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��ࡱ�>��	�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������y�����bjbj��	:��{�{�a5�������������***8bnT*�Z��4������%�'�'�'�'�'�'�$x��*�~K���!���!�!K����ء�F�F�F�!���%��F�!%��F�FnIfAi�����p%o��������?~Qg ��0�qg���.Df��@Ai,mip���j46�����Fs������K�K��EZ�����!�!�!�!�������������������������������������������������������������������������������� �:INCREASED COMPLEMENT C3 PROTEIN EXPRESSION IN LIVER TISSUE IN 
NONALCOHOLIC STEATOHEPATITIS

Subheading: Increased C3 Expression in NASH

Zulfukar Polat1, Fatih Tangi2, Rahsan I. Sagkan3, Ugur Musabak3, H. Cem Gul4, Ayhan Ozcan5, Cagatay Oktenli6

1Department of Gastroenterology, G�lhane Military Medical Academy, Ankara, TURKEY
2Division of Internal Medicine, GATA Haydarpasa Training Hospital, Istanbul, TURKEY
3Department of Immunology and Allergic Diseases, G�lhane Military Medical Academy, Ankara, TURKEY
4Department of Infectious Diseases and Clinical Microbiology, G�lhane Military Medical Academy, Ankara, TURKEY
5Department of Pathology, G�lhane Military Medical Academy, Ankara, TURKEY
6Department of Internal Medicine, Anadolu Medical Center, Kocaeli, TURKEY




Corresponding Author
Prof. Cagatay Oktenli, MD.
Department of Internal Medicine, Anadolu Medical Center, TR-41400 Kocaeli/Turkey 
E-mail: cagatay.oktenli@anadolusaglik.org or coktenli@yahoo.com
Tel: +90 216 5471122; Fax: +90 216 3179503
Abstract
Backround: Although we previously suggested both acylation stimulating protein and complement 3 was found to be increased in patients with nonalcoholic fatty liver disease, it is not clear whether the main source of elevated circulating complement 3 and acylation stimulating protein levels is the liver or is adipose tissue. Therefore, we aimed to find differences in protein expression of acylation stimulating protein, complement 3 and adipsin in liver biopsy specimens between patients with nonalcoholic steatohepatitis and type B chronic viral hepatitis by Western blot analysis.
Methods: Forty-one male patients with histologically proven nonalcoholic steatohepatitis and 11 male patients with type B chronic viral hepatitis were recruited. All patients included in the present study underwent a percutaneous liver biopsy under ultrasonic guidance. Liver samples were divided two pieces, one of them was processed for routine diagnostic histology. The other specimen washed in cold phosphate buffer saline and it was quickly frozen and stored at -80�C until use for western blot analysis.
Results: There is no differences in acylation stimulating protein expression between patients with nonalcoholic steatohepatitis and type B chronic viral hepatitis. Increased complement 3 protein expression was observed in patients with nonalcoholic steatohepatitis. Lastly, we were unable to display any signal for adipsin.
Conclusions: We observed higher complement 3 protein expression in liver tissue in patients with nonalcoholic steatohepatitis as compared to type B chronic viral hepatitis patients. acylation stimulating protein expression was not differ between the patients with nonalcoholic steatohepatitis and type B chronic viral hepatitis, suggesting no direct effect of acylation stimulating protein on pathogenesis of nonalcoholic steatohepatitis.
Key Words: Acylation stimulating protein, adipsin, complement 3, nonalcoholic steatohepatitis 
Introduction

