Concentrations of Connective Tissue Growth Factor in Patients with Nonalcoholic Fatty Liver Disease: Association with Liver Fibrosis

Çolak, Yaşar; Şenateş, Ebubekir; Çoşkunpınar, Ender; Oltulu, Yasemin Müşteri; Zemherı, Ebru; Öztürk, Oğuzhan; Doganay, Levent; Mesçi, Banu; Yilmaz, Yusuf; Enç, Feruze Yılmaz; Kızıltaş, Şafak; Ulaşoğlu, Celal; Tuncer, İlyas

doi:10.1155/2012/283726

Cited by 14 publications

(13 citation statements)

References 21 publications

(24 reference statements)

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“…CTGF-positive cell number is the best candidate to monitor the disease progress among the selected biochemical, histological and immunostaining parameters, showing a steady increase with comparatively little variance (among top ANOVA results, p adj = 7.9E-10). This is consistent with data from other studies, which observed a correlation of increased CTGF levels with histological fibrosis stages [ 34 , 35 ]. Since CTGF can be measured in patients’ blood, it was suggested as valuable diagnostic marker with potential application in the follow-up of patients suffering from chronic liver diseases [ 36 ].…”

Section: Resultssupporting

confidence: 93%

Pathobiochemical signatures of cholestatic liver disease in bile duct ligated mice

et al. 2015

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BackgroundDisrupted bile secretion leads to liver damage characterized by inflammation, fibrosis, eventually cirrhosis, and hepatocellular cancer. As obstructive cholestasis often progresses insidiously, markers for the diagnosis and staging of the disease are urgently needed. To this end, we compiled a comprehensive data set of serum markers, histological parameters and transcript profiles at 8 time points of disease progression after bile duct ligation (BDL) in mice, aiming at identifying a set of parameters that could be used as robust biomarkers for transition of different disease progression phases.ResultsStatistical analysis of the more than 6,000 data points revealed distinct temporal phases of disease. Time course correlation analysis of biochemical, histochemical and mRNA transcript parameters (=factors) defined 6 clusters for different phases of disease progression. The number of CTGF-positive cells provided the most reliable overall measure for disease progression at histological level, bilirubin at biochemical level, and metalloproteinase inhibitor 1 (Timp1) at transcript level. Prominent molecular events exhibited by strong transcript peaks are found for the transcriptional regulator Nr0b2 (Shp) and 1,25-dihydroxyvitamin D(3) 24-hydroxylase (Cyp24a1) at 6 h. Based on these clusters, we constructed a decision tree of factor combinations potentially useful as markers for different time intervals of disease progression. Best prediction for onset of disease is achieved by fibronectin (Fn1), for early disease phase by Cytochrome P450 1A2 (Cyp1a2), passage to perpetuation phase by collagen1α-1 (Col1a1), and transition to the progression phase by interleukin 17-a (Il17a), with early and late progression separated by Col1a1. Notably, these predictions remained stable even for randomly chosen small sub-sets of factors selected from the clusters.ConclusionOur detailed time-resolved explorative study of liver homogenates following BDL revealed a well-coordinated response, resulting in disease phase dependent parameter modulations at morphological, biochemical, metabolic and gene expression levels. Interestingly, a small set of selected parameters can be used as diagnostic markers to predict disease stages in mice with cholestatic liver disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-015-0229-0) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 93%

Pathobiochemical signatures of cholestatic liver disease in bile duct ligated mice

et al. 2015

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“…Nevertheless, this possibility might be verified by a study examining levels of Hsp47 mRNA in liver biopsies at various stages of fibrosis. In addition, a few studies utilized IHC and ELISA (enzyme-linked immunosorbent assay), and revealed that TGF- β 1 and CTGF were up-regulated in hepatic fibrosis induced by hepatitis B virus infection, hepatitis C virus infection and non-alcoholic fatty liver (Kanzler et al 2001; Lu et al 2003; Colak et al 2012). In our opinion, quantitative evaluation of mRNA levels in liver specimens was helpful to investigate their correlation with the progression of CS.…”

