Higher circulating levels of ANGPTL8 are associated with body mass index, triglycerides, and endothelial dysfunction in patients with coronary artery disease

Fadaei, Reza; Shateri, Hossein; DiStefano, Johanna K.; Mohammadi, Mohammad; Emami, Farzad; Aghajani, Hassan; Ziamajidi, Nasrin

doi:10.1007/s11010-020-03725-7

Cited by 16 publications

(7 citation statements)

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“…Cardiac fibrosis, as a typical feature of pathological cardiac hypertrophy, is characterized by cardiac collagen accumulation [ 28 , 29 ]. In contrast to previous studies, ANGPTL8 promoted endothelial barrier dysfunction and proliferation in cancer [ 21 , 30 – 32 ]. Our study first demonstrated that ANGPTL8 knockout aggravated cardiac fibrosis and exaggerated fibrotic marker expression in vivo.…”

Section: Discussioncontrasting

confidence: 83%

“…ANGPTL8 is known as betatrophin, lipasin and TD26 and shows a regulatory function in lipid and glucose metabolism [ 19 ], which is involved in metabolic diseases such as diabetes, obesity [ 12 , 13 ] and metabolic syndrome [ 20 ]. Circulating ANGPTL8 was not only enhanced in patients with infectious disease [ 21 ], but ANGPTL8 mRNA was also expressed at high levels in mice treated with LPS, acting as a “brake” for inflammation [ 9 , 17 , 22 ]. Moreover, serum ANGPTL8 levels were increased in patients with hypertension [ 11 ] and atherosclerotic cardiovascular disease [ 21 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Circulating ANGPTL8 was not only enhanced in patients with infectious disease [ 21 ], but ANGPTL8 mRNA was also expressed at high levels in mice treated with LPS, acting as a “brake” for inflammation [ 9 , 17 , 22 ]. Moreover, serum ANGPTL8 levels were increased in patients with hypertension [ 11 ] and atherosclerotic cardiovascular disease [ 21 , 23 ]. These studies mainly focused on lipid and glucose metabolism and their relationship with cardio-metabolic risk factors, but there was no research reporting the influence of ANGPTL8 on pathological cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

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ANGPTL8 is a negative regulator in pathological cardiac hypertrophy

Wei

Zhang

et al. 2022

Cell Death Dis

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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.

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Section: Discussioncontrasting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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ANGPTL8 is a negative regulator in pathological cardiac hypertrophy

Wei

Zhang

et al. 2022

Cell Death Dis

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“…In previous clinical studies, Leiherer et al [ 15 ] included 201 CAD patients for an 8-year follow-up study, and the results showed that elevated levels of betatrophin have predictive value for the occurrence of cardiovascular events. Moreover, the study by Fadaei et al [ 16 ] revealed that the higher circulating levels of betatorphin in patients with CHD are related to BMI, TG and endothelial dysfunction. In a previous study based on Chinese CHD patients, Jiao et al [ 17 ] also showed that the circulating full-length betatrophin levels in nondiabetic CHD patients were increased, and they could be used as an independent risk factor for CHD.…”

Section: Discussionmentioning

confidence: 99%

Correlation between betatrophin/angiogenin-likeprotein3/lipoprotein lipase pathway and severity of coronary artery disease in Kazakh patients with coronary heart disease

