogenic factors (PPARG2, SREBF1, MOGAT2 and DGAT1) in palmitate-treated human hepatocytes. Together, ANGPTL8 is involved in the resolution of NAFLD after bariatric surgery partially by the inhibition of lipogenesis in steatotic hepatocytes.

Increased Circulating Angiopoietin-Like Protein 8 Levels Are Associated with Thoracic Aortic Dissection and Higher Inflammatory Conditions.

PURPOSE: Thoracic aortic dissection (TAD) is characterized by an inflammatory response. Angiopoietin-like protein 8 (ANGPTL8) is a hormone involved in the regulation of lipid metabolism and inflammation. However, the relationship between ANGPTL8 and TAD remains unknown. METHODS: This case-control study included 78 TAD patients and 72 controls. The aortic diameter was evaluated by computed tomography and used to assess TAD severity. Circulating ANGPTL8 levels were measured by enzyme-linked immunosorbent assay. Associations of ANGPTL8 with TAD were determined by multivariate logistic regression. RESULTS: Serum ANGPTL8 levels were significantly higher in TAD patients compared with controls (562.50 ± 20.84 vs. 419.70 ± 22.65 pg/mL, respectively; P < 0.001). After adjusting for confounding factors, circulating ANGPTL8 levels were an independent risk factor for TAD (odds ratio = 1.587/100 pg ANGPTL8, 95% confidence interval [CI] = 1.121-2.247, P < 0.001) and positively associated with diameter (ß = 1.081/100 pg ANGPTL8, 95% CI = 0.075-2.086, P = 0.035) and high-sensitivity C-reactive protein (hs-CRP) (ß = 0.845/100 pg ANGPTL8, 95% CI = 0.020-1.480, P = 0.009). The area under the curve (AUC) on receiver operating characteristic (ROC) analysis of the combination of ANGPTL8, hs-CRP, and D-dimer was 0.927, and the specificity and sensitivity were 98.46% and 79.49%, respectively. ANGPTL8 was significantly increased in TAD tissue compared with controls. In vitro, ANGPTL8 was increased in angiotensin II (AngII)-treated macrophages and vascular smooth muscle cells (VSMCs), while ANGPTL8 siRNA-mediated knockdown decreased inflammatory factors in AngII-treated macrophages and decreased apoptosis in AngII-treated VSMCs. CONCLUSION: ANGPTL8 is associated with TAD occurrence and development, which may involve pro-inflammatory effects on macrophages. ANGPTL8 combined with D-dimer and hs-CRP might be a useful clinical predictor of TAD. TRIAL REGISTRATION: ChiCTR-COC-17010792 http://www.chictr.org.cn/showproj.aspx?proj=18288.

Angiopoietin-like protein 8 expression and association with extracellular matrix metabolism and inflammation during intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is considered the primary culprit for low back pain. Although the underlying mechanisms remain unknown, hyperactive catabolism of the extracellular matrix (ECM) and inflammation are suggested to play critical roles in IDD progression. This study was designed to elucidate the role of angiopoietin-like protein 8 (ANGPTL8) in the progression of IDD, especially the relationship of ANGPTL8 with ECM metabolism and inflammation. A positive association between ANGPTL8 expression and degenerative grades of IDD was detected in the analysis of human nucleus pulposus tissue samples. Silencing of ANGPTL8 attenuated the degradation of the anabolic protein type collagen II, and reduced the expression of the catabolic proteins MMP3 and MMP9, and the inflammatory cytokine IL-6 through inhibition of NF-κB signalling activation. In addition, the effect of ANGPTL8 was evaluated in a rat model of puncture-induced IDD. Based on the imaging results and histological examination in animal study, knockdown of ANGPTL8 was demonstrated to ameliorate the IDD progression. These results demonstrate the detrimental role of ANGPTL8 expression in the pathogenesis of IDD and may provide a new therapeutic target for IDD treatment.

