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. 2025 Feb 26;26(5):2039.
doi: 10.3390/ijms26052039.

GDF15 Circulating Levels Are Associated with Metabolic-Associated Liver Injury and Atherosclerotic Cardiovascular Disease

Josefa Girona  1   2   3   4 , Montse Guardiola  1   2   3   4 , Emma Barroso  4   5   6   7 , María García-Altares  4   8 , Daiana Ibarretxe  1   2   3   4 , Núria Plana  1   2   3   4 , Josep Ribalta  1   2   3   4 , Núria Amigó  3   4   8   9   10 , Xavier Correig  4   8 , Manuel Vázquez-Carrera  4   5   6   7 , Lluís Masana  1   2   3   4 , Ricardo Rodríguez-Calvo  1   2   3   4
Affiliations

GDF15 Circulating Levels Are Associated with Metabolic-Associated Liver Injury and Atherosclerotic Cardiovascular Disease

Josefa Girona et al. Int J Mol Sci. .

Abstract

There is growing evidence linking growth differentiation factor 15 (GDF15) to both metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular (CV) risk. Nevertheless, the potential relationship between circulating levels of GDF15 and key features of MASLD being predisposed to atherosclerotic CV disease is not fully unveiled. The aim of this study was to deepen into the role of circulating GDF15 levels on metabolic-associated liver injury and atherosclerotic CV disease. We determined the serum GDF15 levels in 156 participants of a metabolic patient-based cohort, and cross-sectionally explored its associations with liver injury and an advanced atherosclerotic lipoprotein profile assessed by nuclear magnetic resonance (1H-NMR). Additionally, we prospectively evaluated the association between GDF15 levels at baseline and incident atherosclerotic CV disease after a 10-year follow-up. GDF15 was related to liver injury and inflammatory hallmarks, and it increased the likelihood for liver steatosis independently of confounding factors. Likewise, GDF15 was positively associated with an atherogenic profile, particularly with the number of very-low-density lipoproteins (VLDL) particles and its cholesterol and triglyceride content, and with an indicator of subclinical atherosclerosis (i.e., carotid intima-media thickness (cIMT)). The baseline serum GDF15 levels were higher in the patients with atherosclerotic CV disease (10.6%) after a 10-year follow-up than in the individuals without CV disease. Altogether, this study provides new insights into the role of GDF15 in both MASLD and CV disease.

Keywords: CV risk; GDF15; MASLD; atherosclerotic profile.

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Conflict of interest statement

Núria Amigó was employed by the company Biosfer Teslab. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Serum GDF15 levels increased in patients with metabolic disturbances. Data are expressed as the means ± SEM. * p < 0.05 vs. healthy volunteers. p values are adjusted by age, insulin therapy, oral antidiabetic therapy and hypotensive therapy through the analysis of covariance (ANCOVA).
Figure 2
Figure 2
(A) Serum GDF15 levels increased in subjects with liver steatosis. Serum GDF15 levels are shown in patients with FLI ≥ 60 or those with FLI < 60. Data are expressed as the means ± SEM. *** p < 0.001 vs. FLI < 60 individuals. (B) Univariate and multivariate logistic regression models (odds ratio, OR and 95% confidence interval, CI) were used to explore the associations between serum GDF15 and liver steatosis as outcomes. * Multivariate logistic regressions models were adjusted for age, insulin therapy, oral antidiabetic therapy and hypotensive therapy (METOD = Wald).
Figure 3
Figure 3
Plots of plasma correlations between GDF15 and cIMT. r from rho coefficients from the Spearman correlation analysis. GDF15 and cIMT was log-transformed to reduce skewness. GDF15: growth differentiation factor 15; cIMT: carotid intima–media thickness.
Figure 4
Figure 4
Baseline serum GDF15 levels of the patients according to cardiovascular (CV) disease after a 10-years follow-up. Data are expressed as the means ± SEM. ** p < 0.01 vs. non-CV disease patients.
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