Cytochrome P450 1A1 (CYP1A1) protects against nonalcoholic fatty liver disease caused by Western diet containing benzo[a]pyrene in mice - PubMed (original) (raw)

Comparative Study

Cytochrome P450 1A1 (CYP1A1) protects against nonalcoholic fatty liver disease caused by Western diet containing benzo[a]pyrene in mice

Shigeyuki Uno et al. Food Chem Toxicol. 2018 Mar.

Abstract

The Western diet contributes to nonalcoholic fatty liver disease (NAFLD) pathogenesis. Benzo[a]pyrene (BaP), a prototypical environmental pollutant produced by combustion processes, is present in charcoal-grilled meat. Cytochrome P450 1A1 (CYP1A1) metabolizes BaP, resulting in either detoxication or metabolic activation in a context-dependent manner. To elucidate a role of CYP1A1-BaP in NAFLD pathogenesis, we compared the effects of a Western diet, with or without oral BaP treatment, on the development of NAFLD in Cyp1a1(-/-) mice versus wild-type mice. A Western diet plus BaP induced lipid-droplet accumulation in liver of Cyp1a1(-/-) mice, but not wild-type mice. The hepatic steatosis observed in Cyp1a1(-/-) mice was associated with increased cholesterol, triglyceride and bile acid levels. Cyp1a1(-/-) mice fed Western diet plus BaP had changes in expression of genes involved in bile acid and lipid metabolism, and showed no increase in Cyp1a2 expression but did exhibit enhanced Cyp1b1 mRNA expression, as well as hepatic inflammation. Enhanced BaP metabolic activation, oxidative stress and inflammation may exacerbate metabolic dysfunction in liver of Cyp1a1(-/-) mice. Thus, Western diet plus BaP induces NAFLD and hepatic inflammation in Cyp1a1(-/-) mice in comparison to wild-type mice, indicating a protective role of CYP1A1 against NAFLD pathogenesis.

Keywords: Benzo[a]pyrene; Bile acids; Inflammation; Lipogenesis; Nonalcoholic fatty liver disease; Western diet.

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Conflict of interest statement

Disclosure

The authors declare no conflicts of interest.

Figures

Fig. 1

Combined treatment with the Western diet and BaP induces hepatic steatosis in Cyp1a1(−/−) mice. (A) Hematoxylin-and-eosin staining of liver samples. (B) Hepatic cholesterol, triglyceride and bile acid levels. (C) Plasma cholesterol, triglyceride and bile acid levels. (D) Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. (E) Body weight changes and food intake. Wild-type (WT) and Cyp1a1(−/−) mice were fed a control diet versus Western diet, with or without dietary BaP for 3 weeks (D and E) and 15 weeks (A, B, C and D). *P < 0.05, **P < 0.01, ***P < 0.001 (one-way ANOVA followed by Tukey’s multiple comparisons); †† P <0.01, ††† P <0.001 compared to wild-type mice fed the same diet (Student’s _t_-test).

Fig. 2

Hepatic expression of genes involved in bile acid and cholesterol transport. (A) mRNA levels of bile-acid-export transporters BSEP (Abcb11), Mrp3, Mrp4, OSTα (Slc51a) and OSTβ (Slc51b). (B) mRNA levels of bile-acid-import transporters NTCP (Scl10a1), OATP1A1 (Slco1a1) and OATP1B2 (Slco1b2). (C) mRNA levels of cholesterol-export transporters Abcg5 and Abcg8. (D) Protein levels of MRP4 and OATP1A1. Wild-type (WT) and Cyp1a1(−/−) mice were fed the control diet versus Western diet, with or without dietary BaP, for 3 weeks. *P < 0.05, **P < 0.01, ***P < 0.001 (one-way ANOVA followed by Tukey’s multiple comparisons); †P < 0.05, ††P < 0.01 compared to wild-type mice fed the same diet (Student’s t test).

Fig. 3

Hepatic expression of genes involved in bile acid and lipid synthesis. (A) mRNA levels of bile-acid-synthesis enzymes Cyp7a1, Cyp8b1 and Cyp27a1. (B) mRNA levels of lipogenesis genes SREBP-1c (Srebf1), SCD (Scd1, Scd2, Scd3 and Scd4), Acc and Lpl. (C) Protein levels of LPL. Wild-type (WT) and Cyp1a1(−/−) mice were fed the control diet versus Western diet, with or without BaP, for 3 weeks. *P < 0.05, **P < 0.01, ***P < 0.001 (one-way ANOVA followed by Tukey’s multiple comparisons); †P < 0.05, ††P < 0.01 compared to wild-type mice fed the same diet (Student’s t test).

Fig. 4

Hepatic expression of genes involved in BaP metabolism. mRNA levels of Cyp1a1, Cyp1a2, Cyp1b1, epoxide hydrolase 1 (Ephx1), Gsta1 and Nqo1 in wild-type (WT) and Cyp1a1(−/−) mice receiving the control diet versus Western diet, with or without BaP, for 3 weeks. *P < 0.05, **P < 0.01, ***P < 0.001 (one-way ANOVA followed by Tukey’s multiple comparisons); †P < 0.05, †††P < 0.001 compared to wild-type mice fed the same diet (Student’s t test). n.d., not detected.

Fig. 5

Combined treatment with the Western diet plus BaP induces hepatic inflammation in Cyp1a1(−/−) mice. (A) mRNA levels of NOX2 (Cybb), Nox4, Duox2 and Tnf. (B) Hepatic levels of TNF-α protein. *P < 0.05, **P < 0.01 (one-way ANOVA followed by Tukey’s multiple comparisons); †P < 0.05, ††P < 0.01 compared to wild-type mice fed the same diet (Student’s t test). (C) Immunostaining of liver with anti-F4/80 antibody. Wild-type (WT) and Cyp1a1(−/−) mice fed the control diet versus Western diet, with or without BaP, for 3 weeks.

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Cytochrome P450 1A1 (CYP1A1) protects against nonalcoholic fatty liver disease caused by Western diet containing benzo[a]pyrene in mice - PubMed (original) (raw)