Nonalcoholic fatty liver disease (NAFLD) is a rapidly growing entity and it is an important cause of chronic liver injury [1,2]. Nonalcoholic steatohepatitis (NASH) is considered part of a spectrum of NAFLD, ranging in severity from simple steatosis to steatohepatitis with necroinflammation and progressive fibrosis [3-5].
Acylation stimulating protein (ASP) is a small (8.9-kDa), basic 76-amino-acid long peptide identical to C3adesArg, and is generated by post-translational modification of its precursor protein third component of complement (C3) through combined action of adipsin, and cofactor B [6-8]. The ASP stimulates reesterification of FFA into triglycerides and storage them in fat cells by increasing fatty acid and glucose uptake [9,10]. ASP stimulates free fatty acid esterification to form triglycerides by activating diacylglycerol acyltransferase [11] and supresses lipolysis via inhibiton of hormone sensitive lipase [12].
Accumulating data suggested elevated fasting plasma ASP concentrations in obese subjects [12,13]. Likewise, ASP, C3, factor B and adipsin were shown to be increased in type 2 diabetic men, which probably contributes to increased ASP levels [14]. However,  even in the absence of obesity, both ASP and its precursor C3 have been reported to be increased in diabetes [15], cardiovascular disease [16], nephrotic syndrome [17], NAFLD [2], thyroidal dysfunction [18] and PCOS [19]. In an experimental study, ASP administration has been shown to facilitate lipid and glucose clearance in mice [20]. ASP may be of clinical significance in NAFLD because elevations of fatty acids, particularly in the postprandial phase, the period in which most fatty acid flux to the liver occurs [2]. In this way, impaired ASP activity could decrease adipose tissue efficiency to clear postprandial dietary fat, exposing key tissues such as muscle and liver to lipotoxicity [21,22]. Recently, Rensen et al. suggested a widespread activation of the complement system in NAFLD [23]. In a previous study, although we suggested both ASP and C3 was found to be increased in patients with NAFLD [2], it is not clear whether the main source of elevated circulating C3 and ASP levels is the liver or is adipose tissue. Therefore, we aimed to find differences in protein expression of ASP, C3 and adipsin in liver biopsy specimens between patients with NASH and type B chronic viral hepatitis by Western blot analysis.




Materials and Methods

Forty-one male patients with histologically proven NASH and 11 male patients with type B chronic viral hepatitis were recruited in the study from the Gastroenterology and Infectious Diseases and Clinical Microbiology departments at the G�lhane Military Medical Academy Hospital (Ankara, Turkey). All patients included in the present study underwent a percutaneous liver biopsy under ultrasonic guidance. Liver samples were divided two pieces, one of them was processed for routine diagnostic histology. The other specimen washed in cold phosphate buffer saline (PBS) and it was quickly frozen and stored at -80�C until use for western blot analysis. An independent pathologist who was unaware of the clinical data of patients made the histological diagnostic. In patients with with type B chronic hepatitis (group 1), the histopathological findings of liver biopsy specimens showed varying degrees of portal inflammation and parenchymal injury without advanced fibrosis and/or cirrhosis. Use of interferon or antiviral treatment within last one month was excluded. Patients with type B chronic hepatitis who had > 5% steatosis in biopsy specimens were also excluded. The pathologist reviewed and scored the liver biopsy specimens according to the necroinflammatory (NIA) grading system for steatohepatitis (group 2), and defined as grade 1 (mild), grade 2 (moderate), and grade 3 (severe) steatohepatitis [9]. The liver specimens were also scored histologically with the NASH scoring system defined by the Pathology Committee of the NASH Clinical Research Network [10]. Each subject gave his informed consent to the study, which was previously approved by our local ethics committee and institutional review board.
Patients who reported a history of hypertension, diabetes, pancreatic, pulmonary, chronic inflammatory, malignant and vascular diseases, gastrointestinal surgical procedures, infectous diseases, current smoking were excluded. None of the patients had ingested drugs such as statins, fibrate, oxacillin, tetracycline, chloroquine, sulfasalazine, methotrexate, nonsteroid anti-inflammatory drugs, corticosteroids, amiodarone, calcium channel blockers or spironolactone. Alcohol consumption (>20 g per day) was also an exclusion criterion from the study. All patients had normal renal and thyroid functions and they underwent detailed laboratory tests for rue out other causes of liver disorder such as autoimmune hepatitis, sclerosing cholangitis or primary biliary cirrhosis, hemochromatosis, and genetic liver diseases. 
Venous blood samples were obtained for laboratory analyses, after an overnight fast. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting serum glucose, total cholesterol, HDL-cholesterol and triglyceride levels were evaluated with a spectrophotometric technique by the Olympus AU-2700 autoanalyzer using commercial kits (Olympus, Hamburg, Germany). Low-density lipoprotein (LDL) cholesterol was calculated by Friedewald�s formula. Plasma high sensitivity C-reactive protein (hs-CRP) and insulin levels were determined with a chemiluminoassay technique by the Immulite 2000 hormone autoanalyzer using commercial kits (Bio-DPC, Los Angeles, CA, USA). BMI was calculated as weight (kilograms) divided by height (meters) squared. The estimate of insulin resistance by homeostasis model assessment for insulin resistance (HOMA-IR, %) was calculated from fasting plasma insulin and glucose levels as (insulin (microunits per milliter) x glucose (millimoles per liter))/22.5. 