Regulation of angiopoietin-like protein 8 expression under different nutritional and metabolic status.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with increasing prevalence worldwide. Angiopoietin-like protein 8 (ANGPTL8), a member of the angiopoietin-like protein family, is involved in glucose metabolism, lipid metabolism, and energy homeostasis and believed to be associated with T2DM. Expression levels of ANGPTL8 are often significantly altered in metabolic diseases, such as non-alcoholic fatty liver disease (NAFLD) and diabetes mellitus. Studies have shown that ANGPTL8, together with other members of this protein family, such as angiopoietin-like protein 3 (ANGPTL3) and angiopoietin-like protein 4 (ANGPTL4), regulates the activity of lipoprotein lipase (LPL), thereby participating in the regulation of triglyceride related lipoproteins (TRLs). In addition, members of the angiopoietin-like protein family are varyingly expressed among different tissues and respond differently under diverse nutritional and metabolic status. These findings may provide new options for the diagnosis and treatment of diabetes, metabolic syndromes and other diseases. In this review, the interaction between ANGPTL8 and ANGPTL3 or ANGPTL4, and the differential expression of ANGPTL8 responding to different nutritional and metabolic status during the regulation of LPL activity were reviewed.

Loss of Glycine N-Methyltransferase Associates with Angiopoietin-Like Protein 8 Expression in High Fat-Diet-Fed Mice.

Imbalance of lipid metabolism is a main cause of metabolic syndrome leading to life-threatening metabolic diseases. Angiopoietin-like protein 8 (Angptl8) was recently identified as a liver and adipose tissue-released hormone that is one of the molecules involved in triglyceride metabolism. However, the regulatory mechanism of Angptl8 is largely unknown. A high fat diet (HFD)-fed mouse model, which showed high cholesterol, high triglyceride, and high insulin in the blood, revealed the upregulation of hepatic and plasma Angptl8 and the downregulation of hepatic glycine N-methyltransferase (GNMT). The inverse correlation of hepatic Angptl8 and GNMT expression in the livers of HFD-fed mice was also confirmed in a publicly available microarray dataset. The mechanistic study using primary hepatocytes showed that the Angptl8 expression could be induced by insulin treatment in a dose- and time-dependent manner. Inhibition of PI3K/Akt pathway by the specific inhibitors or the dominant-negative Akt blocked the insulin-induced Angptl8 expression. Moreover, knockout of GNMT promoted the Akt activation as well as the Angptl8 expression. These results suggested that GNMT might be involved in insulin-induced Angptl8 expression in HFD-mediated metabolic syndrome.

CRISPR/Cas9-mediated Angptl8 knockout suppresses plasma triglyceride concentrations and adiposity in rats.

Angiopoietin-like protein (ANGPTL)8 is a liver- and adipocyte-derived protein that controls plasma triglyceride (TG) levels. Most animal studies have used mouse models. Here, we generated an Angptl8 KO rat model using a clustered regulatory interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) (CRISPR/Cas9) system to clarify the roles of ANGPTL8 in glucose and lipid metabolism. Compared with WT rats, Angptl8 KO rats had lower body weight and fat content, associated with impaired lipogenesis in adipocytes; no differences existed between the groups in food intake or rectal temperature. Plasma TG levels in both the fasted and refed states were significantly lower in KO than in WT rats, and an oral fat tolerance test showed decreased plasma TG excursion in Angptl8 KO rats. Higher levels of lipase activity in the heart and greater expression of genes related to ß-oxidation in heart and skeletal muscle were observed in Angptl8 KO rats. However, there were no significant differences between KO and WT rats in glucose metabolism or the histology of pancreatic ß-cells on both standard and high-fat diets. In conclusion, we demonstrated that Angptl8 KO in rats resulted in lower body weight and plasma TG levels without affecting glucose metabolism. ANGPTL8 might be an important therapeutic target for obesity and dyslipidemia.

Angiopoietin-like protein 8 in early pregnancy improves the prediction of gestational diabetes.

