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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-1056
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 3 1081-1086
Copyright © 2006 by The Endocrine Society

Increased Serum Resistin in Nonalcoholic Fatty Liver Disease Is Related to Liver Disease Severity and Not to Insulin Resistance

Claudio Pagano, Giorgio Soardo, Catia Pilon, Carla Milocco, Lorenza Basan, Gabriella Milan, Debora Donnini, Diego Faggian, Michele Mussap, Mario Plebani, Claudio Avellini, Giovanni Federspil, Leonardo A. Sechi and Roberto Vettor

Endocrine-Metabolic Laboratory, Department of Medical and Surgical Sciences, University of Padua (C.Pa., C.Pi., G.M., G.F., R.V.), 35100 Padua, Italy; Liver Unit, Internal Medicine, Department of Pathology and Experimental and Clinical Medicine (G.S., C.M., L.B., D.D., L.A.S.), and Pathology Unit (C.A.), University of Udine, I-33100 Udine, Italy; and Department of Laboratory Medicine, University Hospital of Padua (D.F., M.M., M.P.), I-35100 Padua, Italy

Address all correspondence and requests for reprints to: Dr. Claudio Pagano, Department of Medical and Surgical Sciences, University of Padova, Via Ospedale 105, 35100 Padova, Italy. E-mail: claudio.pagano{at}unipd.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The recently discovered hormone resistin is linked to the development of insulin resistance, but direct evidence of resistin levels in humans with nonalcoholic fatty liver disease (NAFLD) is lacking.

Methods: We conducted this study to assess the relationship between serum resistin and NAFLD. We measured serum resistin and biochemical, hormonal, and histological correlates in 28 NAFLD patients, 33 controls, and 30 obese patients [body mass index (BMI), >30 kg/m2] without NAFLD.

Results: Resistin and adiponectin expression were measured in sc adipose tissue by quantitative RT-PCR. Resistin was higher in NAFLD patients compared with controls (5.87 ± 0.49 vs. 4.30 ± 0.20 ng/ml; P = 0.002) and obese patients (4.37 ± 0.27 ng/ml; P = 0.002). Increased resistin mRNA was also found in the adipose tissue of NAFLD patients compared with controls and obese subjects.

Conclusions: Both NAFLD and obese patients had lower adiponectin levels, whereas leptin was increased only in the obese group. No correlation was found between resistin and high-sensitivity C-reactive protein, BMI, homeostasis model assessment, insulin, glucose, transaminases, and lipid values. A positive correlation was found between resistin and histological inflammatory score. These data report increased resistin in NAFLD patients that is related to the histological severity of the disease, but do not support a link between resistin and insulin resistance or BMI in these patients.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
NONALCOHOLIC FATTY LIVER disease (NAFLD) represents a spectrum of disorders characterized by macrovescicular hepatic fat accumulation occurring in individuals without relevant alcohol consumption. It is a complex metabolic condition in which both lifestyle and genetic factors play a pathogenic role (1) and has been increasingly recognized as a major cause of liver-related morbidity and mortality (2). Moreover, NAFLD has been convincingly associated with the metabolic syndrome and insulin resistance (3). Insulin resistance, through inhibition of lipid oxidation and increased fatty acid and triglycerides synthesis, is believed to be a key factor in the development of fatty liver. Moreover, insulin resistance states, such as obesity and diabetes, are also characterized by altered production of adipokines (adiponectin, leptin, resistin, TNF{alpha}, TGFß, and plasminogen activator inhibitor-1) (4, 5, 6, 7). Their roles in the development of type 2 diabetes and other complications of obesity were previously suggested (8). Resistin, also known as found in inflammatory zone-3 (FIZZ3), is a 108-amino acid protein expressed in white adipose tissue and mononuclear cells. Its role in insulin resistance has been well established in mice, but in rats and humans its role is under debate (6, 9, 10). In mice, resistin has relevant effects on hepatic glucose and lipid metabolism and seems to be a major determinant of hepatic insulin resistance induced by high fat feeding (11). To date, no data are available on resistin levels in humans with NAFLD, a condition in which insulin resistance plays a major role in the complex picture of the metabolic syndrome.

Adipokines are believed to act through their effects on insulin sensitivity, but new lines of evidence indicate an important action on stimulation/inhibition of the inflammatory process (12, 13, 14, 15, 16). Because activation of inflammatory mechanisms was found in adipose tissue (17), and it was proposed that inflammatory mechanisms are involved in the development of complications of obesity (18), it is possible that changes in the resistin concentration may be involved in the pathogenesis of NAFLD.

