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Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model.

Li YC, Hsieh CC - PLoS ONE (2014)

Bottom Line: Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver.The important regulatory roles are played by adipokines including interleukin-1β, interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release.Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Science and Biotechnology, Tunghai University, Taichung, Taiwan.

ABSTRACT
Hepatic manifestations of the metabolic syndrome are related obesity, type 2 diabetes/insulin resistance and non-alcoholic fatty liver disease. Here we investigated how the anti-inflammatory properties of lactoferrin can protect against the onset of hepatic manifestations of the metabolic syndrome by using a murine model administered with high-fructose corn syrup. Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver. Immunohistochemical staining of Toll-like receptor-4 and thymic stromal lymphopoietin indicated that lactoferrin can modulate lipopolysaccharide-mediated inflammatory cascade. The important regulatory roles are played by adipokines including interleukin-1β, interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release. These beneficial effects of lactoferrin related to the downregulation of the lipopolysaccharide-induced inflammatory cascade in the liver. Furthermore, lactoferrin reduced serum and hepatic triglycerides to prevent lipid accumulation in the liver, and reduced lipid peroxidation, resulting in 4-hydroxynonenal accumulation. Lactoferrin reduced oral glucose tolerance test and homeostasis model assessment-insulin resistance. Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis. Taken together, these results suggest that lactoferrin protected against high-fructose corn syrup induced hepatic manifestations of the metabolic syndrome.

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Treatment with lactoferrin improved the histology of livers of HFCS-induced HMMS mice.Immunohistochemical staining with 4-HNE, TLR-4, and TSLP show lipid peroxidation (4-HNE) and associated inflammatory markers (TLR-4 and TSLP). The control group showed lipid vascular accumulation and stained positive for 4-HNE, TLR-4, and TSLP, compared to the naïve group (indicated by arrows). Open arrows indicate negative staining for TLR-4 and TSLP, which indicate without infiltration of inflammatory cells. Treatment with lactoferrin at 50, 100, and 200 mg/kg markedly reduced 4-HNE, TLR-4, and TSLP expression. Scale bars represent 100 µm (4-HNE) and 50 µm (TLR-4 and TSLP).
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pone-0097341-g002: Treatment with lactoferrin improved the histology of livers of HFCS-induced HMMS mice.Immunohistochemical staining with 4-HNE, TLR-4, and TSLP show lipid peroxidation (4-HNE) and associated inflammatory markers (TLR-4 and TSLP). The control group showed lipid vascular accumulation and stained positive for 4-HNE, TLR-4, and TSLP, compared to the naïve group (indicated by arrows). Open arrows indicate negative staining for TLR-4 and TSLP, which indicate without infiltration of inflammatory cells. Treatment with lactoferrin at 50, 100, and 200 mg/kg markedly reduced 4-HNE, TLR-4, and TSLP expression. Scale bars represent 100 µm (4-HNE) and 50 µm (TLR-4 and TSLP).

Mentions: After eight weeks of lactoferrin administration (50, 100, and 200 mg/kg) to mice with HFCS-induced HMMS, the mice were sacrificed, and their livers subjected to gross and microscopic examination. Mice from the control group (no lactoferrin) had fatty livers, while lipid accumulation was markedly reduced in the groups administered with lactoferrin (Figure 1). HE staining of paraffinized sections showed oil droplet vacuoles in the control group that were reduced in the lactoferrin treatment groups. A similar effect was shown in the frozen sections stained with Oil Red O (Figure 1). The control group's histopathological steatosis score was significantly higher than naïve group (Table 2; P<0.001). The lactoferrin treatment groups (50, 100, and 200 mg/kg) had significantly lower histopathological steatosis scores than the control group (Table 2; P<0.01). In the measurement of Oil Red O stain, lipid droplet area (%) and numbers were significantly lower in the lactoferrin-treated groups (Table 3; P<0.05). The hepatic homogenate was analyzed to measure fat accumulation. Hepatic triglyceride (hTG) and serum triglyceride (sTG) levels were significantly reduced in the lactoferrin treatment groups compared to the control group (Table 4, 5; P<0.05). In addition, serum concentrations of total cholesterol (sCHOL) were significantly increased in the HFCS-induced NASH control group (Table 4; P<0.05). Administration of lactoferrin (50, 100, and 200 mg/kg) significantly reduced sCHOL levels compared to the control group (Table 4; P<0.05). Severe lipid accumulation results in lipid peroxidation and inflammation. 4-HNE is an important indicator of lipid peroxidation, and immunohistochemical staining showed that 4-HNE staining in the liver tissue of the control group was significantly higher, but significantly reduced by lactoferrin treatment (Figure 2). In the control group, sALT increased significantly (Table 4; P<0.05), but reduced by lactoferrin administration (Table 4; P<0.05). These data indicate that lactoferrin was significantly reduced oil droplet accumulation and liver damage.


Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model.