Section: Discussionmentioning

confidence: 99%

Expression of heat shock protein 47, transforming growth factor-beta 1, and connective tissue growth factor in liver tissue of patients with Schistosoma japonicum-induced hepatic fibrosis

Huang

et al. 2014

Parasitology

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SUMMARYTo detect the expression of pro-fibrotic molecules, such as heat shock protein 47 (Hsp47), transforming growth factor-beta 1 (TGF-β1) and connective tissue growth factor (CTGF) in liver specimens, and analyse their correlations with the progression of schistosomal hepatic fibrosis, liver biopsy was performed in 42 chronic schistosomiasis (CS) patients, 16 chronic hepatitis B (CHB) patients and five healthy individuals (HI). Immunohistochemistry (IHC) analyses displayed that the expression of Hsp47, TGF-β1 and CTGF was increased in CS and CHB patients compared with HI. Using real-time PCR, the mRNA levels of Hsp47, TGF-β1 and CTGF were higher in CS patients compared with HI. In CS patients, the mRNA levels of these genes were correlated with the stage of fibrosis, and TGF-β1 mRNA expression was associated with the grade of inflammation. Additional analyses indicated that the mRNA levels of Hsp47 and CTGF were highly correlated with liver stiffness value and spleen thickness diameter, both of which represented the severity of fibrosis. In conclusion, the three molecules are involved in the pathogenesis of hepatic fibrosis infected by Schistosoma japonicum. TGF-β1 participates not only in the inflammatory process, but also in the fibrotic process in which Hsp47 and CTGF probably play a key role.

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“…CTGF is a central mediator of TGFβ-dependent fibrogenesis. Expression has been found to be elevated in liver biopsies from NASH patients and serum levels have been found to be positively correlated with fibrosis stage in NAFLD patients, thus underlining a key role in disease and potential application as biomarker [67][68][69]. CTGF is induced by IL-13, supporting a link between chronic inflammatory signaling and the promotion of fibrosis that is possibly independent of TGFβ-induced signaling [44,70].…”

Section: Growth Factorsmentioning

confidence: 94%

Hepatic Stellate Cell Activation and Inactivation in NASH-Fibrosis—Roles as Putative Treatment Targets?

2021

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Hepatic fibrosis is the primary predictor of mortality in patients with non-alcoholic steatohepatitis (NASH). In this process, the activated hepatic stellate cells (HSCs) constitute the principal cells responsible for the deposition of a fibrous extracellular matrix, thereby driving the hepatic scarring. HSC activation, migration, and proliferation are controlled by a complex signaling network involving growth factors, lipotoxicity, inflammation, and cellular stress. Conversely, the clearance of activated HSCs is a prerequisite for the resolution of the extracellular fibrosis. Hence, pathways regulating the fate of the HSCs may represent attractive therapeutic targets for the treatment and prevention of NASH-associated hepatic fibrosis. However, the development of anti-fibrotic drugs for NASH patients has not yet resulted in clinically approved therapeutics, underscoring the complex biology and challenges involved when targeting the intricate cellular signaling mechanisms. This narrative review investigated the mechanisms of activation and inactivation of HSCs with a focus on NASH-associated hepatic fibrosis. Presenting an updated overview, this review highlights key cellular pathways with potential value for the development of future treatment modalities.

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Concentrations of Connective Tissue Growth Factor in Patients with Nonalcoholic Fatty Liver Disease: Association with Liver Fibrosis

Cited by 14 publications

References 21 publications

Pathobiochemical signatures of cholestatic liver disease in bile duct ligated mice

Pathobiochemical signatures of cholestatic liver disease in bile duct ligated mice

Expression of heat shock protein 47, transforming growth factor-beta 1, and connective tissue growth factor in liver tissue of patients with Schistosoma japonicum-induced hepatic fibrosis

Hepatic Stellate Cell Activation and Inactivation in NASH-Fibrosis—Roles as Putative Treatment Targets?

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