AIMS/HYPOTHESIS: Screening high-risk individuals for gestational diabetes mellitus (GDM) in early pregnancy conventionally relies on established maternal risk factors; however, the sensitivity and specificity of these factors are not satisfactory. The present study aimed to determine whether the concentration of angiopoietin-like protein 8 (ANGPTL8), either alone or combined with other risk factors in early pregnancy, could be used to predict subsequent GDM. METHODS: From August 2015 to January 2016, 474 women receiving prenatal care at around 12-16 weeks of gestation were recruited into the study. ANGPTL8 levels were measured at the first prenatal visit. All the participants received a 75 g OGTT during weeks 24-28 of gestation. RESULTS: ANGPTL8 levels in early pregnancy were considerably higher in women who developed GDM than those who maintained normal glucose tolerance (2822 ± 938 vs 2120 ± 1118 pg/ml, respectively; p < 0.0001). Multivariable logistic regression revealed that ANGPTL8 levels were significantly associated with risk of GDM independent of conventional risk factors. In addition, women in the highest quartile of ANGPTL8 concentration had an 8.75-fold higher risk of developing GDM compared with women in the lowest quartile (OR8.75, 95%CI 2.43, 31.58). More importantly, incorporating ANGPTL8 into the conventional prediction model significantly increased the AUC for prediction of GDM (0.772vs 0.725; p = 0.019). CONCLUSIONS: Our study suggests that ANGPTL8 levels in early pregnancy are significantly and independently associated with risk of GDM at 24-28 weeks of gestation. Combining ANGPTL8 levels with conventional risk factors could thus improve the prediction of GDM.

Associations between circulating full-length angiopoietin-like protein 8 levels and severity of coronary artery disease in Chinese non-diabetic patients: a case-control study.

BACKGROUND: Angiopoietin-like protein 8 (ANGPTL8), which is a novel hormone produced in liver and adipose tissue, is involved in regulating lipid metabolism. Patients with diabetes and coronary artery disease (CAD) have remarkably higher levels of ANGPTL8 than those with only diabetes. However, no studies have investigated the involvement of ANGPTL8 in CAD in Chinese non-diabetic individuals. Therefore, we investigated full-length circulating ANGPTL8 levels in patients with CAD and the association between ANGPT8 levels and severity of CAD in Chinese individuals without diabetes. METHODS: We performed a case-control study in 149 Chinese non-diabetic subjects, including 80 patients with CAD and 69 controls. The Gensini stenosis scoring system was used to assess the severity of CAD. Circulating full-length ANGPTL8 levels were measured by an enzyme-linked immunosorbent assay kit. The associations between circulating full-length ANGPTL8 levels and CAD were determined by multivariate logistic regression analysis. The association between ANGPTL8 levels and Gensini scores was determined by multivariate linear regression analysis. RESULTS: Circulating full-length ANGPTL8 levels were significantly higher in Chinese non-diabetic patients with CAD compared with controls (665.90 ± 243.49 vs 462.27 ± 151.85 pg/ml, P < 0.001). After adjusting for confounding factors, we found that circulating full-length ANGPTL8 levels were an independent risk factor for CAD (odds ratio = 2.002/100 pg ANGPTL8, 95% CI 1.430-2.803, P < 0.001) and circulating ANGPTL8 levels were positively associated with the Gensini score (ß = 5.701/100 pg ANGPTL8, 95% CI 1.306-10.096, P = 0.012). CONCLUSIONS: This study shows that the circulating ANGPTL8 levels are significantly increased in patients with CAD compared with controls in Chinese non-diabetic individuals. Circulating full-length ANGPTL8 levels are an independent risk factor for CAD and they are positively associated with the severity of CAD. Trial registration This study was registered in the Chinese Clinical Trial Registry (No. ChiCTR-COC-17010792).

Association between circulating full-length angiopoietin-like protein 8 and non-high-density lipoprotein cholesterol levels in Chinese non-diabetic individuals: a cross-sectional study.

BACKGROUND: Angiopoietin-like protein 8 (ANGPTL8) is a novel hormone involved in the regulation of lipid metabolism and glucose homeostasis. There are inconsistent results regarding the association between ANGPTL8 and lipids in humans. We aimed to investigate the associations between ANGPTL8 and lipids in people without diabetes. METHODS: This was a cross-sectional study of 107 patients with dyslipidemia and 141 patients without. Dyslipidemia diagnosis was based on Chinese guidelines for the prevention and treatment of dyslipidemia in adults. Total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol (HDL-C) were examined. Non-HDL-C was calculated by subtracting HDL-C from TC. Circulating full-length ANGPTL8 concentrations were measured using enzyme-linked immunosorbent assay. Associations between log-transformed circulating full-length ANGPTL8 and serum lipids were examined using multivariate linear regression analysis. RESULTS: Circulating ANGPTL8 concentrations were significantly elevated in patients with dyslipidemia compared with patients without dyslipidemia. Circulating full-length ANGPTL8 concentrations were positively associated with non-HDL-C, TG and TC levels after adjusting for age, gender, body mass index, high-sensitivity C-reactive protein, alanine aminotransferase, and creatinine. CONCLUSION: In people without diabetes, circulating full-length ANGPTL8 concentrations in patients with dyslipidemia were significantly elevated compared with non-dyslipidemia, and ANGPTL8 was positively associated with serum non-HDL-C levels.