Therefore, the main aim of this study was to determine circulating resistin levels and resistin expression in adipose tissue from patients with NAFLD and to correlate resistin levels with insulin resistance and anthropometric variables, liver function, and histological features. We also correlate the serum concentration of resistin with circulating levels of high-sensitivity C-reactive protein (hs-CRP), which is a marker of systemic inflammation (19).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Twenty-eight NAFLD patients (26 men and two women) with a mean body mass index (BMI) of 27.3 ± 0.6 kg/m2 (range, 20.5–34.9 kg/m2) and 33 control subjects (30 men and three women females) with a mean BMI of 29.9 ± 1.0 kg/m2 (range, 20.3–34.7 kg/m2), matched for age, sex, and BMI, were included in the study. We also studied a group of 30 obese subjects (BMI, >30 kg/m2; range, 30.1–48.4 kg/m2) without ultrasound signs of liver steatosis and normal transaminase levels. All three groups had absent or negligible alcohol consumption (<20 g/d). Body weight and height were measured by standard techniques, and BMI was defined as the body weight in kilograms divided by the square of the height in meters.

The diagnosis of NAFLD was established based on chronic elevation of transaminase levels (>1.5 times the upper normal value for 3 months or longer), absence of hepatitis B and C virus markers, absence of autoantibodies indicative of autoimmune hepatitis (antinuclear, antismooth muscle, antiliver and -kidney microsomes, and antimitochondria autoantibodies) or celiac disease (antitransglutaminase autoantibodies), and bright liver at ultrasound scanning (2). Bright liver was defined as evident sonographic contrast between hepatic and renal parenchyma, vessel blurring, focal sparing, and narrowing of the lumen of the hepatic veins, according to international guidelines (20). In all patients, the diagnosis was confirmed by liver biopsy. The control group was comparable for age, weight, and sex and was free from hepatic diseases. Patients and controls had no history of malignancy. Patients and controls showing clinical and/or biochemical evidence of hypo- or hyperthyroidism, cortisol excess or deficiency, hypogonadism, GH deficiency and pituitary adenoma, or renal failure were also excluded. NAFLD was excluded based on normal transaminase values and normal liver ultrasound. Previously diagnosed diabetic patients, according to the American Diabetes Association classification, were excluded.

All patients were recruited in the outpatient clinic and were on an unrestricted dietary regimen. Body weight was stable during the 3 months preceding the study. A blood sample for determination of resistin, leptin, adiponectin, glucose, insulin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), {gamma}-glutamyl transpeptidase ({gamma}GT), alkaline phosphatase (ALP), total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol and triglycerides concentrations was collected between 0800–0900 h after an overnight fast. Plasma was immediately separated, frozen, and stored at –80 C until subsequent analysis. Written informed consent was obtained from all patients for blood sampling for resistin, leptin, and adiponectin measurements and for the anonymous use of their clinical data after illustration of the purpose of the study. All other investigations were carried out as standard procedures for the diagnosis and follow-up of NAFLD (2). The protocol was approved by the hospital ethics committee.

Pathology

Liver biopsies were stained with hematoxylin-eosin and were examined and scored by an experienced hepatopathologist (C.A.). All cases showed macrovesicular steatosis affecting at least 5% of hepatocytes. Pure fatty liver (n = 11) was defined as the presence of fat infiltration of the liver biopsy and was scored as grade 1 (5–33% of hepatocytes affected), grade 2 (33–66% of hepatocytes affected), or grade 3 (>66% of hepatocytes affected). Nonalcoholic steatohepatitis (NASH; n = 17) was defined as the presence of fat infiltration together with lobular inflammatory infiltrate and either ballooning cells or perisinusoidal/pericellular fibrosis in zone 3 of the hepatic acinus. Steatosis, fibrosis, and necroinflammatory scores were assigned according to the method described by Brunt et al. (21). The NASH score was calculated as the sum of the fibrosis and necroinflammatory scores (21).

Analytical procedures

AST, ALT, {gamma}GT, ALP, total, HDL and LDL cholesterol, and triglycerides were measured by automated enzymatic methods. Glucose was measured in triplicate by the glucose oxidase method (glucose analyzer, Beckman Instruments, Palo Alto, CA). Insulin and leptin were measured by RIA using commercially available kits (Linco Research, Inc., St. Charles, MO). Resistin was measured by ELISA using a commercially available kit (BioVendor, Heidelberg, Germany). The assay sensitivity was 1 ng/ml, and inter- and intraassay coefficients of variation were less than 10% and less than 5%, respectively. The assay was linear between 1 and 20 ng/ml. All patients’ samples were within this range, and no dilution of samples was needed. No cross-reactivity was detected against human resistin-like molecule-ß, leptin and leptin receptor, adiponectin, TNF{alpha}, IL-6, or agouti-related protein. hs-CRP was measured in serum using latex-enhanced immunonephelometric assays on a BN II analyzer (Dade Behring, Milan, Italy) as described previously (22).

