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Inhibition of soluble epoxide hydrolase attenuates high-fat-diet-induced hepatic steatosis by reduced systemic inflammatory status in mice.

Liu Y, Dang H, Li D, Pang W, Hammock BD, Zhu Y - PLoS ONE (2012)

Bottom Line: Non-alcoholic fatty liver disease is associated with obesity and considered an inflammatory disease.Soluble epoxide hydrolase (sEH) is a major enzyme hydrolyzing epoxyeicosatrienoic acids and attenuates their cardiovascular protective and anti-inflammatory effects.Surprisingly, the induced expression of sEH in liver occurred only with the long-term but not short-term HF diet, which suggests a secondary effect of HF diet on regulating sEH expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, Peking University Health Science Center, Beijing, China. chisti@icddrb.org

ABSTRACT
Non-alcoholic fatty liver disease is associated with obesity and considered an inflammatory disease. Soluble epoxide hydrolase (sEH) is a major enzyme hydrolyzing epoxyeicosatrienoic acids and attenuates their cardiovascular protective and anti-inflammatory effects. We examined whether sEH inhibition can protect against high-fat (HF)-diet-induced fatty liver in mice and the underlying mechanism. Compared with wild-type littermates, sEH- mice showed lower diet-induced lipid accumulation in liver, as seen by Oil-red O staining and triglycerides levels. We studied the effect of sEH inhibition on diet-induced fatty liver by feeding C57BL/6 mice an HF diet for 8 weeks (short-term) or 16 weeks (long-term) and administering t-AUCB, a selective sEH inhibitor. sEH inhibition had no effect on the HF-diet-increased body and adipose tissue weight or impaired glucose tolerance but alleviated the diet-induced hepatic steatosis. Adenovirus-mediated overexpression of sEH in liver increased the level of triglycerides in liver and the hepatic inflammatory response. Surprisingly, the induced expression of sEH in liver occurred only with the long-term but not short-term HF diet, which suggests a secondary effect of HF diet on regulating sEH expression. Furthermore, sEH inhibition attenuated the HF-diet-induced increase in plasma levels of proinflammatory cytokines and their mRNA upregulation in adipose tissue, which was accompanied by increased macrophage infiltration. Therefore, sEH inhibition could alleviate HF-diet-induced hepatic steatosis, which might involve its anti-inflammatory effect in adipose tissue and direct inhibition in liver. sEH may be a therapeutic target for HF-diet-induced hepatic steatosis in inhibiting systemic inflammation.

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sEH inhibition decreased 16-week HF-diet–induced activation of inflammatory pathways in the liver.Male C57BL/6 mice were fed a regular chow or HF diet for 16 weeks with or without sEHI t-AUCB in drinking water starting 3 days before diet. (A) Western blot analysis of protein levels of sEH and β-actin as a normalization control in liver. (B) sEH activity in liver. (C) Quantitative RT-PCR analysis of mRNA levels of TNF-α and IL-6 in liver. (D) Western blot analysis of protein levels of phosphorylated Jun N-terminal kinase (p-JNK), JNK1, p-p38, p38 and β-actin and relative protein content compared to that of JNK1 or p38. Data are mean ± SEM. (* P<0.05, ** P<0.01).
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pone-0039165-g005: sEH inhibition decreased 16-week HF-diet–induced activation of inflammatory pathways in the liver.Male C57BL/6 mice were fed a regular chow or HF diet for 16 weeks with or without sEHI t-AUCB in drinking water starting 3 days before diet. (A) Western blot analysis of protein levels of sEH and β-actin as a normalization control in liver. (B) sEH activity in liver. (C) Quantitative RT-PCR analysis of mRNA levels of TNF-α and IL-6 in liver. (D) Western blot analysis of protein levels of phosphorylated Jun N-terminal kinase (p-JNK), JNK1, p-p38, p38 and β-actin and relative protein content compared to that of JNK1 or p38. Data are mean ± SEM. (* P<0.05, ** P<0.01).

Mentions: We investigated the role of sEH in the pathogenesis of hepatic steatosis and found that as compared with an 8-week HF diet, a 16-week HF diet produced 2.6-fold increased sEH protein level in mouse liver (Fig. 5A) relative to the controls, with reinforced epoxide hydrolase activity of sEH (Fig. 5B). Furthermore, the long-term HF-diet activation of inflammatory pathways in the liver, including increased phosphorylation of JNK and p38 and mRNA levels of TNF-α and IL-6, was markedly reduced with sEH inhibition (Fig. 5C and D). To investigate the direct effect of sEH in the liver of mice, C57BL/6 mice were intravenously injected with recombinant adenoviruses encoding human sEH (Ad-sEH) or green fluorescence protein (Ad-GFP). At 7 days post-injection, sEH mRNA and protein levels and activity were higher in the liver of mice receiving Ad-sEH than the control Ad-GFP (Fig. 6A–C). The overexpression of sEH alone was sufficient for elevating the plasma and liver levels of triglycerides (Fig. 6D–F). Moreover, sEH overexpression increased the phosphorylation of JNK and p38 and the mRNA levels of TNF-α and IL-6 in the liver (Fig. 6G and H). Thus, the secondary upregulation of hepatic sEH with a long-term HF diet may play an important role in the progression of fatty liver and hepatic inflammation, from simple hepatic steatosis to steatohepatitis.


