The contribution of metabolic disorders to development and progression of cardiovascular diseases has been extensively studied. In recent years, however, the important role of cytokines, and resultant inflammation, in this etiological relationship has been recognized. Mainly characterized as a metabolic factor, the newly-recognized cytokine characteristics of FGF21 have stimulated research interest in its putative roles in the inflammation-related processes of metabolic disorders and diseases. The collective evidence, however, has revealed a more complex role for this factor in normal metabolic processes and pathogeneses. For example, animal studies have demonstrated that FGF21 promotes glycolipid metabolism and insulin sensitivity but clinical studies of humans have yielded opposite results , . Mraz M, et al. reported that serum FGF21 level becomes elevated under conditions of insulin resistance , and An et al. showed that increased serum FGF21 level accompanied the development of carotid artery plaques in patients with type 2 diabetes .
Studies of the relationship of enhanced FGF21 levels with NAFLD have provided slightly more consistent evidence. Cross-sectional clinical studies have demonstrated an incremental increase in FGF21 levels with increased severity of NAFLD ; in particular increased mRNA expression of FGF21 has been shown in hepatic biopsies . Furthermore, a 3-year follow-up of NAFLD subject outcome indicated that serum FGF21 level might be a clinically-relevant disease biomarker, suggesting its potential for monitoring response to therapy . In the present study, NAFLD subjects were found to have higher level of serum FGF21 and those subjects with multiple metabolic disorders were found to have the highest level of serum FGF21, thereby supporting the hypothesis that this factor is involved in glycolipid metabolism.
The etiological process leading from NAFLD to atherosclerosis is believed to involve a cluster of metabolic disorders and other co-morbidities (possibly inflammation-related). The most dangerous atherosclerosis manifestation is coronary atherosclerotic heart disease and research efforts have focused on defining the relationship between metabolic-related and inflammation-related serum factors (such as FGF21) and CAD. In a recent study to determine the clinical profile of CAD, using findings from electrocardiogram, serology and physical symptoms (such as chest discomfort), it was found that elevated serum FGF21 level was a distinctive marker ; this observation also served to indicate that FGF21 might be involved in the pathophysiological process of CAD. Lee et al. studied the relation between serum FGF21 and CAD diagnosis according to computed tomography findings and found that serum FGF21 level was significantly correlated with serum TG, LDL-c, HOMA-IR and the occurrence of MS; however, no relationship was found between serum FGF21 level and CAD diagnosed by computed tomography . Both of these studies of the clinical features of CAD relied on in-patient populations with a high risk of various metabolic disorders, but ignored the possible influence of NAFLD. In the current study of the relationship between FGF21 and CAD, subjects undergoing coronary arteriography were analyzed. A significant elevation of serum FGF21 among CAD subjects was discovered independently of NAFLD status. Multivariate logistic regression analysis also identified serum FGF21 level as one of the independent factors of CAD occurrence.
Enhanced serum FGF21 level has been previously demonstrated in subjects with obesity, diabetes, and dyslipidemia. Moreover, the enhanced serum FGF21 level has been correlated to presence of insulin resistance, and increased levels of TC and TG. For example, Cheng et al. identified FGF21 as a predictive marker of diabetes, but also showed that the elevated level did not correlate with disease duration . Similarly, Li et al. reported significantly increased level of FGF21 in individuals with impaired glucose tolerance, and showed a significant positive relationship of FGF21 level with TC and TG level . The findings of the current study presented herein agree with these data, collectively supporting the hypothesis that serum FGF21 level is likely involved in the process of CAD; the current study provides novel insights into the contribution of FGF21 being independent of such traditional cardiac risk factors as age, hyperglycemia, hypertension, dyslipidemia, and even NAFLD.
Insulin resistance is a main pathophysiological foundation of NAFLD, along with type 2 diabetes and even MS and cardiovascular diseases. Serum FGF21 level has been found to be higher in insulin resistance status in both human-based studies and rat experiments . In addition, Shargorodsky M, et al. found that subjects with significant improvement of insulin resistance also tended to show significant improvement on central aortic augmentation index. This result suggested that insulin resistance might be involved in the process of arterial lesions . A Japanese study even recommended using ALT/AST ratio to reflect the extent of insulin resistance . Therefore, FGF21, a mainly liver-derived cytokine, was found to be associated with the occurrence of CAD in this study, which might be explained, concerning the mechanism, by the involvement of insulin resistance.
Individuals with a cluster of metabolic disorders have increased serum FGF21 level, and research has implicated the up-regulation of this cytokine as acting to compensate for the abnormal metabolic status . This compensatory mechanism may explain the apparent inconsistent findings from animal and human studies of FGF21 and metabolic disorders. Elevated mRNA expression of FGF21 was found in rat cardiac micro-vascular endothelial cells (CMECs) cultured in atherosclerosis-like conditions ; furthermore, exogenous FGF21 infusion to the CMEC atherosclerosis-promoting culture significantly inhibited the cells’ apoptosis. These findings suggested that up-regulated FGF21 expression might be protective at the early stage of atherosclerosis, helping the cells to recover normal endothelial function. Thus, it is possibly that the elevated FGF21 observed in the CAD subjects of our study represent a similar compensatory mechanism, by which the system is attempting to protect against atherosclerosis. While this study is the first to provide clinical evidence of the relationship between serum FGF21 level and CAD diagnosed by coronary arteriography, further animal studies should be conducted to reveal the exact mechanism between FGF21 and atherosclerosis.
Some inherent features of the current study’s design may have affected the results and may limit generalization of the findings. First, the sample size was relatively small for the cross-sectional study design and some inherent bias may have been masked. Second, the study population was relatively homogenous, characterized by Chinese adults, middle- and old-aged, presenting at a single health institute and focused clinical care department (cardiology); generally, these subjects represent a high-risk of CAD.