Quantification of gene expression by real-time RT-PCR in adipose tissue

Resistin and adiponectin mRNA expression was assessed by quantitative RT-PCR in sc adipose tissue obtained by percutaneous needle biopsies of the gluteal region of a different set of lean (n = 9), obese (n = 9), and NAFLD (n = 10) subjects. These patients were comparable to the NAFLD patients, in whom serum resistin was measured, for gender, BMI, and clinical characteristics. Written informed consent was obtained from all patients. Total RNA was extracted with RNeasy lipid tissue mini kit (QIAGEN, Hilden, Germany) following the supplier instructions. Five hundred nanograms of RNA was treated with deoxyribonuclease treatment and removal reagents (Ambion, Inc., Austin, TX) and reverse transcribed for 1 h at 37 C in a 50-µl reaction containing 1x reverse transcriptase buffer, 150 ng random hexamers, 0.5 mM deoxy-NTPs, 20 U of RNasin ribonuclease inhibitor, and 200 U of Moloney murine leukemia virus reverse transcriptase (Promega Corp., Madison, WI). Oligonucleotide primers and probe for human resistin were designed using the OMIGA 2.0 program (Oxford Molecular Ltd., San Diego, CA). For adiponectin, 18S, and hydroxymethyl-bilane synthase (HMBS) mRNA quantification, primers were designed using OMIGA software (Oxford Molecular), and quantitative PCR was performed using SYBR Green PCR Master Mix (Applied Biosystems, Foster City, CA). PCR was carried out on DNA Engine Opticon TM 2 Continuous Fluorescence Detection System (MJ Research, Cambridge, MA), and all reactions were performed on at least two occasions. Standard curves for resistin and adiponectin amplification were constructed using 50 ng RNA reverse transcribed from peripheral blood mononuclear cells or adipose tissue of a healthy subject and serially diluted (1:3); standard curves for reference genes with 50 ng RNA reverse transcribed from adipose tissue of a normal subject serially diluted (1:10), by plotting values for log cDNA quantity (in arbitrary units) vs. cycle threshold. For each sample, results were normalized by HMBS and rRNA18S contents. Because normalization by the two housekeeping genes produced similar results, only data normalized by HMBS are reported in the results. Each sample was assayed in triplicate and a no-template control was included in every reaction. In a subgroup of patients in whom mRNA expression of resistin was measured (five NAFLD and four controls), serum resistin was also measured as described above.

Statistical analysis

Results are expressed as the mean ± SE. After testing data for normality of distribution, different groups were compared by ANOVA with Bonferroni correction. Correlations between different variables were analyzed by linear regression analysis and Spearman rank correlation to examine the relationship between serum resistin concentration and different continuous or categorical parameters in the whole population and separately in control, NAFLD, and obese groups, using MDAS 2.0 (Medical Data Analysis System) software package (EsKay Software, Pittsburgh, PA). P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Anthropometric, clinical, and biochemical parameters of NALFD and obese patients and controls are illustrated in Table 1Go. No significant differences were observed in fasting glucose, whereas insulin and homeostasis model assessment (HOMA) were significantly higher in NAFLD patients compared with control subjects. Triglycerides were significantly higher in NAFLD patients, whereas total and LDL cholesterol were slightly, but not significantly, higher in NAFLD patients (Table 1Go). No difference was found in HDL cholesterol. Plasma adiponectin was significantly reduced in NAFLD patients, but no significant difference was found in leptin concentrations (Table 1Go).


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  		TABLE 1. Anthropometric, clinical, and biochemical characteristics of NAFLD and control subjects

 
Serum resistin was higher in NAFLD patients compared with both controls (5.87 ± 0.49 vs. 4.30 ± 0.20 ng/ml; P = 0.002) and obese patients (4.37 ± 0.27 ng/ml; P = 0.007). When NAFLD patients were divided according to liver histology (pure fatty liver vs. NASH), significantly higher resistin levels were found in patients with steatohepatitis than in those with pure fatty liver (Fig. 1Go).


