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Determining the association between adipokine expression in multiple tissues and phenotypic features of non-alcoholic fatty liver disease in obesity.

Wolfs MG, Gruben N, Rensen SS, Verdam FJ, Greve JW, Driessen A, Wijmenga C, Buurman WA, Franke L, Scheja L, Koonen DP, Shiri-Sverdlov R, van Haeften TW, Hofker MH, Fu J - Nutr Diabetes (2015)

Bottom Line: We identified that the expression of leptin, angiopoietin 2 (ANGPT2) and chemerin in visceral adipose tissue (VAT) was associated with different NAFLD features, including steatosis, ballooning, portal and lobular inflammation.In addition, the expression of tumor necrosis factor (TNF), plasminogen activator inhibitor type 1 (PAI-1), insulin-like growth factor 1 (somatomedin C) (IGF1) and chemokine (C-X-C motif) ligand 10 (CXCL10) in the liver tissue and the expression of interleukin 1 receptor antagonist (IL1RN) in both the liver and SAT were associated with NAFLD features.The correlations between ANGPT2 and CXCL10, and NAFLD features were dependent on insulin resistance and T2D, but for the other genes the correlation with at least one NAFLD feature remained significant after correcting for the covariates.

View Article: PubMed Central - PubMed

Affiliation: Molecular Genetics Section, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

ABSTRACT

Objectives: Non-alcoholic fatty liver disease (NAFLD) is an obesity-associated disease, and in obesity adipokines are believed to be involved in the development of NAFLD. However, it is still not clear whether adipokines in the liver and/or adipose tissues can be related to the development of specific characteristics of NAFLD, such as steatosis and inflammation. We aimed to address this question by simultaneously examining the adipokine expression in three tissue types in obese individuals.

Methods: We enrolled 93 severely obese individuals with NAFLD, varying from simple steatosis to severe non-alcoholic steatohepatitis. Their expression of 48 adipokines in the liver, visceral and subcutaneous adipose tissue (SAT) was correlated to their phenotypic features of NAFLD. We further determined whether the correlations were tissue specific and/or independent of covariates, including age, sex, obesity, insulin resistance and type 2 diabetes (T2D).

Results: The expression of adipokines showed a liver- and adipose tissue-specific pattern. We identified that the expression of leptin, angiopoietin 2 (ANGPT2) and chemerin in visceral adipose tissue (VAT) was associated with different NAFLD features, including steatosis, ballooning, portal and lobular inflammation. In addition, the expression of tumor necrosis factor (TNF), plasminogen activator inhibitor type 1 (PAI-1), insulin-like growth factor 1 (somatomedin C) (IGF1) and chemokine (C-X-C motif) ligand 10 (CXCL10) in the liver tissue and the expression of interleukin 1 receptor antagonist (IL1RN) in both the liver and SAT were associated with NAFLD features. The correlations between ANGPT2 and CXCL10, and NAFLD features were dependent on insulin resistance and T2D, but for the other genes the correlation with at least one NAFLD feature remained significant after correcting for the covariates.

Conclusions: Our results suggest that in obese individuals, VAT-derived leptin and chemerin, and hepatic expression of TNF, IGF1, IL1RN and PAI-1 are involved in the development of NAFLD features. Further, functional studies are warranted to establish a causal relationship.

No MeSH data available.


Related in: MedlinePlus

The tissue-specific correlation between adipokine expression and liver histology. Each gene node indicates the expression of a gene in a certain tissue type and each line indicates a significant correlation with liver histology after correction for expression in other tissue types. The arrowhead indicates a positive correlation and the bar head a negative correlation (P<0.05). The dashed line indicates a correlation that is dependent on covariates, including age, sex, BMI, WHR, T2D and/or HOMA-IR.
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fig3: The tissue-specific correlation between adipokine expression and liver histology. Each gene node indicates the expression of a gene in a certain tissue type and each line indicates a significant correlation with liver histology after correction for expression in other tissue types. The arrowhead indicates a positive correlation and the bar head a negative correlation (P<0.05). The dashed line indicates a correlation that is dependent on covariates, including age, sex, BMI, WHR, T2D and/or HOMA-IR.

Mentions: We observed that the expression levels of eight adipokines (angiopoietin 2 (ANGPT2), leptin, chemerin, tumor necrosis factor (TNF), interleukin (IL)-1 receptor antagonist (IL1RN), chemokine (C-X-C motif) ligand 10 (CXCL10), insulin-like growth factor 1 (somatomedin C) (IGF1) and plasminogen activator inhibitor type 1 (PAI-1)) in one or more tissue types correlated with steatosis, ballooning, lobular inflammation, portal inflammation and/or fibrosis at P<7.0 × 10−4 (false discovery rate <0.05) (Table 2 and Figure 3). Large lipogranulomas and glycogenated nuclei did not correlate with adipokine expression levels. As the expression levels of many adipokines showed inter-tissue correlations (Figure 2b), we performed a partial correlation analysis to correct for the impact of the other tissues. This allowed us to identify the most relevant tissue type associated to NAFLD. The expression of chemerin in both SAT and VAT was negatively correlated with lobular inflammation. Taking into account the co-expression of chemerin in both adipose tissues (Figure 2b), the partial correlation analysis showed that only chemerin expression in VAT was associated with lobular inflammation (Table 2). In this way, we identified three adipokines (ANGPT2, leptin and chemerin) whose expression in VAT was associated to lobular inflammation, ballooning and/or steatosis. In addition, the expression of TNF, IL1RN, CXCL10, IGF1 and PAI-1 in the liver, and the expression of IL1RN in SAT, were correlated to NAFLD features (Table 2).


