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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

Plasma proteins as early predictive biomarker for NASH in C57Bl/6 mice. A: Plasma concentration of haptoglobin, TIMP-1, IL-1β, leptin, and insulin were determined by multiplex assay at specific time points during the 21 weeks of dietary intervention after a 6-h fast. White squares, LFL; light-gray squares, LFH; dark-gray squares, HFL; black squares, HFH. Error bars reflect SD. *Significantly different from HFL mice according to Student's t test (P < 0.05). Number of mice per group: n = 4 for LFL, HFL, and HFH and n = 6 for LFH. B: Graphs illustrating the result of multivariate analysis showing the association of protein plasma concentrations at various time points with final liver triglyceride content. The absRSD is the absolute relative standard deviation: the standard deviation of the regression coefficients divided by the absolute mean value of the regression coefficients. Significant proteins display an inverse absRSD value higher than two (bold line indicates the inverse absRSD threshold value of 2). w, weeks.
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Figure 6: Plasma proteins as early predictive biomarker for NASH in C57Bl/6 mice. A: Plasma concentration of haptoglobin, TIMP-1, IL-1β, leptin, and insulin were determined by multiplex assay at specific time points during the 21 weeks of dietary intervention after a 6-h fast. White squares, LFL; light-gray squares, LFH; dark-gray squares, HFL; black squares, HFH. Error bars reflect SD. *Significantly different from HFL mice according to Student's t test (P < 0.05). Number of mice per group: n = 4 for LFL, HFL, and HFH and n = 6 for LFH. B: Graphs illustrating the result of multivariate analysis showing the association of protein plasma concentrations at various time points with final liver triglyceride content. The absRSD is the absolute relative standard deviation: the standard deviation of the regression coefficients divided by the absolute mean value of the regression coefficients. Significant proteins display an inverse absRSD value higher than two (bold line indicates the inverse absRSD threshold value of 2). w, weeks.

Mentions: To find early biomarkers that may predict NASH in C57Bl/6 mice and that may serve as potential mediators between adipose tissue dysfunction and NASH, plasma was collected at different time points of diet intervention and assayed for 70 plasma proteins using multiplex analysis. Levels of most plasma proteins were not consistently different between the subgroups. One exception was the acute phase protein haptoglobin, which was elevated in HFH mice after 12 weeks of diet intervention (Fig. 6A). Similarly, plasma levels of the fibrosis marker TIMP-1 started to deviate at week 12 and further increased until the end. Remarkably, interleukin (IL)-1β and leptin levels were already elevated in HFH after 2 weeks and this pattern was maintained throughout the intervention. Finally, plasma insulin levels indicated that HFH mice became hyperinsulinemic from week 12, suggesting development of insulin resistance.


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)

Plasma proteins as early predictive biomarker for NASH in C57Bl/6 mice. A: Plasma concentration of haptoglobin, TIMP-1, IL-1β, leptin, and insulin were determined by multiplex assay at specific time points during the 21 weeks of dietary intervention after a 6-h fast. White squares, LFL; light-gray squares, LFH; dark-gray squares, HFL; black squares, HFH. Error bars reflect SD. *Significantly different from HFL mice according to Student's t test (P < 0.05). Number of mice per group: n = 4 for LFL, HFL, and HFH and n = 6 for LFH. B: Graphs illustrating the result of multivariate analysis showing the association of protein plasma concentrations at various time points with final liver triglyceride content. The absRSD is the absolute relative standard deviation: the standard deviation of the regression coefficients divided by the absolute mean value of the regression coefficients. Significant proteins display an inverse absRSD value higher than two (bold line indicates the inverse absRSD threshold value of 2). w, weeks.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 6: Plasma proteins as early predictive biomarker for NASH in C57Bl/6 mice. A: Plasma concentration of haptoglobin, TIMP-1, IL-1β, leptin, and insulin were determined by multiplex assay at specific time points during the 21 weeks of dietary intervention after a 6-h fast. White squares, LFL; light-gray squares, LFH; dark-gray squares, HFL; black squares, HFH. Error bars reflect SD. *Significantly different from HFL mice according to Student's t test (P < 0.05). Number of mice per group: n = 4 for LFL, HFL, and HFH and n = 6 for LFH. B: Graphs illustrating the result of multivariate analysis showing the association of protein plasma concentrations at various time points with final liver triglyceride content. The absRSD is the absolute relative standard deviation: the standard deviation of the regression coefficients divided by the absolute mean value of the regression coefficients. Significant proteins display an inverse absRSD value higher than two (bold line indicates the inverse absRSD threshold value of 2). w, weeks.
Mentions: To find early biomarkers that may predict NASH in C57Bl/6 mice and that may serve as potential mediators between adipose tissue dysfunction and NASH, plasma was collected at different time points of diet intervention and assayed for 70 plasma proteins using multiplex analysis. Levels of most plasma proteins were not consistently different between the subgroups. One exception was the acute phase protein haptoglobin, which was elevated in HFH mice after 12 weeks of diet intervention (Fig. 6A). Similarly, plasma levels of the fibrosis marker TIMP-1 started to deviate at week 12 and further increased until the end. Remarkably, interleukin (IL)-1β and leptin levels were already elevated in HFH after 2 weeks and this pattern was maintained throughout the intervention. Finally, plasma insulin levels indicated that HFH mice became hyperinsulinemic from week 12, suggesting development of insulin resistance.

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