Figure 1
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  		FIG. 1. Plasma resistin in patients with NAFLD and control subjects (A) and in NAFLD patients divided according to histological diagnosis (pure steatosis vs. steatohepatitis; B). Data are expressed as the mean ± SEM. *, P < 0.001 vs. control. #, P = 0.01 vs. pure steatosis.

 
When simple regression analysis was performed between serum resistin (dependent variable) and age, BMI, and a number of biochemical variables (glucose; insulin; HOMA; total, LDL, and HDL cholesterol; triglycerides; AST; ALT; {gamma}GT; ALP; leptin; and adiponectin), no significant correlation was found for any of the variables.

Moreover, no correlation was found between hs-CRP (dependent variable) and resistin, adiponectin, or leptin (independent variables). A significant direct correlation was found between hs-CRP and BMI (r = 0.45; P < 0.01), whereas no correlation was found with the HOMA index (r = 0.08; not significant).

Quantitative PCR analysis revealed that adiponectin expression was significantly reduced in sc adipose tissue of NAFLD and obese patients compared with controls, whereas resistin mRNA expression was significantly up-regulated only in NAFLD patients compared with controls (Fig. 2Go). Among the subgroup of subjects in whom adipose tissue resistin mRNA was measured, serum resistin levels in NAFLD patients (n = 5) tended to be higher than control values (n = 4; 6.60 ± 0.73 vs. 4.60 ± 0.70 ng/ml; P = 0.06).


Figure 2
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  		FIG. 2. Adiponectin and resistin mRNA expression in sc adipose tissue of NAFLD patients ({blacksquare}), obese subjects (dashed bars) and control subjects ({square}). Data are expressed as the mean ± SEM. *, P < 0.01; #, P < 0.05 (vs. controls).

 
Univariate correlation analysis revealed that serum resistin was correlated with the histological NASH score, whereas no correlation was found with the steatosis score (Table 2Go).


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  		TABLE 2. Spearman rank correlation between serum resistin and histological scores in NAFLD patients

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study essentially shows that NAFLD patients have increased circulating resistin and that increased levels are not correlated to either insulin resistance or BMI, but only to the histological severity of the disease. Moreover this study shows that NAFLD patients have reduced plasma levels of adiponectin associated with reduced expression of adiponectin in adipose tissue, thus enforcing the findings of previous studies that reported that alteration of circulating levels of this adipokine is present in this condition (23, 24). We extended resistin measurements to obese subjects in whom NAFLD was excluded based on ultrasound scanning and normal transaminase values. In these subjects we found resistin levels comparable to those in the control group, suggesting that excess weight and whole body insulin resistance, as assessed by the HOMA index, are not linked to high resistin levels.

The relationship between resistin and BMI and insulin resistance is under debate in humans. Serum resistin was found by some researchers to be increased in obesity and to be positively correlated with BMI or body fat (25, 26, 27, 28, 29), but this observation was not confirmed by other studies (30, 31, 32, 33, 34). In contrast, resistin was found to be related to insulin resistance and to be increased in type 2 diabetes (25, 30, 33, 34), but other studies did not confirm this association (27, 28, 31, 32, 35, 36). Our results do not support an association between high resistin levels and obesity or insulin resistance as assessed by the HOMA index. Based on our results, we speculate that the presence or absence of NAFLD could help to explain the inconstant association between obesity/diabetes and high resistin levels. In fact, we recently reported that serum resistin is increased in patients with Prader-Willi syndrome, a disorder characterized by various degrees of obesity and a very frequent finding of NAFLD (37). Our hypothesis is also supported by data recently reported by Bajaj et al. (35, 38), who showed that serum resistin correlated with hepatic fat content and hepatic insulin resistance, but not with peripheral insulin resistance measured by the euglycemic hyperinsulinemic clamp, in type 2 diabetic patients. In fact, a major target organ of resistin is the liver, where resistin induces insulin resistance and increases glucose production. This concept was supported by experiments in rodents that clearly showed major roles for resistin in hepatic glucose metabolism and the pathogenesis of diet-induced hepatic insulin resistance (11, 39, 40, 41). Moreover, chronic hyper- resistinemia produced by adenovirus infection reduces phosphorylation of insulin receptor substrate-2, AMPK-activated protein kinase, and Akt in mouse liver (9). However, the hypothesis of a link between resistin and hepatic insulin resistance needs additional confirmation in humans.