Determining the association between adipokine expression in multiple tissues and phenotypic features of non-alcoholic fatty liver disease in obesity.

Wolfs MG, Gruben N, Rensen SS, Verdam FJ, Greve JW, Driessen A, Wijmenga C, Buurman WA, Franke L, Scheja L, Koonen DP, Shiri-Sverdlov R, van Haeften TW, Hofker MH, Fu J - Nutr Diabetes (2015)

The tissue-specific correlation between adipokine expression and liver histology. Each gene node indicates the expression of a gene in a certain tissue type and each line indicates a significant correlation with liver histology after correction for expression in other tissue types. The arrowhead indicates a positive correlation and the bar head a negative correlation (P<0.05). The dashed line indicates a correlation that is dependent on covariates, including age, sex, BMI, WHR, T2D and/or HOMA-IR.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4338415&req=5

fig3: The tissue-specific correlation between adipokine expression and liver histology. Each gene node indicates the expression of a gene in a certain tissue type and each line indicates a significant correlation with liver histology after correction for expression in other tissue types. The arrowhead indicates a positive correlation and the bar head a negative correlation (P<0.05). The dashed line indicates a correlation that is dependent on covariates, including age, sex, BMI, WHR, T2D and/or HOMA-IR.
Mentions: We observed that the expression levels of eight adipokines (angiopoietin 2 (ANGPT2), leptin, chemerin, tumor necrosis factor (TNF), interleukin (IL)-1 receptor antagonist (IL1RN), chemokine (C-X-C motif) ligand 10 (CXCL10), insulin-like growth factor 1 (somatomedin C) (IGF1) and plasminogen activator inhibitor type 1 (PAI-1)) in one or more tissue types correlated with steatosis, ballooning, lobular inflammation, portal inflammation and/or fibrosis at P<7.0 × 10−4 (false discovery rate <0.05) (Table 2 and Figure 3). Large lipogranulomas and glycogenated nuclei did not correlate with adipokine expression levels. As the expression levels of many adipokines showed inter-tissue correlations (Figure 2b), we performed a partial correlation analysis to correct for the impact of the other tissues. This allowed us to identify the most relevant tissue type associated to NAFLD. The expression of chemerin in both SAT and VAT was negatively correlated with lobular inflammation. Taking into account the co-expression of chemerin in both adipose tissues (Figure 2b), the partial correlation analysis showed that only chemerin expression in VAT was associated with lobular inflammation (Table 2). In this way, we identified three adipokines (ANGPT2, leptin and chemerin) whose expression in VAT was associated to lobular inflammation, ballooning and/or steatosis. In addition, the expression of TNF, IL1RN, CXCL10, IGF1 and PAI-1 in the liver, and the expression of IL1RN in SAT, were correlated to NAFLD features (Table 2).

Bottom Line: We identified that the expression of leptin, angiopoietin 2 (ANGPT2) and chemerin in visceral adipose tissue (VAT) was associated with different NAFLD features, including steatosis, ballooning, portal and lobular inflammation.In addition, the expression of tumor necrosis factor (TNF), plasminogen activator inhibitor type 1 (PAI-1), insulin-like growth factor 1 (somatomedin C) (IGF1) and chemokine (C-X-C motif) ligand 10 (CXCL10) in the liver tissue and the expression of interleukin 1 receptor antagonist (IL1RN) in both the liver and SAT were associated with NAFLD features.The correlations between ANGPT2 and CXCL10, and NAFLD features were dependent on insulin resistance and T2D, but for the other genes the correlation with at least one NAFLD feature remained significant after correcting for the covariates.

View Article: PubMed Central - PubMed

Affiliation: Molecular Genetics Section, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

ABSTRACT

Objectives: Non-alcoholic fatty liver disease (NAFLD) is an obesity-associated disease, and in obesity adipokines are believed to be involved in the development of NAFLD. However, it is still not clear whether adipokines in the liver and/or adipose tissues can be related to the development of specific characteristics of NAFLD, such as steatosis and inflammation. We aimed to address this question by simultaneously examining the adipokine expression in three tissue types in obese individuals.

Methods: We enrolled 93 severely obese individuals with NAFLD, varying from simple steatosis to severe non-alcoholic steatohepatitis. Their expression of 48 adipokines in the liver, visceral and subcutaneous adipose tissue (SAT) was correlated to their phenotypic features of NAFLD. We further determined whether the correlations were tissue specific and/or independent of covariates, including age, sex, obesity, insulin resistance and type 2 diabetes (T2D).

Results: The expression of adipokines showed a liver- and adipose tissue-specific pattern. We identified that the expression of leptin, angiopoietin 2 (ANGPT2) and chemerin in visceral adipose tissue (VAT) was associated with different NAFLD features, including steatosis, ballooning, portal and lobular inflammation. In addition, the expression of tumor necrosis factor (TNF), plasminogen activator inhibitor type 1 (PAI-1), insulin-like growth factor 1 (somatomedin C) (IGF1) and chemokine (C-X-C motif) ligand 10 (CXCL10) in the liver tissue and the expression of interleukin 1 receptor antagonist (IL1RN) in both the liver and SAT were associated with NAFLD features. The correlations between ANGPT2 and CXCL10, and NAFLD features were dependent on insulin resistance and T2D, but for the other genes the correlation with at least one NAFLD feature remained significant after correcting for the covariates.

Conclusions: Our results suggest that in obese individuals, VAT-derived leptin and chemerin, and hepatic expression of TNF, IGF1, IL1RN and PAI-1 are involved in the development of NAFLD features. Further, functional studies are warranted to establish a causal relationship.

No MeSH data available.


Related in: MedlinePlus