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Strong Association between Serum Hepatocyte Growth Factor and Metabolic Syndrome

The Third Department of Internal Medicine and The Cardiovascular Research Institute, Kurume University School of Medicine, Kurume 830-0011, Japan

Address all correspondence and requests for reprints to: Hisashi Adachi, M.D., The Third Department of Internal Medicine and The Cardiovascular Research Institute, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan. E-mail: hadac{at}med.kurume-u.ac.jp.

	Abstract

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Hepatocyte growth factor (HGF) is one of the adipocytokines. We evaluated whether serum levels of HGF are related to the metabolic syndrome. A total of 1474 subjects of a general population free of liver, kidney, and lung diseases received a health examination. We measured blood pressure, waist circumference, body mass index, fasting plasma glucose, lipid profiles, serum insulin, liver enzymes, and HGF concentrations. Uni- and multivariate analyses for determinant of HGF were performed. In univariate analysis, all of the components (waist circumference, triglycerides, high-density lipoprotein-cholesterol, blood pressure, and fasting plasma glucose) of the metabolic syndrome and liver enzymes were significantly related to HGF levels. By the use of multiple stepwise regression analysis, HGF levels were significantly related to waist circumference (P < 0.001), high-density lipoprotein-cholesterol (P < 0.05, inversely), and liver enzymes (P < 0.001). HGF levels were higher (P < 0.05) in proportion to the accumulation of the number of the component of the metabolic syndrome. A significant association (P < 0.05) was shown between quartiles of HGF levels and the degree of abnormality of the component of the metabolic syndrome. In conclusion, our results indicate that serum HGF levels are strongly associated with the metabolic syndrome, independent of liver function.

	Introduction

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THE ADIPOSE TISSUE is now recognized as an endocrine organ that secretes multiple growth factors and cytokines (1, 2), such as TNF, leptin, and adiponectin (1, 2, 3). One of them is hepatocyte growth factor (HGF) (4). The 3T3-L1 adipocyte cell line can secrete HGF in vitro (4), thus suggesting that adipocytes may also be able to synthesize and secrete HGF in vivo. It has been shown in a small number of subjects (<100) that serum HGF levels are elevated in patients with essential hypertension (5) and extreme obesity (6), suggesting the role of HGF in the pathophysiology of the metabolic syndrome. However, it is well known that plasma HGF levels are influenced by liver function (7, 8) and that obese subjects have a higher prevalence of fatty liver (9). Accordingly, our aim in this study was to evaluate the relationship between the metabolic syndrome and plasma HGF levels in a large number (1500 subjects) of a general population, irrespective of liver function.

	Subjects and Methods

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In 1999 we carried out a physical examination on the inhabitants of Tanushimaru in Fukuoka Prefecture (a cohort of the Seven Countries Study). Informed consent was obtained from all subjects in accordance with ethics committee guidelines of our university. As reported previously, the demographic backgrounds of the subjects in this area are similar to those of the Japanese general population (10). We examined 1492 persons over the age of 40 yr. Eighteen subjects who had the histories of liver, kidney, and lung diseases were excluded from the study; subsequently we enrolled 1474 subjects (597 men and 877 women).

The subjects’ medical history, use of alcohol, and smoking were ascertained by a questionnaire. Alcohol intake and smoking were classified as current habitual use or not. Height and weight were measured, and body mass index (BMI) was calculated as weight (kilograms) divided by the square of height (square meters) as an index of obesity. Waist circumference was measured at the level of the umbilicus in the standing position. Blood pressure (BP) was measured in the supine position twice at 3-min intervals using an upright standard sphygmomanometer. Vigorous physical activity and smoking were avoided for at least 30 min before BP measurement. The second BP with the fifth-phase diastolic pressure was used for analysis. Blood was drawn from the antecubital vein for determinations of fasting plasma glucose (FPG), glycosylated hemoglobin A_1c, lipids [total cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglycerides], immunoreactive insulin (IRI), and liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and -glutamyl transpeptidase (-GTP)], and HGF levels in the morning after a 12-h fast. Fasting blood samples were centrifuged immediately after collection. Plasma HGF levels by the ELISA (11) and the other chemistries were measured at a commercial-based laboratory (The Kyodo Igaku Laboratory, Fukuoka, Japan).