To our knowledge this is the first demonstration of increased resistin levels in NAFLD patients whose diagnosis was based on histological findings. It is interesting to note that control and NAFLD groups had similar BMI and age, and both groups were similarly overweight. Despite this, NAFLD patients had increased serum resistin and were more insulin resistant than controls, although the regression analysis did not demonstrate any correlation between resistin and BMI or HOMA index. However, because the HOMA index reflects both peripheral and hepatic insulin resistance, it is possible that the lack of correlation between resistin and HOMA may not necessarily reflect a lack of association between resistin and hepatic insulin resistance.

We found higher resistin levels in patients with histological diagnosis of NASH than in those with pure fatty liver, and a positive correlation was found with the NASH score, an index that takes into account necrosis, inflammation, and fibrosis in liver biopsies and reflects the severity of the disease, whereas no correlation was found between resistin and the steatosis score, an index of liver fat content. Based on this finding, the present study is in agreement with the hypothesis that resistin may play a role in the progression of natural history of NAFLD. However, it is also possible that portal resistin concentration and the regulation of a putative resistin receptor(s) in the liver may also be relevant for the putative deleterious effects of resistin on liver.

Because the pathogenesis of NAFLD was postulated to also involve inflammatory mechanisms, and resistin displays proinflammatory properties (15), we were interested to evaluate whether higher serum resistin levels were associated with the systemic inflammation frequently found in the metabolic syndrome. hs-CRP is a reliable marker of systemic inflammation and was reported to be related to adipokines and to be a weak predictor of NAFLD (42, 43). In our study, hs-CRP levels were similar in NAFLD and control groups. Moreover, no correlation was found between resistin and hs-CRP or white cells count (data not shown), supporting the concept that higher resistin levels are not linked to systemic inflammation in NAFLD patients. On the contrary, a positive correlation was found between hs-CPR and BMI and leptin, confirming a previous report of a positive association between CRP and adiposity in healthy men (44) and in a wider population including different ethnic groups with different degrees of glucose tolerance (45). Therefore, at least in our NAFLD population, resistin is not linked to systemic low-grade inflammation, and based on these results, it is not possible to sustain its role in the complications of the metabolic syndrome. However the positive correlation between resistin and the NASH score suggests that resistin, through mechanisms that do not include systemic inflammation and largely remain to be determined, may be involved in the pathogenesis or progression of NAFLD.

Resistin is also produced also by cells of the immune system, as previously reported by our laboratory (46). Moreover, evidence is accumulating to indicate that resistin has potent proinflammatory properties in vivo, in part through the stimulation of IL-6 and TNF{alpha} (15). Both IL-6 and TNF{alpha} are increased in blood of NAFLD patients, and their levels improve with lifestyle modification together with improvement of liver damage (47). Therefore, it is possible that resistin may participate in the pathways underlying liver damage and the progression of pure fatty liver to NASH and fibrosis (48). Furthermore, we cannot rule out the possibility that increased resistin in NAFLD patients may come from increased production in immune and inflammatory cells. Finally, because hepatic stellate cells produce a variety of cytokines (49), it may be that elevated circulating resistin levels reflect increased resistin production by these cells inside the liver.

The inconstant link among serum resistin, obesity, and insulin resistance could also be explained by genetic factors. In fact, it has been reported that a genetic polymorphism in the promoter region of the resistin gene may be an independent predictor of circulating resistin in humans (38, 50). Hence, it is not possible to exclude that a gene polymorphism(s) may be responsible for the high resistin levels in NAFLD patients.

Other relevant issues should be considered when interpreting results of resistin assays. A major issue will be understanding the specificity of currently available assays, which may recognize different forms of resistin or react with low- and high-molecular weight polymers with different affinity (51). Moreover, an alternative splice variant of the resistin gene is present in human tissues that predicts a shorter protein (26 amino acids missing) that might circulate together with full-length resistin (52). These issues could explain the discrepancy between results of the different studies.

In conclusion, our study reported higher resistin levels in serum of NAFLD patients that were not correlated to insulin resistance and adiposity and confirms previous data on low circulating adiponectin in NAFLD patients due to lower expression in adipose tissue. Although the precise molecular mechanisms still need to be clarified, the present study supports a role for these two adipokines in the link between adipose tissue and fatty liver disease.


   Footnotes
 
First Published Online January 4, 2006

Abbreviations: ALP, Alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; {gamma}GT, {gamma}-glutamyl transpeptidase; HDL, high-density lipoprotein; HMBS, hydroxymethyl-bilane synthase; HOMA, homeostasis model assessment; hs-CRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.

Received May 12, 2005.

Accepted December 27, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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