Expression of angiopoietin-like protein 8 correlates with VEGF in patients with proliferative diabetic retinopathy.

PURPOSE: To investigate the vitreous and serum levels of angiopoietin-like protein 8 (ANGPTL-8) and vascular endothelial growth factor (VEGF) in patients with proliferative diabetic retinopathy (PDR). The serum levels of these factors were also analyzed in patients with diabetes and no diabetic retinopathy (NDR) and with non-proliferative diabetic retinopathy (NPDR), to detect the possible correlation between the ANGPTL-8 levels and hyperlipidemia. METHODS: Vitreous samples were obtained from 28 patients with PDR and from 12 patients without diabetes and with idiopathic macular hole (IMH). Serum samples were also obtained from 26 patients with NDR and 22 patients with NPDR. ANGPTL-8 levels and other factors were determined using an enzyme-linked immunosorbent assay. RESULTS: The ANGPTL-8 and VEGF levels in the vitreous and serum of the patients with PDR were higher than those in the patients with IMH, and were significantly correlated. The vitreous and serum ANGPTL-8 levels were more correlated with the triglyceride and low-density lipoprotein cholesterol levels than with the high-density lipoprotein cholesterol or total cholesterol levels in the patients with PDR. CONCLUSIONS: The vitreous and serum ANGPTL-8 levels were both upregulated in patients with PDR. There was an association between the elevation in the ANGPTL-8 levels and angiogenic and hyperlipidemic factors in the patients with PDR. These results suggest that ANGPTL-8 is a potential new diagnostic marker and therapeutic target for PDR treatment.

Association Between rs2278426 Polymorphism of the ANGPTL8 Gene and Polycystic Ovary Syndrome.

Purpose: To study the relationship between the single nucleotide polymorphism (SNP) rs2278426 in the angiopoietin-like protein 8 gene (ANGPTL8) and polycystic ovary syndrome (PCOS). Patients and methods: A total of 122 patients with PCOS and 108 controls were recruited for comparison of glucose, lipid, insulin, sex hormone, and ANGPTL8 levels. Polymerase chain reaction (PCR) and gene sequencing were performed for comparison of the frequency of the CC, CT, and TT rs2278426 genotypes and the rs2278426 allele distributions between the PCOS and control groups and between the obese and non-obese subgroups of the PCOS and control groups. Results: The frequency of the T allele was significantly higher in the PCOS group than that in the controls (P = 0.037). In the dominant genetic model, the proportion of the CT+TT genotype in the PCOS group was significantly higher than that in the controls (P = 0.047). Subgroup analysis demonstrated that the T allele proportion was significantly higher in obese PCOS group than obese control group (P = 0.027). PCOS with the CT+TT genotype had significantly higher body mass index (BMI; P = 0.001), triglyceride (TG; P = 0.005), homeostasis model assessment of insulin resistance (HOMA-IR; P = 0.035), testosterone (P = 0.041), and ANGPTL8 (P = 0.037) levels and significantly lower high-density lipoprotein (HDL) levels (P = 0.025) than PCOS with the CC genotype. Obese PCOS group with the CT+TT genotype had significantly higher TG (P = 0.015), luteinizing hormone (LH; P = 0.030), fasting insulin (FINS; P = 0.039), HOMA-IR (P = 0.018), and ANGPTL8 (P = 0.049) levels than obese PCOS group with the CC genotype. Conclusion: Polymorphisms of rs2278426 may induce glycolipid metabolic disorders by affecting ANGPTL8 levels and functions in Han Chinese females with obesity from the Shandong region, increasing the risk of PCOS in this population.

Predictive value of angiopoietin-like protein 8 in metabolic dysfunction-associated fatty liver disease and its progression: A case-control study.