Li YC, Hsieh CC - PLoS ONE (2014)

Treatment with lactoferrin improved the histology of livers of HFCS-induced HMMS mice.Immunohistochemical staining with 4-HNE, TLR-4, and TSLP show lipid peroxidation (4-HNE) and associated inflammatory markers (TLR-4 and TSLP). The control group showed lipid vascular accumulation and stained positive for 4-HNE, TLR-4, and TSLP, compared to the naïve group (indicated by arrows). Open arrows indicate negative staining for TLR-4 and TSLP, which indicate without infiltration of inflammatory cells. Treatment with lactoferrin at 50, 100, and 200 mg/kg markedly reduced 4-HNE, TLR-4, and TSLP expression. Scale bars represent 100 µm (4-HNE) and 50 µm (TLR-4 and TSLP).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4016362&req=5

pone-0097341-g002: Treatment with lactoferrin improved the histology of livers of HFCS-induced HMMS mice.Immunohistochemical staining with 4-HNE, TLR-4, and TSLP show lipid peroxidation (4-HNE) and associated inflammatory markers (TLR-4 and TSLP). The control group showed lipid vascular accumulation and stained positive for 4-HNE, TLR-4, and TSLP, compared to the naïve group (indicated by arrows). Open arrows indicate negative staining for TLR-4 and TSLP, which indicate without infiltration of inflammatory cells. Treatment with lactoferrin at 50, 100, and 200 mg/kg markedly reduced 4-HNE, TLR-4, and TSLP expression. Scale bars represent 100 µm (4-HNE) and 50 µm (TLR-4 and TSLP).
Mentions: After eight weeks of lactoferrin administration (50, 100, and 200 mg/kg) to mice with HFCS-induced HMMS, the mice were sacrificed, and their livers subjected to gross and microscopic examination. Mice from the control group (no lactoferrin) had fatty livers, while lipid accumulation was markedly reduced in the groups administered with lactoferrin (Figure 1). HE staining of paraffinized sections showed oil droplet vacuoles in the control group that were reduced in the lactoferrin treatment groups. A similar effect was shown in the frozen sections stained with Oil Red O (Figure 1). The control group's histopathological steatosis score was significantly higher than naïve group (Table 2; P<0.001). The lactoferrin treatment groups (50, 100, and 200 mg/kg) had significantly lower histopathological steatosis scores than the control group (Table 2; P<0.01). In the measurement of Oil Red O stain, lipid droplet area (%) and numbers were significantly lower in the lactoferrin-treated groups (Table 3; P<0.05). The hepatic homogenate was analyzed to measure fat accumulation. Hepatic triglyceride (hTG) and serum triglyceride (sTG) levels were significantly reduced in the lactoferrin treatment groups compared to the control group (Table 4, 5; P<0.05). In addition, serum concentrations of total cholesterol (sCHOL) were significantly increased in the HFCS-induced NASH control group (Table 4; P<0.05). Administration of lactoferrin (50, 100, and 200 mg/kg) significantly reduced sCHOL levels compared to the control group (Table 4; P<0.05). Severe lipid accumulation results in lipid peroxidation and inflammation. 4-HNE is an important indicator of lipid peroxidation, and immunohistochemical staining showed that 4-HNE staining in the liver tissue of the control group was significantly higher, but significantly reduced by lactoferrin treatment (Figure 2). In the control group, sALT increased significantly (Table 4; P<0.05), but reduced by lactoferrin administration (Table 4; P<0.05). These data indicate that lactoferrin was significantly reduced oil droplet accumulation and liver damage.

Bottom Line: Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver.The important regulatory roles are played by adipokines including interleukin-1β, interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release.Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Science and Biotechnology, Tunghai University, Taichung, Taiwan.

ABSTRACT
Hepatic manifestations of the metabolic syndrome are related obesity, type 2 diabetes/insulin resistance and non-alcoholic fatty liver disease. Here we investigated how the anti-inflammatory properties of lactoferrin can protect against the onset of hepatic manifestations of the metabolic syndrome by using a murine model administered with high-fructose corn syrup. Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver. Immunohistochemical staining of Toll-like receptor-4 and thymic stromal lymphopoietin indicated that lactoferrin can modulate lipopolysaccharide-mediated inflammatory cascade. The important regulatory roles are played by adipokines including interleukin-1β, interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release. These beneficial effects of lactoferrin related to the downregulation of the lipopolysaccharide-induced inflammatory cascade in the liver. Furthermore, lactoferrin reduced serum and hepatic triglycerides to prevent lipid accumulation in the liver, and reduced lipid peroxidation, resulting in 4-hydroxynonenal accumulation. Lactoferrin reduced oral glucose tolerance test and homeostasis model assessment-insulin resistance. Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis. Taken together, these results suggest that lactoferrin protected against high-fructose corn syrup induced hepatic manifestations of the metabolic syndrome.

Show MeSH
Related in: MedlinePlus