Western blot analysis
Coronary atherosclerotic plaque specimens from patients corresponding to the two different patient groups (group A and B) were pooled for Western blot analysis. The samples were washed with PBS and then lysed in homogenization buffer [50 mM Tris-HCL, pH 8.0; 0.25% (w/v) SDS; 1% (w/v) Nonidet P40 [NP40]; 1 mM (w/v) paramethylsulfonide [PMSF]; 150 mM (w/v) NaCl; 1X protease inhibitor cocktail]. Collected proteins measured using Qubit Fluorometer (Invitrogen, Carlsbad, CA, USA). Approximately, 65 �g/ml of protein samples loaded to gel. Proteins were separated on NuPAGE 4-12% Bis-Tris Gel (Invitrogen, Carlsbad, CA, USA). Proteins were transferred by dry-blotting via Cu ions (iBlot Gel Transfer Stacks to a PVDF membrane) (Invitrogen, Carlsbad, CA, USA). Adipsin (1/200), C3 (1/200) and �-actin (1/200) were detected using the mouse monoclonal antibodies (Santa Cruz Biotechnology, Santa Cruz, CA, USA) and we also used ASP (1/5000) which is a mouse monoclonal antibody against human peptide with aminoacid sequence RASHLGLA which is located in C-terminal part of the human ASP (BioVendor, Candler, NC, USA) as primary antibodies. Detected with an alkaline phosphatase-conjugated mouse anti-mouse IgG secondary antibody using a Western Breeze Immunodetection System (Invitrogen, Carlsbad, CA, USA). The signals from the Western blots were normalized to the constitutive �-actin control. We showed that adipsin:b-actin, ASP:b-actin and C3:b-actin ratios, as determined by densitometric scanning of signals from two groups. Quantum-Capture Software was used for the densitometric analyses.








RESULTS


The mean age of patients with NASH was 38.89 � 4.21 years; (range 29-50), while it was 21.32 � 1.56 years; (range 20-24) in patients with type B chronic viral hepatitis. In Table 1, the mean levels and comparisons of parameters between the groups were given. The mean levels of BMI, HOMA-IR, LDL and triglyceride were significantly higher in patients with NASH than patients with type B chronic viral hepatitis, whereas hs-CRP was found to be high in type B chronic viral hepatitis patients as compared with NASH patients. ALT and AST did not significantly differ between the groups. 
Histopathologic examination of liver biopsies revealed that 36 of the patients with NASH (88 %) had grade 1 and 5 patients (12 %) had grade 2 steatohepatitis according to the NIA grading system,. There is no patient in grade 3. According to NASH scoring system, there is 2 patients in NASH Score 1; 3 patients in NASH Score 2; 17 patients in NASH Score 3; 14 patients in NASH Score 4; 3 patients in NASH Score 5 and 2 patients in NASH Score 6.
Liver biopsy specimens from patients corresponding to the two different groups were pooled for Western blot analysis. There is no differences in ASP protein expression between group 1 and group 2 (Figure 1). Increased C3 protein expression was observed in group 2 (Figure 2). Lastly, we were unable to display any signal for adipsin (Figure 3).






