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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

A subpopulation of mice fed an HFD develops NASH. A: Changes in body weight in C57Bl/6 mice fed an LFD (□; n = 10) or HFD (■; n = 8). B: Mean energy intake of mice fed an LFD or HFD during 21 weeks of dietary intervention. C: Weight of epididymal fat pad after 21 weeks of dietary intervention. Error bars reflect SD. *Significantly different from mice fed an LFD according to Student's t test (P < 0.05). H-E staining (D) and oil red O staining (E) of representative liver sections of the four subgroups (LFL, LFH, HFL, and HFH). F: liver triglyceride concentration. G: Liver weight (expressed as percentage of total body weight [BW]). H: Activity of alanine aminotransferase (ALT) (glutamate pyruvate transaminase) in plasma. Error bars reflect SD. Bars with different letters are statistically different (P < 0.05 according to Student's t test). n = 4 mice per group for LFL, HFL, and HFH, and n = 6 mice per group for LFH. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 1: A subpopulation of mice fed an HFD develops NASH. A: Changes in body weight in C57Bl/6 mice fed an LFD (□; n = 10) or HFD (■; n = 8). B: Mean energy intake of mice fed an LFD or HFD during 21 weeks of dietary intervention. C: Weight of epididymal fat pad after 21 weeks of dietary intervention. Error bars reflect SD. *Significantly different from mice fed an LFD according to Student's t test (P < 0.05). H-E staining (D) and oil red O staining (E) of representative liver sections of the four subgroups (LFL, LFH, HFL, and HFH). F: liver triglyceride concentration. G: Liver weight (expressed as percentage of total body weight [BW]). H: Activity of alanine aminotransferase (ALT) (glutamate pyruvate transaminase) in plasma. Error bars reflect SD. Bars with different letters are statistically different (P < 0.05 according to Student's t test). n = 4 mice per group for LFL, HFL, and HFH, and n = 6 mice per group for LFH. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: To study the effect of chronic high-fat feeding on liver metabolic functions, C57Bl/6 mice were fed an LFD or HFD for 21 weeks. Mice fed the HFD gained more weight compared with mice fed the LFD (Fig. 1A), which was already evident after 2 weeks. Enhanced weight gain in mice fed a HFD may be related to increased energy intake (Fig. 1B). After 21 weeks, weight of the epididymal fat pad, which was assumed to reflect overall adiposity of the animals, was markedly higher in mice fed an HFD (Fig. 1C).


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)

A subpopulation of mice fed an HFD develops NASH. A: Changes in body weight in C57Bl/6 mice fed an LFD (□; n = 10) or HFD (■; n = 8). B: Mean energy intake of mice fed an LFD or HFD during 21 weeks of dietary intervention. C: Weight of epididymal fat pad after 21 weeks of dietary intervention. Error bars reflect SD. *Significantly different from mice fed an LFD according to Student's t test (P < 0.05). H-E staining (D) and oil red O staining (E) of representative liver sections of the four subgroups (LFL, LFH, HFL, and HFH). F: liver triglyceride concentration. G: Liver weight (expressed as percentage of total body weight [BW]). H: Activity of alanine aminotransferase (ALT) (glutamate pyruvate transaminase) in plasma. Error bars reflect SD. Bars with different letters are statistically different (P < 0.05 according to Student's t test). n = 4 mice per group for LFL, HFL, and HFH, and n = 6 mice per group for LFH. (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 1: A subpopulation of mice fed an HFD develops NASH. A: Changes in body weight in C57Bl/6 mice fed an LFD (□; n = 10) or HFD (■; n = 8). B: Mean energy intake of mice fed an LFD or HFD during 21 weeks of dietary intervention. C: Weight of epididymal fat pad after 21 weeks of dietary intervention. Error bars reflect SD. *Significantly different from mice fed an LFD according to Student's t test (P < 0.05). H-E staining (D) and oil red O staining (E) of representative liver sections of the four subgroups (LFL, LFH, HFL, and HFH). F: liver triglyceride concentration. G: Liver weight (expressed as percentage of total body weight [BW]). H: Activity of alanine aminotransferase (ALT) (glutamate pyruvate transaminase) in plasma. Error bars reflect SD. Bars with different letters are statistically different (P < 0.05 according to Student's t test). n = 4 mice per group for LFL, HFL, and HFH, and n = 6 mice per group for LFH. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: To study the effect of chronic high-fat feeding on liver metabolic functions, C57Bl/6 mice were fed an LFD or HFD for 21 weeks. Mice fed the HFD gained more weight compared with mice fed the LFD (Fig. 1A), which was already evident after 2 weeks. Enhanced weight gain in mice fed a HFD may be related to increased energy intake (Fig. 1B). After 21 weeks, weight of the epididymal fat pad, which was assumed to reflect overall adiposity of the animals, was markedly higher in mice fed an HFD (Fig. 1C).

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