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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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4-week sEH inhibitor administration attenuated 8-week HF-diet–induced triglycerides accumulation in mouse liver.Male C57BL/6 mice were fed regular chow or a HF diet for 8 weeks with or without sEH inhibitor (sEHI) t-AUCB administration in drinking water from week 5 (n=8 mice/group). (A) Body weight, liver weight and epididymal fat weight. (B) Plasma levels of triglycerides and cholesterol. (C) Oil-red O staining in liver sections. (D) Levels of triglycerides and cholesterol in liver. (E) Western blot analysis of protein levels of sEH and β-actin as a normalization control in liver. (F) sEH activity in liver. Data are mean ± SEM. (* P<0.05, ** P<0.01).
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pone-0039165-g002: 4-week sEH inhibitor administration attenuated 8-week HF-diet–induced triglycerides accumulation in mouse liver.Male C57BL/6 mice were fed regular chow or a HF diet for 8 weeks with or without sEH inhibitor (sEHI) t-AUCB administration in drinking water from week 5 (n=8 mice/group). (A) Body weight, liver weight and epididymal fat weight. (B) Plasma levels of triglycerides and cholesterol. (C) Oil-red O staining in liver sections. (D) Levels of triglycerides and cholesterol in liver. (E) Western blot analysis of protein levels of sEH and β-actin as a normalization control in liver. (F) sEH activity in liver. Data are mean ± SEM. (* P<0.05, ** P<0.01).

Mentions: To study whether sEH inhibition can reverse the effect of an HF diet on fatty liver, we fed mice an HF diet for 8 weeks and administered a selective sEH inhibitor, t-AUCB, in drinking water to half of the mice for 4 weeks starting from week 5. t-AUCB had no effect on HF-diet–increased body weight and fat tissue weight or plasma level of cholesterol and triglycerides (Fig. 2A, B) but reduced the HF-diet–induced mild hepatic steatosis (Fig. 2C, D). Of note, neither sEH deficiency nor activity inhibition altered the impaired glucose tolerance and insulin resistance in mice (Fig. S1). To determine whether an HF diet regulated sEH expression in the liver, which may play a role in lipid metabolism, we measured the protein expression of sEH in the liver and found no effect of the diet on sEH expression and slightly increased sEH activity (Fig. 2E, F). Hydrolase activity of sEH in liver was largely inhibited by sEH inhibition, but protein levels of sEH were increased, perhaps through a feedback mechanism. Thus, sEH expression does not play a major role in HF-diet–induced hepatic steatosis in these mice.


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)

4-week sEH inhibitor administration attenuated 8-week HF-diet–induced triglycerides accumulation in mouse liver.Male C57BL/6 mice were fed regular chow or a HF diet for 8 weeks with or without sEH inhibitor (sEHI) t-AUCB administration in drinking water from week 5 (n=8 mice/group). (A) Body weight, liver weight and epididymal fat weight. (B) Plasma levels of triglycerides and cholesterol. (C) Oil-red O staining in liver sections. (D) Levels of triglycerides and cholesterol in liver. (E) Western blot analysis of protein levels of sEH and β-actin as a normalization control in liver. (F) sEH activity in liver. 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-g002: 4-week sEH inhibitor administration attenuated 8-week HF-diet–induced triglycerides accumulation in mouse liver.Male C57BL/6 mice were fed regular chow or a HF diet for 8 weeks with or without sEH inhibitor (sEHI) t-AUCB administration in drinking water from week 5 (n=8 mice/group). (A) Body weight, liver weight and epididymal fat weight. (B) Plasma levels of triglycerides and cholesterol. (C) Oil-red O staining in liver sections. (D) Levels of triglycerides and cholesterol in liver. (E) Western blot analysis of protein levels of sEH and β-actin as a normalization control in liver. (F) sEH activity in liver. Data are mean ± SEM. (* P<0.05, ** P<0.01).
Mentions: To study whether sEH inhibition can reverse the effect of an HF diet on fatty liver, we fed mice an HF diet for 8 weeks and administered a selective sEH inhibitor, t-AUCB, in drinking water to half of the mice for 4 weeks starting from week 5. t-AUCB had no effect on HF-diet–increased body weight and fat tissue weight or plasma level of cholesterol and triglycerides (Fig. 2A, B) but reduced the HF-diet–induced mild hepatic steatosis (Fig. 2C, D). Of note, neither sEH deficiency nor activity inhibition altered the impaired glucose tolerance and insulin resistance in mice (Fig. S1). To determine whether an HF diet regulated sEH expression in the liver, which may play a role in lipid metabolism, we measured the protein expression of sEH in the liver and found no effect of the diet on sEH expression and slightly increased sEH activity (Fig. 2E, F). Hydrolase activity of sEH in liver was largely inhibited by sEH inhibition, but protein levels of sEH were increased, perhaps through a feedback mechanism. Thus, sEH expression does not play a major role in HF-diet–induced hepatic steatosis in these mice.

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