Discussion

The current report is the first to determine differences in protein expression of ASP and, its precursors, C3 and adipsin by Western blot analysis in liver biopsy specimens between patients with NASH and type B chronic viral hepatitis. The main finding of our study is, in NASH, increased C3 protein expression in liver tissue as compared to type B chronic viral hepatitis patients. Interestingly, there is no differences in ASP protein expression between the groups. Conversely, we suggested previously both ASP and C3 was found to be increased in patients with NAFLD as compared with chronic viral hepatitis patients [2]. In that study, we speculated the most likely reason for increased fasting ASP levels in patients with NAFLD is resistance at the level of adipose tissue for ASP rather than hepatic overproduction[2]. Present data support the our previous idea and are in line with previous finding that ASP seems to have little direct effect on the liver [26]. Adipsin is a unique member of the alternative pathway of complement and adipose tissue is the major source of plasma adipsin [6]. Although it is well known that human hepatocytes produce significant amounts of adipsin [27], we were unable to display any signal for adipsin in liver biopsy specimens in our patients. In addition, adipsin is not only a factor for generation of ASP, but also it is necessary for conversion of C3 to ASP [12]. In spite of the increased expression of C3, an important precursor of ASP, there is no differences in ASP protein expression between the groups. Speculatively, although the physiological mechanisms behind this remain unclear, this may be due to lack of adipsin in liver tissue specimens.
Although, we observed increased C3 protein expression in liver tissue in patients with NASH, we unable to determine whether this increment is a cause or a consequence of NASH. Liver is the major source of circulating C3; macrophages and adipocytes also secrete C3 [28]. Previously, we observed plasma C3 levels are also higher in patients with NAFLD [2], alanine aminotransferase was reported to be associated with plasma levels of C3 [29]. In a recent study, complement factors play an crucial role in clearance of apoptotic cells, hepatic fibrosis, and liver regeneration in the pathogenesis and progression of NAFLD [23]. In addition, there is different and intercepting roles for complement in protection and regeneration of liver [30,31]. Moreover, overexpressed C3 gene was also demonstrated in NASH and it may contribute to impaired insulin sensitivity [32]. It is also well known that insulin increases the production of C3 in adipocytes [33-35]. Moreover, it has been proposed that there is a direct links between insulin resistance and C3 production in hepatic and adipose tissue [36]. Likewise, obesity are known to have an elevated fasting C3 concentration [37] and weight gain is associated with an increase in C3 [38]. Not surprisingly, BMI and HOMA-IR, a marker for insulin sensitivity, was found to be high in NASH patients as compared with chronic viral hepatitis group. Obesity, along with insulin resistance in NASH group, it could be hypothesized that increased liver tissue C3 expression in NASH is related with increased fat mass and insulin resistance. However, whether this relation is simply attributable to an increased secretion of C3 from increased fat mass or due to secondary mechanisms involving C3 synthesis in hepatocytes remains to be established in detail. 
The current study had a number of limitations need to be mentioned. First, the sample size of this study was small. Second, localization or origin of C3 and adipsin in liver biopsy specimens are unknown. Therefor, the detection of the localization of these proteins in immunohistochemical studies, would be much more convincing. Third, since the current study was perfomed in both patients with NASH and type B chronic viral hepatitis, it cannot be readily generalized to individuals without chronic hepatitis. Finally, as all patients were men in the current study, whether these conclusions can be extended to women awaits confirmation in sex-matched studies. 
	In conclusion, we observed higher C3 protein expression in liver tissue in patients with NASH as compared to type B chronic viral hepatitis patients. ASP protein expression was not differ between the patients with NASH and type B chronic viral hepatitis in the present study, suggesting no direct effect of ASP on pathogenesis of NASH. 


Acknowledgements

This study was supported by grant from the Research Center of G�lhane Military Medical Academy. The authors of this manuscript would like to dedicate this work to Prof. Zeki Yesilova, whose unexpected loss in the course of study is not replaceable.


Disclosure statement
	Authors of this study have no interest which might be perceived as posing a conflict or bias.










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35. Scantlebury T, Sniderman AD, Cianflone K. (2001) Retinoic acid regulation of acylation stimulating protein (ASP) and complement C3 in human adipocytes. Biochem J 356: 445-452.
36. Weyer C, Tataranni PA, Pratley RE. (2000) Insulin action and insulinemia are closely related to the fasting complement C3, but not acylation stimulating protein concentration. Diabetes Care  23: 779-785.
37. Pomeroy C, Mitchell J, Eckert E, Raymond N, Crosby R, et al. (1997) Effect of body weight and caloric restriction on plasma complement proteins, including factor D, adipsin: studies in anorexia nervosa and obesity. Clin Exp Immunol 108: 507-515.
38. Onat A, Can G, Rezvani R, Cianflone K. (2011) Complement C3 and cleavage products in cardiometabolic risk. Clin Chim Acta 412: 1171-1179.





















Figure Legends

Fig 1. Western blot analysis of protein level for ASP (M, marker). For quantification of ASP protein content, the ratio of ASP and �-actin band densities of group 1 and group 2 samples of liver.

Fig 2. Western blot analysis of protein level for C3 (M, marker). For quantification of C3 protein content, the ra��ǵ������������������?�@�J�L�`�o�p�w�������̷ͷ����������������������������������Ⱥ�����������voh�o�o�hQr�h�.�h�\Ph�.�h�d�5�mH	sH	h�.�5�mH	sH	h�pCh�fNh�.�h�.�h;'
h�.�h�.�5�B*mH	ph333sH	h�pC5�B*mH	ph333sH	hz�5�B*mH	ph333sH	h�pCB*mH	ph333sH	ht�ht+hUy6ht+h�c�ht+hRZ	ht+6�h�c�hUy6ht�hUy6(K�L�M�N�O�P�Q�R�S�T�U�V�W�X�Y�Z�[�\�]�^�_�`�o�p���������L�����������������������������
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h�.�h�d�5�B*mH	ph333sH	h�huh�.�mH	sH	h�d�Uh�.�h�\Ph�.�tio of C3 and �-actin band densities of group 1 and group 2 samples of liver.

Fig 3. Western blot analysis of protein level for Adipsin in liver samples (M, marker)















Table legend

Table 1. The Mean Levels and Comparisons Results of Parameters Between the Groups














PAGE  38




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