Inhibition of soluble epoxide hydrolase attenuates high-fat-diet-induced hepatic steatosis by reduced systemic inflammatory status in mice.

Liu Y, Dang H, Li D, Pang W, Hammock BD, Zhu Y - PLoS ONE (2012)

sEH inhibition decreased 16-week HF-diet–induced activation of inflammatory pathways in the liver.Male C57BL/6 mice were fed a regular chow or HF diet for 16 weeks with or without sEHI t-AUCB in drinking water starting 3 days before diet. (A) Western blot analysis of protein levels of sEH and β-actin as a normalization control in liver. (B) sEH activity in liver. (C) Quantitative RT-PCR analysis of mRNA levels of TNF-α and IL-6 in liver. (D) Western blot analysis of protein levels of phosphorylated Jun N-terminal kinase (p-JNK), JNK1, p-p38, p38 and β-actin and relative protein content compared to that of JNK1 or p38. Data are mean ± SEM. (* P<0.05, ** P<0.01).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3375303&req=5

pone-0039165-g005: sEH inhibition decreased 16-week HF-diet–induced activation of inflammatory pathways in the liver.Male C57BL/6 mice were fed a regular chow or HF diet for 16 weeks with or without sEHI t-AUCB in drinking water starting 3 days before diet. (A) Western blot analysis of protein levels of sEH and β-actin as a normalization control in liver. (B) sEH activity in liver. (C) Quantitative RT-PCR analysis of mRNA levels of TNF-α and IL-6 in liver. (D) Western blot analysis of protein levels of phosphorylated Jun N-terminal kinase (p-JNK), JNK1, p-p38, p38 and β-actin and relative protein content compared to that of JNK1 or p38. Data are mean ± SEM. (* P<0.05, ** P<0.01).
Mentions: We investigated the role of sEH in the pathogenesis of hepatic steatosis and found that as compared with an 8-week HF diet, a 16-week HF diet produced 2.6-fold increased sEH protein level in mouse liver (Fig. 5A) relative to the controls, with reinforced epoxide hydrolase activity of sEH (Fig. 5B). Furthermore, the long-term HF-diet activation of inflammatory pathways in the liver, including increased phosphorylation of JNK and p38 and mRNA levels of TNF-α and IL-6, was markedly reduced with sEH inhibition (Fig. 5C and D). To investigate the direct effect of sEH in the liver of mice, C57BL/6 mice were intravenously injected with recombinant adenoviruses encoding human sEH (Ad-sEH) or green fluorescence protein (Ad-GFP). At 7 days post-injection, sEH mRNA and protein levels and activity were higher in the liver of mice receiving Ad-sEH than the control Ad-GFP (Fig. 6A–C). The overexpression of sEH alone was sufficient for elevating the plasma and liver levels of triglycerides (Fig. 6D–F). Moreover, sEH overexpression increased the phosphorylation of JNK and p38 and the mRNA levels of TNF-α and IL-6 in the liver (Fig. 6G and H). Thus, the secondary upregulation of hepatic sEH with a long-term HF diet may play an important role in the progression of fatty liver and hepatic inflammation, from simple hepatic steatosis to steatohepatitis.

Bottom Line: Non-alcoholic fatty liver disease is associated with obesity and considered an inflammatory disease.Soluble epoxide hydrolase (sEH) is a major enzyme hydrolyzing epoxyeicosatrienoic acids and attenuates their cardiovascular protective and anti-inflammatory effects.Surprisingly, the induced expression of sEH in liver occurred only with the long-term but not short-term HF diet, which suggests a secondary effect of HF diet on regulating sEH expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, Peking University Health Science Center, Beijing, China. chisti@icddrb.org

ABSTRACT
Non-alcoholic fatty liver disease is associated with obesity and considered an inflammatory disease. Soluble epoxide hydrolase (sEH) is a major enzyme hydrolyzing epoxyeicosatrienoic acids and attenuates their cardiovascular protective and anti-inflammatory effects. We examined whether sEH inhibition can protect against high-fat (HF)-diet-induced fatty liver in mice and the underlying mechanism. Compared with wild-type littermates, sEH- mice showed lower diet-induced lipid accumulation in liver, as seen by Oil-red O staining and triglycerides levels. We studied the effect of sEH inhibition on diet-induced fatty liver by feeding C57BL/6 mice an HF diet for 8 weeks (short-term) or 16 weeks (long-term) and administering t-AUCB, a selective sEH inhibitor. sEH inhibition had no effect on the HF-diet-increased body and adipose tissue weight or impaired glucose tolerance but alleviated the diet-induced hepatic steatosis. Adenovirus-mediated overexpression of sEH in liver increased the level of triglycerides in liver and the hepatic inflammatory response. Surprisingly, the induced expression of sEH in liver occurred only with the long-term but not short-term HF diet, which suggests a secondary effect of HF diet on regulating sEH expression. Furthermore, sEH inhibition attenuated the HF-diet-induced increase in plasma levels of proinflammatory cytokines and their mRNA upregulation in adipose tissue, which was accompanied by increased macrophage infiltration. Therefore, sEH inhibition could alleviate HF-diet-induced hepatic steatosis, which might involve its anti-inflammatory effect in adipose tissue and direct inhibition in liver. sEH may be a therapeutic target for HF-diet-induced hepatic steatosis in inhibiting systemic inflammation.

Show MeSH
Related in: MedlinePlus