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Identification of serum insulin-like growth factor binding protein 1 as diagnostic biomarker for early-stage alcohol-induced liver disease.

Li HH, Doiron K, Patterson AD, Gonzalez FJ, Fornace AJ - J Transl Med (2013)

Bottom Line: Most notably, the Igfbp1 (Insulin-Like Growth Factor Binding Protein 1) was selected as the best candidate gene for early detection of liver damage since it showed early and continuously enhanced induction during the treatment course.Consistent with the microarray data, both Igfbp1mRNA expression in the liver tissue and the IGFBP1 serum protein levels showed progressive and significant increases over the course of pre-ALD development.The results suggest that in conjunction with other tests, serum IGFBPI protein could provide an easily measured biomarker for early detection of alcohol-induced liver injury in humans.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, 3970 Reservoir Road, NW, New Research Building, Room E504, Washington, DC 20057, USA. af294@georgetown.edu.

ABSTRACT

Background: Alcohol consumption is a major cause of liver disease in humans. The use and monitoring of biomarkers associated with early, pre-clinical stages of alcohol-induced liver disease (pre-ALD) could facilitate diagnosis and treatment, leading to improved outcomes.

Methods: We investigated the pathological, transcriptomic and protein changes in early stages of pre-ALD in mice fed the Lieber-Decarli liquid diet with or without alcohol for four months to identify biomarkers for the early stage of alcohol induced liver injury. Mice were sampled after 1, 2 and 4 months treatment.

Results: Pathological examination revealed a modest increase in fatty liver changes in alcohol-treated mice. Transcriptomics revealed gene alterations at all time points. Most notably, the Igfbp1 (Insulin-Like Growth Factor Binding Protein 1) was selected as the best candidate gene for early detection of liver damage since it showed early and continuously enhanced induction during the treatment course. Consistent with the microarray data, both Igfbp1mRNA expression in the liver tissue and the IGFBP1 serum protein levels showed progressive and significant increases over the course of pre-ALD development.

Conclusions: The results suggest that in conjunction with other tests, serum IGFBPI protein could provide an easily measured biomarker for early detection of alcohol-induced liver injury in humans.

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Two dimensional clustering of differential genes in livers of alcohol-treated mice compared to liquid-diet control. (A) Two dimensional clustering of differential genes in livers of alcohol-treated mice compared to liquid-diet control. Treatments for three time points are displayed, one-, two-, four-month. This clustering was derived from the ratio (treated/control) data. Red and green represented the levels of induction and repression of a particular gene respectively. The patterns of change were similar at two- and four-months. (B) Ingenuity Pathway Analysis results for differential genes. The orange line indicates the threshold of p-value of 0.05, i.e. -log10(p-value) of 1.3. Several metabolic pathways were modulated by alcohol treatment.
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Figure 1: Two dimensional clustering of differential genes in livers of alcohol-treated mice compared to liquid-diet control. (A) Two dimensional clustering of differential genes in livers of alcohol-treated mice compared to liquid-diet control. Treatments for three time points are displayed, one-, two-, four-month. This clustering was derived from the ratio (treated/control) data. Red and green represented the levels of induction and repression of a particular gene respectively. The patterns of change were similar at two- and four-months. (B) Ingenuity Pathway Analysis results for differential genes. The orange line indicates the threshold of p-value of 0.05, i.e. -log10(p-value) of 1.3. Several metabolic pathways were modulated by alcohol treatment.

Mentions: The quality of the RNA obtained from each liver was assessed and only RNA samples with an RIN (RNA integrity number) of at least 7.0 were pooled for microarray analysis. Dual color microarray analysis was performed to reveal changes in gene expression between the alcohol- and control-diet groups at each time point. In order to compare time-course effects of chronic alcohol consumption on the liver transcriptome, the microarray datasets from three time points were analyzed by two-dimensional clustering (Figure 1A). Expression of about 100 to 200 genes was increased by at least 2 fold and a roughly equal number showed a decreased expression at the three time points of exposure (Additional file 3: Table S1). On one hand, common genes were found among the three time points and, on the other hand, unique signatures occurred among the different time points. Eight hundred fifty-one sequences out of 41,000 unique mouse genes and transcripts had a change of more than 2 fold at one or more time points. These genes were selected for further Ingenuity pathway analysis.


