Elsevier

Journal of Hepatology

Volume 53, Issue 5, November 2010, Pages 934-940
Journal of Hepatology

Research Article
Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride

https://doi.org/10.1016/j.jhep.2010.05.018Get rights and content

Background & Aims

Fibroblast growth factor 21 (FGF21), a hormone primarily secreted by the liver in response to peroxisome proliferator-activated receptor-α (PPARα) activation, has recently been shown to possess beneficial effects on lipid metabolism and hepatic steatosis in animal models. This study investigated the association of FGF21 with nonalcoholic fatty liver disease (NAFLD) in Chinese patients.

Methods

Serum FGF21 levels were determined by enzyme-linked immunosorbent assay (ELISA) in 224 NAFLD and 124 control subjects, and their association with parameters of adiposity, glucose, and lipid profiles and levels of liver injury markers was studied. Besides serum concentrations, the mRNA expression of FGF21 in the liver tissue was also quantified by real-time PCR in 17 subjects with different degrees of steatosis, and was correlated with the levels of intrahepatic lipid. The protein levels of FGF21 were determined by quantitative ELISA.

Results

Serum FGF21 levels in patients with NAFLD (402.38 pg/ml [242.03, 618.25]) were significantly higher than those in control subjects (198.62 pg/ml [134.96, 412.62]) (p <0.01). In human liver tissues, FGF21 mRNA expression increased with the degree of steatosis. Both FGF21 mRNA expression and serum FGF21 concentrations were positively correlated with intrahepatic triglyceride (TG) having r = 0.692 and r = 0.662, respectively, at p <0.01. Furthermore, the increased expression of FGF21 was accompanied by elevated protein levels in liver tissues.

Conclusions

These results support the role of FGF21 as a key regulator of hepatic lipid metabolism in humans, and suggest that serum FGF21 can be potentially used as a biomarker for NAFLD.

Introduction

The human fibroblast growth factor (FGF) family includes at least 22 members with diverse biological functions such as cell growth, differentiation, and wound healing [1]. Recent studies indicate that three members of this family, including FGF19, FGF21, and FGF23 act as endocrine factors involved in hormone-like metabolic effects by interacting with FGF receptors [1], [2], [3], [4]. FGF21, a polypeptide with 210 amino acid residues most abundantly expressed in the liver, has recently been shown to be an important regulator of glucose and lipid metabolism in animal models [2], [5]. The therapeutic intervention with recombinant FGF21 caused a reduction of blood glucose and triglyceride (TG) to near normal levels in both ob/ob and db/db diabetic mice [2]. In diabetic rhesus monkeys, chronic treatment with recombinant FGF21 led to a dramatic decline in fasting plasma glucose, insulin, and glucagon, and to a significant improvement in lipoprotein profiles [6]. Systemic administration of FGF21 resulted in a significant decrease in hepatic steatosis in diet-induced obese mice [7]. A recent study also reported that a hypocaloric high-protein diet improves fatty liver via up-regulation of FGF21 [8]. Multiple findings have indicated that FGF21 is a downstream target of peroxisome proliferator-activated receptor-α (PPARα) [9], [10]. PPARα agonists might mediate the therapeutic benefits by stimulating hepatic FGF21 production [11]. Taken together, these findings demonstrate an important role of FGF21 as a potent metabolic regulator with effects on lipid metabolism and hepatic steatosis.

Although these animal-based studies demonstrate that FGF21 might represent a promising therapeutic agent for diabetes and fatty liver disease, the physiological roles of FGF21 in humans remain insufficiently understood. Several recent epidemiological studies showed that serum FGF21 levels were elevated in obese subjects and in hypertriglyceridemic, impaired glucose tolerance (IGT), and type 2 diabetes (T2DM) patients [12], [13], [14], [15]. In our previous study, a significant positive association of serum FGF21 levels with alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT) was found in Chinese subjects. Besides TG and total cholesterol (TC), GGT was found to be independently associated with serum FGF21 by multiple stepwise regression analysis. Our data suggest that the function of FGF21 is closely related to lipid metabolism instead of insulin sensitivity in humans [14]. However, the clinical relevance of FGF21 in nonalcoholic fatty liver disease (NAFLD) patients has never been explored so far.

The prevalence of NAFLD, a pathological condition closely associated with obesity and insulin resistance, is rapidly increasing worldwide [16]. In fact, NAFLD is regarded as the hepatic manifestation of metabolic syndrome. It ranges from simple fatty liver (SFL) to nonalcoholic steatohepatitis (NASH) to cirrhosis. In clinical practice, the diagnosis of NAFLD is usually suspected upon the evidence of elevated serum ALT and/or fatty liver on imaging studies. Ultrasonography is the most commonly used imaging technique for screening patients with steatosis. However, it is subjective and not sensitive to mild steatosis [17], [18]. Magnetic resonance spectroscopy (MRS) overcomes these defects of ultrasonography but is relatively expensive [19]. The limitation of liver biopsy and the challenge of epidemiological screening make the development of a noninvasive, readily available, and easy-to-perform serum marker of NAFLD a high priority. The fundamental pathophysiological change of NAFLD is the accumulation of free fatty acids (FFAs) and TG in hepatocytes [20]. Based on our previous findings, we hypothesized that FGF21, a hormone principally secreted by the liver in response to PPARα activation, might be involved in the pathogenesis and might mirror the progression of NAFLD. The objective of the study was to investigate the clinical relevance of FGF21 in NAFLD patients.

Section snippets

Study subjects

This epidemiological survey of diabetes and metabolic syndrome in two Shanghai communities from June to August 2008 followed a multi-stage stratified design. All subjects underwent comprehensive physical examinations, routine biochemical analyses of blood, 75-g oral glucose tolerance test, hepatitis B surface antigen, hepatitis C virus antibody and B ultrasonography. All participants completed a uniform questionnaire containing questions about the histories of present and past illnesses and

Characteristics of subjects

The clinical characteristics of the study subjects are shown in Table 1. No significant differences in age were observed in control and NAFLD subjects. The male to female ratio in NAFLD group was significantly higher than that of the control group (p <0.01). After adjustment for age and gender, subjects with NAFLD had higher BMI, waist circumference, fat percentage, systolic blood pressure (SBP), and diastolic blood pressure (DBP) than those of control subjects (all p <0.001). Concentrations of

Discussion

In this study, we provide the first clinical evidence showing that serum concentrations of FGF21 were elevated in patients with NAFLD taken from the Chinese population. FGF21 was found to have beneficial effects on islet insulin content, glucose-induced insulin secretion and insulin sensitivity in diabetic animals and 3T3-L1 adipocytes [25], [26]. However, the relationship between FGF21 and insulin sensitivity in humans is controversial. It has been reported that plasma FGF21 levels were

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

Acknowledgements

This work was supported by the Key Project from Science and Technology Commission of Shanghai Municipality (04DZ19501), Major Program of Shanghai Municipality for Basic Research (08dj1400601) and Shanghai Key Laboratory of Diabetes Mellitus (08DZ2230200).

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    These authors contributed equally to this work.

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