We defined the metabolic syndrome according to the Adult Treatment Panel III (ATP III) (12). ATP III identified five components of the metabolic syndrome [abdominal obesity, given as waist circumference (men, > 101.6 cm, women, > 88.9 cm); triglycerides ( 1.69 mmol/liter), HDL-cholesterol (men, < 1.03 mmol/liter, women, < 1.29 mmol/liter); BP ( 130/ 85 mm Hg); and fasting glucose ( 6.11 mmol/liter)]. However, Japanese are much smaller than people of Western countries; therefore, it is not appropriate to use the criteria of abdominal obesity of ATP III. Accordingly, we adopted more than 85 cm for men and more than 90 cm for women of waist circumference, proposed by the Japanese Society for the Obesity (13).

Statistical methods

Results are presented as mean ± SD. Because of skewed distributions, the natural logarithmic transformation was performed for HGF, IRI, and triglycerides. Mean HGF levels stratified by quartiles of the increasing values of waist circumference and HDL-cholesterol were compared using analysis of covariance, adjusted for liver enzymes. Mean HGF levels stratified by the number of the components of the metabolic syndrome were compared using analysis of covariance, adjusted for liver enzymes.

Statistical significance was defined as P < 0.05. All statistical analyses were performed with the use of the SAS system statistical software (14).

	Results

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The characteristics of the 1474 subjects are presented in Table 1. The data indicate that most people were nonobese, normotensive, normolipidemic, and nondiabetic with normal renal and hepatic function. Table 2 shows results of a univariate analysis for determinant of HGF levels. Components of the metabolic syndrome and liver enzymes were all related to HGF levels. For the significant factors shown in Table 2, we performed multiple stepwise regression analysis (Table 3). Gender lost its significance. Waist circumference, AST, -GTP, and HDL-cholesterol remained significant and were independently related to HGF levels. To further examine the association between HGF and the metabolic syndrome, we demonstrate the following analyses. After adjustments for liver enzymes, mean values of HGF are shown across quartiles of waist circumference and HDL-cholesterol levels in Fig. 1, A and B. Strong and significant relations were shown between HGF and waist circumference and between HGF and HDL-cholesterol (inversely). Mean HGF levels stratified by the number of components of the metabolic syndrome (0, 1, 2, and more than 3) were compared using analysis of covariance adjusted for AST and -GTP. A linear and significant trend (P < 0.05) was demonstrated (Fig. 2). Finally, a significant association (P < 0.05) was shown between quartiles of HGF levels and the degree of abnormality of the components of the metabolic syndrome (Table 4).

View larger version (18K): [in this window] [in a new window]   FIG. 1. A, AST and -GTP-adjusted means of HGF levels stratified by quartiles of waist circumference levels. B, AST and -GTP-adjusted means of HGF levels stratified by quartiles of HDL-cholesterol levels.

View larger version (9K): [in this window] [in a new window]   FIG. 2. AST and -GTP-adjusted means of HGF levels stratified by the number of the components of the metabolic syndrome.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

