Angiopoietin-Like Protein 8/Leptin Crosstalk Influences Cardiac Mass in Youths With Cardiometabolic Risk: The BCAMS Study

Abstract

Objectives: The link between excess adiposity and left ventricular hypertrophy is multifaceted with sparse data among youths. Given that adipokines/hepatokines may influence lipid metabolism in myocardium, we aimed to investigate the relation of the novel hepatokine angiopoietin-like protein 8 (ANGPTL8) and other adipokines with cardiac structure in a cohort of youths and explore to what extent these adipokines/hepatokines affect cardiac structure through lipids.

Methods: A total of 551 participants (aged 15-28 years) from the Beijing Child and Adolescent Metabolic Syndrome Study (BCAMS) cohort underwent echocardiographic measurements plus a blood draw assayed for five adipokines/hepatokines including adiponectin, leptin, retinol binding protein 4, fibroblast growth protein 21 and ANGPTL8.

Results: Both ANGPTL8 (β = -0.68 g/m^2.7 per z-score, P= 0.015) and leptin (β = -1.04 g/m^2.7 per z-score, P= 0.036) were significantly inversely associated with left ventricular mass index (LVMI) independent of classical risk factors. Total cholesterol and low-density lipoprotein cholesterol significantly mediated the ANGPTL8-LVMI association (proportion: 19.0% and 17.1%, respectively), while the mediation effect of triglyceride on the ANGPTL8-LVMI relationship was strongly moderated by leptin levels, significantly accounting for 20% of the total effect among participants with higher leptin levels. Other adipokines/hepatokines showed no significant association with LVMI after adjustment for body mass index.

Conclusions: Our findings suggest ANGPTL8, particularly interacting with leptin, might have a protective role in cardiac remodeling among youths with risk for metabolic syndrome. Our results offer insights into the pathogenesis of the cardiomyopathy and the potential importance of tissue-tissue crosstalk in these effects.

Trial registration: ClinicalTrials.gov NCT03421444.

Keywords: angiopoietin-like protein 8; left ventricular mass; leptin; lipids; youth.

Figure 1

The model used to evaluate the mediation effects of lipids on ANGPTL8-LVMI association. (A) We hypothesized that ANGPTL8 may indirectly affect left ventricular mass index (LVMI) by regulating lipids metabolism including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG). (B) TC significantly mediated 19.0% of the effect of ANGPTL8 on LVMI. (C) LDL-C significantly mediated 17.1% of the effect of ANGPTL8 on LVMI. (D) The effect that was mediated by TG was 7.7%, although it was not significant. Mediation effects were adjusted for age, sex, body mass index, and systolic blood pressure; per z-score increment of ln-ANGPTL8. β = standardized regression coefficient; β₁ = indirect effect 1; β₂ = indirect effect 2; β_Ind = total indirect effect; β_Dir = direct effect; β_Tot = total effect; Data based on 5000 bootstrap samples. *P < 0.05; **P < 0.01; ***P < 0.001.

Figure 2

Interaction between ANGPTL8 and leptin on lipids profiles. Liner regression analysis of ANGPTL8 on lipids (TG, TC and LDL-C) stratified by high and low (above/below sex-specific median) levels of leptin. Ln-transformed for triglyceride (TG) and ANGPTL8, per z-score increment of each ln-ANGPTL8. Liner regression models and the P for interaction were shown adjusted for age, sex, body mass index, and systolic blood pressure. β, parameter estimate from linear regression; CI, confidence interval; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol.

Figure 3

The moderated-mediation model used to evaluate the effects of leptin and TG on ANGPTL8-LVMI association. (A) We hypothesized that leptin might modulate the mediation effects of triglyceride (TG) on the association of ANGPTL8 and left ventricular mass index (LVMI) in a moderated mediation template model 7. (B) Moderated effect of leptin for TG is significant, with increment of 0.064 mmol/L TG each additional ln-leptin z-score; the index of moderated mediation, which qualify the relationship between moderator leptin and the size of the indirect effect of ANGPTL8 on LVMI through mediator TG, was significant, with a 0.078 g/m^2.7 lower LVMI each additional ln-leptin z-score at a given level of ANGPTL8. Mediation and moderation effects were adjusted for age, sex, body mass index, and systolic blood pressure. β =standardized regression coefficient; β₁ = indirect effect 1; β₂ = indirect effect 2; β_Dir = direct effect. Data based on 5000 bootstrap samples. Ln-transformed for TG, ANGPTL8 and leptin, per z-score interaction of each ln-adipokine/hepatokine. *P < 0.05; **P < 0.01.

Figure 4

A proposed mechanistic model for interaction between ANGPTL8 and leptin on LVH through triglyceride. The hepatokine ANGPTL8 might facilitate angiopoietin-like protein 3 (ANGPTL3) to inhibit lipoprotein lipase (LPL) activity for conversion of triglyceride (TG) into fatty acids (FAs) in myocardium, resulting in increased circulating TG and decreased FAs uptake into cardiomyocytes, and coordinating the trafficking of TG to white adipose tissue for storage, and ultimately, inducing higher leptin secretion. Meanwhile, high leptin levels might stimulate β-oxidation of FAs and inhibit de novo lipogenesis in cardiomyocytes to further prevent myocardial TG accumulation and lipid cardiomyopathy, leading to a favorable LVMI. Thereby, the adipokine leptin and the hepatokine ANGPTL8 cooperate together to decrease cardiac TG involved in mechanism of protective effect on cardiac remodeling.