BACKGROUND: The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is rapidly increasing, currently affecting approximately 25% of the global population. Liver fibrosis represents a crucial stage in the development of MAFLD, with advanced liver fibrosis elevating the risks of cirrhosis and hepatocellular carcinoma. Simple serum markers are less effective in diagnosing liver fibrosis compared to more complex markers. However, imaging techniques like transient elastography face limitations in clinical application due to equipment and technical constraints. Consequently, it is imperative to identify a straightforward yet effective method for assessing MAFLD-associated liver fibrosis. AIM: To investigate the predictive value of angiopoietin-like protein 8 (ANGPTL8) in MAFLD and its progression. METHODS: We analyzed 160 patients who underwent abdominal ultrasonography in the Endocrinology Department, Xiaogan Central Hospital affiliated to Wuhan University of Science and Technology, during September 2021-July 2022. Using abdominal ultrasonography and MAFLD diagnostic criteria, among the 160 patients, 80 patients (50%) were diagnosed with MAFLD. The MAFLD group was divided into the liver fibrosis group (n = 23) and non-liver fibrosis group (n = 57) by using a cut-off fibrosis-4 index ≥ 1.45. Logistical regression was used to analyze the risk of MAFLD and the risk factors for its progression. Receiver operating characteristic curves were used to evaluate the predictive value of serum ANGPTL8 in MAFLD and its progression. RESULTS: Compared with non-MAFLD patients, MAFLD patients had higher serum ANGPTL8 and triglyceride-glucose (TyG) index (both P < 0.05). Serum ANGPTL8 (r = 0.576, P < 0.001) and TyG index (r = 0.473, P < 0.001) were positively correlated with MAFLD. Serum ANGPTL8 was a risk factor for MAFLD [odds ratio (OR): 1.123, 95% confidence interval (CI): 1.066-1.184, P < 0.001). Serum ANGPTL8 and ANGPTL8 + TyG index predicted MAFLD [area under the curve (AUC): 0.832 and 0.886, respectively; both P < 0.05]. Compared with MAFLD patients without fibrosis, those with fibrosis had higher serum ANGPTL8 and TyG index (both P < 0.05), and both parameters were positively correlated with MAFLD-associated fibrosis. Elevated serum ANGPTL8 (OR: 1.093, 95%CI: 1.044-1.144, P < 0.001) and TyG index (OR: 2.383, 95%CI: 1.199-4.736, P < 0.013) were risk factors for MAFLD-associated fibrosis. Serum ANGPTL8 and ANGPTL8 + TyG index predicted MAFLD-associated fibrosis (AUC: 0.812 and 0.835, respectively; both P < 0.05). CONCLUSION: The serum levels of ANGPTL8 are elevated and positively correlated with MAFLD. They can serve as predictors for the risk of MAFLD and liver fibrosis, with the ANGPTL8 + TyG index potentially exhibiting even higher predictive value.

Circulating ANGPTL8 as a Potential Protector of Metabolic Complications in Patients with Psoriasis.

Angiopoietin-like protein 8 (ANGPTL8) exerts pleiotropic effects, taking part in lipid and carbohydrate metabolism, inflammation, hematopoiesis and oncogenesis. So far, the exact molecular targets of ANGPTL8 remain poorly defined. We aimed to evaluate the serum concentration of ANGPTL8 in individuals with psoriasis and examine how systemic therapy affects the concentration of ANGPTL8. The study enrolled 35 patients with plaque-type psoriasis that were followed for 3 months of treatment with methotrexate or acitretin, and 18 healthy volunteers without psoriasis as controls. Serum ANGPTL8 concentrations were analyzed by ELISA and differences between groups were determined using Student's t-test or the Mann-Whitney test, while correlations were assessed using Spearman's rank test. The average concentration of ANGPTL8 differed significantly between the psoriasis group (before and after therapy) and the control group (p < 0.05). Significant negative correlations between ANGPTL8 and total cholesterol and LDL levels were noted (both p < 0.05). A significant increase in ANGPTL8 concentration was observed after acitretin (p < 0.05), whereas in patients treated with methotrexate the ANGPTL8 did not change significantly (p > 0.05). Additionally, a negative, statistically significant correlation with PASI was found after treatment (p < 0.05). Based on our study, it appears that elevated levels of ANGPTL8 may reduce the likelihood of atherogenic dyslipidemia in individuals with psoriasis, and treatment for psoriasis may impact the protective effects of ANGPTL8.

Angiopoietin-like protein 8 deficiency attenuates thoracic aortic aneurysm/dissection development in ß-aminopropionitrile monofumarate-induced model mice.