A recent report (6) described the relationship between obesity and serum HGF levels. It is also well known that serum HGF levels are elevated in subjects with liver disease (7, 8, 15, 16). Thus, the elevated HGF levels in obese subjects may be due to fatty liver secondary to obese. This issue has never been addressed. In this study, we excluded subjects with apparent liver disease, and moreover, our multivariate analysis showed that liver enzymes and obesity are positively and independently associated with plasma levels of HGF. Because 48.4% of men were alcohol drinkers, we performed multiple regression analysis in the subgroup of nonalcoholic subjects (n = 1163). Again there were strong associations between HGF and waist circumference (standardized regression coefficient 0.208, P < 0.001) and AST (standardized regression coefficient 0.170, P < 0.001). Thus, our results indicate that the elevated HGF levels in obese subjects are not due to liver dysfunction. Our results support those by Rehman et al. (6) reporting that HGF levels are elevated in obese subjects. However, they dealt only with extreme obese subjects (mean BMI 48 kg/m²). As apparent from Table 1, the mean value of BMI was 23 kg/m² in our study, and there were only 34 subjects (2%) with BMI 30 kg/m² or greater. We performed this epidemiological study in the Japanese general population in which the prevalence of obesity is low. However, compared with Western people, Asian people have the higher incidence of metabolic syndrome at the comparable level of BMI (17); they have high incidence of metabolic syndrome in the absence of extreme obesity (18). Thus, our findings are not surprising, even though our population is not obese.

Another issue may deserve consideration. It is well known that a component of metabolic syndrome is large waist circumference but not obese per se. Our findings indicate that waist circumference but not BMI affects plasma HGF, suggesting the importance of fat distribution, i.e. central obesity for high plasma HGF. The pathophysiological mechanisms in the role of central obesity for high HGF are not known from our study and need further studies. Taken together, our analysis in a large number of subjects in the absence of extreme obesity suggests a pathophysiological relationship between abdominal obesity and serum HGF levels. Values of HGF in our study were approximately half of those of lean subjects in the study of Rehman et al. (6). The sensitivity of the HGF ELISA kit between the study of Rehman and ours was almost equal. Furthermore, in another study (19) of Japanese healthy subjects, mean values of HGF were 0.26 ng/ml. Therefore, we think the difference in values of HGF in our and Rehman’s studies may be ascribed to the racial difference but not to the sensitivity of the assay.

In our multivariate analysis, both abdominal obesity and low HDL-cholesterol, a component of the metabolic syndrome, was significantly related to HGF. Although multivariate analysis failed to demonstrate the relationships between HGF and the other components of the metabolic syndrome (hypertension, triglycerides, and plasma glucose), analysis of covariance showed that the accumulation of the components of metabolic syndrome (Fig. 2) is associated with higher HGF levels. Furthermore, there was a higher degree of metabolic abnormality in the greater quartiles of HGF levels (Table 4). All these data suggest the strong relationship between HGF and not only obesity but also the metabolic syndrome.

The hallmark of metabolic syndrome may be insulin resistance (20). In this regard, it is interesting to note the association between HGF and plasma insulin shown in Tables 2 and 4, suggesting the pathophysiological link between them. Given the nature of the potent angiogenic and mitogenic effects of HGF (21, 22), elevated HGF levels in the population of high insulin levels may suggest some protective roles in the maintenance of endothelial cell homeostasis rather than just a marker of metabolic syndrome.

In conclusion, it may be a common practice to measure plasma HGF levels in patients with liver disease. However, caution should be used in interpreting the data. We must look for the presence of the metabolic syndrome in patients of liver disease with high plasma HGF levels. Furthermore, at present, the complex mechanisms that link the metabolic syndrome to atherosclerosis are unknown. HGF may be one of the candidates to explain this association from the point of view of its vasoactive and proliferative nature.

	Acknowledgments

 
We are grateful to members of the Japan Medical Association of Ukiha, the elected officials and residents of Tanushimaru, and the team of physicians for their help in performing the health examinations.

	Footnotes

 
This work was supported in part by the Kimura Memorial Heart Foundation (Fukuoka, Japan) and a grant for the Science Frontier Research Promotion Centers from the Ministry of Education, Science Sports, and Culture (Japan).

First Published Online February 15, 2005

Abbreviations: ALT, Alanine aminotransferase; AST, aspartate aminotransferase; ATP III, Adult Treatment Panel III; BMI, body mass index; BP, blood pressure; FPG, fasting plasma glucose; -GTP, -glutamyl transpeptidase; HDL, high-density lipoprotein; HGF, hepatocyte growth factor; IRI, immunoreactive insulin.

Received August 9, 2004.

Accepted February 3, 2005.

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