Lian¹,

Rehemuding²,

Ainiwaer³

et al. 2022

WJCC

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BACKGROUND The results of previous animal experiments and clinical studies have shown that there is a correlation between expression of betatrophin and blood lipid levels. However, there are still differences studies on the correlation and interaction mechanism between betatrophin, angiogenin-likeprotein3 (ANGPTL3) and lipoprotein lipase (LPL). In our previous studies, we found an increase in serum ANGPTL3 Levels in Chinese patients with coronary heart disease (CHD). Therefore, we retrospectively studied Kazakh CHD patients. AIM To explore the correlation between the betatrophin/ANGPTL3/LPL pathway and severity of coronary artery disease (CAD) in patients with CHD. METHODS Nondiabetic patients diagnosed with CHD were selected as the case group; 79 were of Kazakh descent and 72 were of Han descent. The control groups comprised of 61 Kazakh and 65 Han individuals. The serum levels of betatrophin and LPL were detected by enzyme-linked immunosorbent assay (ELISA), and the double antibody sandwich ELISA was used to detect serum level of ANGPTL3. The levels of triglycerides, total cholesterol, and fasting blood glucose in each group were determined by an automatic biochemical analyzer. At the same time, the clinical baseline data of patients in each group were included. RESULTS Betatrophin, ANGPTL3 and LPL levels of Kazakh patients were significantly higher than those of Han patients ( P = 0.031, 0.038, 0.021 respectively). There was a positive correlation between the Gensini score and total cholesterol (TC), triglycerides (TG), low- density lipoprotein cholesterol (LDL-C), betatrophin, and LPL in Kazakh patients ( r = 0.204, 0.453, 0.352, 0.471, and 0.382 respectively), ( P = 0.043, 0.009, 0.048, 0.001, and P < 0.001 respectively). A positive correlation was found between the Gensini score and body mass index (BMI), TC, TG, LDL-C, LPL, betatrophin in Han patients ( r = 0.438, 0.195, 0.296, 0.357, 0.328, and 0.446 respectively), ( P = 0.044, 0.026, 0.003, 0.20, 0.004, and P < 0.001). TG and betatrophin were the risk factors of coronary artery disease in Kazakh patients, while BMI and betatrophin were the risk factors in Han patients. CONCLUSION There was a correlation between the betatrophin/ANGPTL3/LPL pathway and severity of CAD in patients with CHD.

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“…To examine the relationship between plasma A8 levels and various metabolic risk factors and disorders, including obesity ( 22–24 ), type 2 diabetes ( 23–27 ), fatty liver disease ( 28-30 ), and coronary atherosclerosis ( 27 , 31 ), several enzyme-linked immunosorbent assays (ELISAs) have been established. However, most of the studies using these ELISAs focused on small, racially/ethnically homogeneous samples, and thus the contribution of A8 to racial/ethnic differences in energy substrate metabolism has not been fully investigated.…”

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confidence: 99%

Genetic and Metabolic Determinants of Plasma Levels of ANGPTL8

Oldoni

Bass

Kozlitina

et al. 2021

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context ANGPTL8 (A8) plays a key role in determining the tissue fate of circulating triglycerides (TGs). Plasma A8 levels are associated with several parameters of glucose and TG metabolism, but the causality of these relationships and the contribution of genetic variants to differences in A8 levels have not been explored. Objective To characterize the frequency distribution of plasma A8 levels in a diverse population using a newly-developed ELISA and to identify genetic factors contributing to differences in plasma A8 levels. Design and Setting Population-based sample of Dallas County. Participants Individuals in the Dallas Heart Study (DHS-1, n=3,538; DHS-2, n=3,283), including 2,131 individuals with repeated measurements 7-9 years apart (age 18-85 years; >55% female; 52% Black; 29% White; 17% Hispanic; and 2% other). Main Outcome Measure(s) Associations of A8 levels with body-mass index (BMI), plasma levels of glucose, insulin, lipids, hepatic TG and DNA variants identified by exome-wide sequencing. Results A8 levels varied over a 150-fold range (2.1 - 318 ng/mL; median, 13.3 ng/mL) and differed between racial/ethnic groups (Blacks > Hispanics > Whites). A8 levels correlated with BMI, fasting glucose, insulin and TG levels. A variant in A8, R59W, accounted for 17% of the inter-individual variation in A8 levels but was not associated with the metabolic parameters correlated with plasma A8 concentrations. Conclusions A8 levels were strongly associated with indices of glucose and TG metabolism, but the lack of association of genetic variants at the A8 locus that impact A8 levels with these parameters indicates that differences in A8 levels are not causally related to the associated metabolic phenotypes.

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Higher circulating levels of ANGPTL8 are associated with body mass index, triglycerides, and endothelial dysfunction in patients with coronary artery disease

Cited by 16 publications

References 50 publications

ANGPTL8 is a negative regulator in pathological cardiac hypertrophy

ANGPTL8 is a negative regulator in pathological cardiac hypertrophy

Correlation between betatrophin/angiogenin-likeprotein3/lipoprotein lipase pathway and severity of coronary artery disease in Kazakh patients with coronary heart disease

Genetic and Metabolic Determinants of Plasma Levels of ANGPTL8

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