Thoracic aortic aneurysm/dissection (TAAD) is a life-threatening cardiovascular disorder. Endoplasmic reticulum stress (ERS) and vascular smooth muscle cell (VSMC) apoptosis are involved in TAAD progression. The Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) pathway is associated with VSMC apoptosis. Serum Angiopoietin-Like Protein 8 (ANGPTL8) levels are associated with aortic diameter and rupture rate of TAAD. However, a direct role of ANGPTL8 in TAAD has not been determined. ß-Aminopropionitrile monofumarate (BAPN) was used to induce TAAD in C57BL/6 mice. ANGPTL8 knockout mice were used to detect the effects of ANGPTL8 on TAAD development. ANGPTL8knockdown in vitro was used to analyze the role of ANGPTL8 in VSMCs and ERS. In addition, over-expression of ANGPTL8 in VSMCs and a PERK inhibitor were used to assess the effect of ANGPTL8 on the PERK pathway. ANGPTL8 levels were increased in the aortic wall and VSMCs of BAPN-induced TAAD mice. Compared with BAPN-treated wild-type mice, ANGPTL8 knockout significantly reduced the rupture rate of TAAD to 0 %. In addition, the protein levels of proinflammatory cytokines and matrix metalloproteinase 9 (MMP9) and ERS proteins were decreased in the aorta wall. Angptl8 shRNA decreased MMP9 and ERS protein levels in VSMCs in vitro. Overexpression of ANGPTL8 significantly increased the levels of ERS proteins and MMPs, while a PERK inhibitor significantly decreased the effects of ANGPTL8 in VSMCs. ANGPTL8 contributed to TAAD development by inducing ERS activation and degradation of extracellular matrix in the aorta wall. Inhibition of ANGPTL8 may therefore represent a new strategy for TAAD therapy.

Vascular smooth muscle cells specific deletion of angiopoietin-like protein 8 prevents angiotensin II-promoted hypertension and cardiovascular hypertrophy.

AIMS: Angiopoietin-like protein 8 (ANGPTL8) plays important roles in lipid metabolism, glucose metabolism, inflammation, and cell proliferation and migration. Clinical studies have indicated that circulating ANGPTL8 concentrations are increased in patients with hypertension and positively associated with blood pressure. ANGPTL8 deficiency ameliorates blood pressure in mice treated with chronic intermittent hypoxia. Currently, little is known regarding the pathophysiological role of the vascular smooth muscle cell (VSMC)-derived ANGPTL8 in hypertension and hypertensive cardiovascular remodelling. METHODS AND RESULTS: Circulating ANGPTL8 concentrations, as determined by enzyme-linked immunosorbent assay, were significantly higher in hypertensive patients than in controls (524.51 ± 26.97 vs. 962.92 ± 15.91 pg/mL; P < 0.001). In hypertensive mice [angiotensin II (AngII) treatment for 14 days] and spontaneously hypertensive rats, ANGPTL8 expression was increased and predominantly located in VSMCs. In AngII-treated mice, systolic and diastolic blood pressure in Tagln-Cre-ANGPTL8fl/fl mice were approximately 15-25 mmHg lower than that in ANGPTL8fl/fl mice. AngII-induced vascular remodelling, vascular constriction, and increased expression of cell markers of proliferation (PCNA and Ki67) and migration (MMP-2 and MMP-9) were strikingly attenuated in Tagln-Cre-ANGPTL8fl/fl mice compared with ANGPTL8fl/fl mice. Furthermore, the AngII-induced increase in the heart size, heart weight, heart/body weight ratio, cardiomyocyte cross-sectional area, and collagen deposition was ameliorated in Tagln-Cre-ANGPTL8fl/fl mice compared with ANGPTL8fl/fl mice. In rat artery smooth muscle cells, ANGPTL8-short hairpin RNA decreased intracellular calcium levels and prevented AngII-induced proliferation and migration through the PI3K-Akt pathway, as shown using LY294002 (inhibitor of PI3K) and Akt inhibitor VIII. CONCLUSION: This study suggests that ANGPTL8 in VSMCs plays an important role in AngII-induced hypertension and associated cardiovascular remodelling. ANGPTL8 may be a novel therapeutic target against pathological hypertension and hypertensive cardiovascular hypertrophy.