Identification of serum insulin-like growth factor binding protein 1 as diagnostic biomarker for early-stage alcohol-induced liver disease.

Li HH, Doiron K, Patterson AD, Gonzalez FJ, Fornace AJ - J Transl Med (2013)

Two dimensional clustering of differential genes in livers of alcohol-treated mice compared to liquid-diet control. (A) Two dimensional clustering of differential genes in livers of alcohol-treated mice compared to liquid-diet control. Treatments for three time points are displayed, one-, two-, four-month. This clustering was derived from the ratio (treated/control) data. Red and green represented the levels of induction and repression of a particular gene respectively. The patterns of change were similar at two- and four-months. (B) Ingenuity Pathway Analysis results for differential genes. The orange line indicates the threshold of p-value of 0.05, i.e. -log10(p-value) of 1.3. Several metabolic pathways were modulated by alcohol treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016206&req=5

Figure 1: Two dimensional clustering of differential genes in livers of alcohol-treated mice compared to liquid-diet control. (A) Two dimensional clustering of differential genes in livers of alcohol-treated mice compared to liquid-diet control. Treatments for three time points are displayed, one-, two-, four-month. This clustering was derived from the ratio (treated/control) data. Red and green represented the levels of induction and repression of a particular gene respectively. The patterns of change were similar at two- and four-months. (B) Ingenuity Pathway Analysis results for differential genes. The orange line indicates the threshold of p-value of 0.05, i.e. -log10(p-value) of 1.3. Several metabolic pathways were modulated by alcohol treatment.
Mentions: The quality of the RNA obtained from each liver was assessed and only RNA samples with an RIN (RNA integrity number) of at least 7.0 were pooled for microarray analysis. Dual color microarray analysis was performed to reveal changes in gene expression between the alcohol- and control-diet groups at each time point. In order to compare time-course effects of chronic alcohol consumption on the liver transcriptome, the microarray datasets from three time points were analyzed by two-dimensional clustering (Figure 1A). Expression of about 100 to 200 genes was increased by at least 2 fold and a roughly equal number showed a decreased expression at the three time points of exposure (Additional file 3: Table S1). On one hand, common genes were found among the three time points and, on the other hand, unique signatures occurred among the different time points. Eight hundred fifty-one sequences out of 41,000 unique mouse genes and transcripts had a change of more than 2 fold at one or more time points. These genes were selected for further Ingenuity pathway analysis.

Bottom Line: Most notably, the Igfbp1 (Insulin-Like Growth Factor Binding Protein 1) was selected as the best candidate gene for early detection of liver damage since it showed early and continuously enhanced induction during the treatment course.Consistent with the microarray data, both Igfbp1mRNA expression in the liver tissue and the IGFBP1 serum protein levels showed progressive and significant increases over the course of pre-ALD development.The results suggest that in conjunction with other tests, serum IGFBPI protein could provide an easily measured biomarker for early detection of alcohol-induced liver injury in humans.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, 3970 Reservoir Road, NW, New Research Building, Room E504, Washington, DC 20057, USA. af294@georgetown.edu.

ABSTRACT

Background: Alcohol consumption is a major cause of liver disease in humans. The use and monitoring of biomarkers associated with early, pre-clinical stages of alcohol-induced liver disease (pre-ALD) could facilitate diagnosis and treatment, leading to improved outcomes.

Methods: We investigated the pathological, transcriptomic and protein changes in early stages of pre-ALD in mice fed the Lieber-Decarli liquid diet with or without alcohol for four months to identify biomarkers for the early stage of alcohol induced liver injury. Mice were sampled after 1, 2 and 4 months treatment.

Results: Pathological examination revealed a modest increase in fatty liver changes in alcohol-treated mice. Transcriptomics revealed gene alterations at all time points. Most notably, the Igfbp1 (Insulin-Like Growth Factor Binding Protein 1) was selected as the best candidate gene for early detection of liver damage since it showed early and continuously enhanced induction during the treatment course. Consistent with the microarray data, both Igfbp1mRNA expression in the liver tissue and the IGFBP1 serum protein levels showed progressive and significant increases over the course of pre-ALD development.

Conclusions: The results suggest that in conjunction with other tests, serum IGFBPI protein could provide an easily measured biomarker for early detection of alcohol-induced liver injury in humans.

Show MeSH
Related in: MedlinePlus