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

Abstract

<p class="first" id="P1">The Western diet contributes to nonalcoholic fatty liver disease (NAFLD) pathogenesis. Benzo[ <i>a</i>]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 <i>Cyp1a1</i>(−/−) mice versus wild-type mice. A Western diet plus BaP induced lipid-droplet accumulation in liver of <i>Cyp1a1</i>(−/−) mice, but not wild-type mice. The hepatic steatosis observed in <i>Cyp1a1</i>(−/−) mice was associated with increased cholesterol, triglyceride and bile acid levels. <i>Cyp1a1</i>(−/−) mice fed Western diet plus BaP had changes in expression of genes involved in bile acid and lipid metabolism, and showed no increase in <i>Cyp1a2</i> expression but did exhibit enhanced <i>Cyp1b1</i> mRNA expression, as well as hepatic inflammation. Enhanced BaP metabolic activation, oxidative stress and inflammation may exacerbate metabolic dysfunction in liver of <i>Cyp1a1</i>(−/−) mice. Thus, Western diet plus BaP induces NAFLD and hepatic inflammation in <i>Cyp1a1</i>(−/−) mice in comparison to wild-type mice, indicating a protective role of CYP1A1 against NAFLD pathogenesis. </p>