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Adipose tissue dysfunction signals progression of hepatic steatosis towards nonalcoholic steatohepatitis in C57BL/6 mice.

Duval C, Thissen U, Keshtkar S, Accart B, Stienstra R, Boekschoten MV, Roskams T, Kersten S, Müller M - Diabetes (2010)

Bottom Line: Multivariate analysis indicated that in addition to leptin, plasma CRP, haptoglobin, eotaxin, and MIP-1α early in the intervention were positively associated with liver triglycerides.Intermediate prognostic markers of liver triglycerides included IL-18, IL-1β, MIP-1γ, and MIP-2, whereas insulin, TIMP-1, granulocyte chemotactic protein 2, and myeloperoxidase emerged as late markers.Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH.

View Article: PubMed Central - PubMed

Affiliation: Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands.

ABSTRACT

Objective: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity and diabetes, suggesting an important role of adipose tissue in the pathogenesis of NAFLD. Here, we aimed to investigate the interaction between adipose tissue and liver in NAFLD and identify potential early plasma markers that predict nonalcoholic steatohepatitis (NASH).

Research design and methods: C57Bl/6 mice were chronically fed a high-fat diet to induce NAFLD and compared with mice fed a low-fat diet. Extensive histological and phenotypical analyses coupled with a time course study of plasma proteins using multiplex assay were performed.

Results: Mice exhibited pronounced heterogeneity in liver histological scoring, leading to classification into four subgroups: low-fat low (LFL) responders displaying normal liver morphology, low-fat high (LFH) responders showing benign hepatic steatosis, high-fat low (HFL) responders displaying pre-NASH with macrovesicular lipid droplets, and high fat high (HFH) responders exhibiting overt NASH characterized by ballooning of hepatocytes, presence of Mallory bodies, and activated inflammatory cells. Compared with HFL responders, HFH mice gained weight more rapidly and exhibited adipose tissue dysfunction characterized by decreased final fat mass, enhanced macrophage infiltration and inflammation, and adipose tissue remodeling. Plasma haptoglobin, IL-1β, TIMP-1, adiponectin, and leptin were significantly changed in HFH mice. Multivariate analysis indicated that in addition to leptin, plasma CRP, haptoglobin, eotaxin, and MIP-1α early in the intervention were positively associated with liver triglycerides. Intermediate prognostic markers of liver triglycerides included IL-18, IL-1β, MIP-1γ, and MIP-2, whereas insulin, TIMP-1, granulocyte chemotactic protein 2, and myeloperoxidase emerged as late markers.

Conclusions: Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH.

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Related in: MedlinePlus

(Immuno)histochemical staining confirms enhanced inflammation and early fibrosis in HFH mice. A: Immunohistochemical staining of macrophage activation in representative liver sections of HFL (left panel) and HFH (right panel) mice using antibody against the specific macrophage marker Cd68. B: Collagen staining using fast green FCF/sirius red F3B. C: Staining of stellate cell activation using antibody against GFAP. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 3: (Immuno)histochemical staining confirms enhanced inflammation and early fibrosis in HFH mice. A: Immunohistochemical staining of macrophage activation in representative liver sections of HFL (left panel) and HFH (right panel) mice using antibody against the specific macrophage marker Cd68. B: Collagen staining using fast green FCF/sirius red F3B. C: Staining of stellate cell activation using antibody against GFAP. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: The elevated inflammatory status in HFH livers was corroborated by immunostaining for macrophage marker Cd68 (Fig. 3A). Early fibrosis was detected in one HFH mouse (Fig. 3B). Finally, hepatic stellate activation was demonstrated in HFH mice by GFAP immunostaining (Fig. 3C). Overall, these analyses support induction of inflammation and fibrosis in HFH responders, indicating NASH.


Adipose tissue dysfunction signals progression of hepatic steatosis towards nonalcoholic steatohepatitis in C57BL/6 mice.

Duval C, Thissen U, Keshtkar S, Accart B, Stienstra R, Boekschoten MV, Roskams T, Kersten S, Müller M - Diabetes (2010)

(Immuno)histochemical staining confirms enhanced inflammation and early fibrosis in HFH mice. A: Immunohistochemical staining of macrophage activation in representative liver sections of HFL (left panel) and HFH (right panel) mice using antibody against the specific macrophage marker Cd68. B: Collagen staining using fast green FCF/sirius red F3B. C: Staining of stellate cell activation using antibody against GFAP. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992781&req=5

Figure 3: (Immuno)histochemical staining confirms enhanced inflammation and early fibrosis in HFH mice. A: Immunohistochemical staining of macrophage activation in representative liver sections of HFL (left panel) and HFH (right panel) mice using antibody against the specific macrophage marker Cd68. B: Collagen staining using fast green FCF/sirius red F3B. C: Staining of stellate cell activation using antibody against GFAP. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: The elevated inflammatory status in HFH livers was corroborated by immunostaining for macrophage marker Cd68 (Fig. 3A). Early fibrosis was detected in one HFH mouse (Fig. 3B). Finally, hepatic stellate activation was demonstrated in HFH mice by GFAP immunostaining (Fig. 3C). Overall, these analyses support induction of inflammation and fibrosis in HFH responders, indicating NASH.

Bottom Line: Multivariate analysis indicated that in addition to leptin, plasma CRP, haptoglobin, eotaxin, and MIP-1α early in the intervention were positively associated with liver triglycerides.Intermediate prognostic markers of liver triglycerides included IL-18, IL-1β, MIP-1γ, and MIP-2, whereas insulin, TIMP-1, granulocyte chemotactic protein 2, and myeloperoxidase emerged as late markers.Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH.

View Article: PubMed Central - PubMed

Affiliation: Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands.

ABSTRACT

Objective: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity and diabetes, suggesting an important role of adipose tissue in the pathogenesis of NAFLD. Here, we aimed to investigate the interaction between adipose tissue and liver in NAFLD and identify potential early plasma markers that predict nonalcoholic steatohepatitis (NASH).

Research design and methods: C57Bl/6 mice were chronically fed a high-fat diet to induce NAFLD and compared with mice fed a low-fat diet. Extensive histological and phenotypical analyses coupled with a time course study of plasma proteins using multiplex assay were performed.

Results: Mice exhibited pronounced heterogeneity in liver histological scoring, leading to classification into four subgroups: low-fat low (LFL) responders displaying normal liver morphology, low-fat high (LFH) responders showing benign hepatic steatosis, high-fat low (HFL) responders displaying pre-NASH with macrovesicular lipid droplets, and high fat high (HFH) responders exhibiting overt NASH characterized by ballooning of hepatocytes, presence of Mallory bodies, and activated inflammatory cells. Compared with HFL responders, HFH mice gained weight more rapidly and exhibited adipose tissue dysfunction characterized by decreased final fat mass, enhanced macrophage infiltration and inflammation, and adipose tissue remodeling. Plasma haptoglobin, IL-1β, TIMP-1, adiponectin, and leptin were significantly changed in HFH mice. Multivariate analysis indicated that in addition to leptin, plasma CRP, haptoglobin, eotaxin, and MIP-1α early in the intervention were positively associated with liver triglycerides. Intermediate prognostic markers of liver triglycerides included IL-18, IL-1β, MIP-1γ, and MIP-2, whereas insulin, TIMP-1, granulocyte chemotactic protein 2, and myeloperoxidase emerged as late markers.

Conclusions: Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH.

Show MeSH
Related in: MedlinePlus