Introduction: Air pollution associates with increased cardiovascular morbidity and mortality, partly due to induction of dyslipidemia and metabolic syndrome. Our goal was to dissect mechanisms involved. Hypothesis: Diesel exhaust exposure induces hyperlipidemia and liver steatosis by dysregulating lipid metabolism, and altering gut microbiota composition. Methods: We assessed the effects of exposure to air pollution on lipid metabolism in mice through assessment of plasma lipids and lipoproteins, oxidized fatty acids 9-HODE and 13-HODE, lipid and carbohydrate metabolism, and gut microbiota composition. Findings were corroborated and mechanisms further assessed in culture of HepG2 hepatocytes. Results: ApoE KO mice exposed to inhaled diesel exhaust (DE, 6 hours/day, 5 days/week for 16 weeks) exhibited significantly (p< 0.05) elevated plasma cholesterol and triglyceride levels, increased hepatic triglyceride content, and increased hepatic levels of 9-HODE and 13-HODE (oxidative products of linoleic acid) indicative of increased oxidative stress, as compared with control mice treated with filtered air (FA). DE also led to downregulation of Acad9 , which suggested decreased β-oxidation of fatty acids and decreased lipid catabolism. A direct effect of DEP exposure on hepatocytes was demonstrated by treatment of HepG2 cells with a methanol extract of DE particles followed by loading with oleic acid. As observed in vivo , this led to decreased ACAD9 expression, increased triglyceride content, and altered total, mitochondrial and ATP-linked respiration assessed by a Seahorse metabolic flux analyzer, indicative of mitochondrial dysfunction. Direct treatment of mitochondrias with DE particles affected mitochondrial complexes I and IV. Conclusions: Diesel exhaust exposure leads to dyslipidemia and liver steatosis in ApoE KO mice, likely due to mitochondrial dysfunction and decreased lipid catabolism.

Objective

Air pollution is associated with increased cardiovascular morbidity and mortality, as well as dyslipidemia and metabolic syndrome. Our goal was to dissect the mechanisms involved. Approach and Results: We assessed the effects of exposure to air pollution on lipid metabolism in mice through assessment of plasma lipids and lipoproteins, oxidized fatty acids 9-HODE (9-hydroxyoctadecadienoic) and 13-HODE (13-hydroxyoctadecadienoic), lipid, and carbohydrate metabolism. Findings were corroborated, and mechanisms were further assessed in HepG2 hepatocytes in culture. ApoE knockout mice exposed to inhaled diesel exhaust (DE, 6 h/d, 5 days/wk for 16 weeks) exhibited elevated plasma cholesterol and triglyceride levels, increased hepatic triglyceride content, and higher hepatic levels of 9-HODE and 13-HODE, as compared to control mice exposed to filtered air. A direct effect of DE exposure on hepatocytes was demonstrated by treatment of HepG2 cells with a methanol extract of DE particles followed by loading with oleic acid. As observed in vivo, this led to increased triglyceride content and significant downregulation of ACAD9 mRNA expression. Treatment of HepG2 cells with DE particles and oleic acid did not alter de novo lipogenesis but inhibited total, mitochondrial, and ATP-linked oxygen consumption rate, indicative of mitochondrial dysfunction. Treatment of isolated mitochondria, prepared from mouse liver, with DE particles and oleic acid also inhibited mitochondrial complex activity and β-oxidation.

Conclusions

DE exposure leads to dyslipidemia and liver steatosis in ApoE knockout mice, likely due to mitochondrial dysfunction and decreased lipid catabolism.

Objective

Air pollution is associated with increased cardiovascular morbidity and mortality, as well as dyslipidemia and metabolic syndrome. Our goal was to dissect the mechanisms involved. Approach and Results: We assessed the effects of exposure to air pollution on lipid metabolism in mice through assessment of plasma lipids and lipoproteins, oxidized fatty acids 9-HODE (9-hydroxyoctadecadienoic) and 13-HODE (13-hydroxyoctadecadienoic), lipid, and carbohydrate metabolism. Findings were corroborated, and mechanisms were further assessed in HepG2 hepatocytes in culture. ApoE knockout mice exposed to inhaled diesel exhaust (DE, 6 h/d, 5 days/wk for 16 weeks) exhibited elevated plasma cholesterol and triglyceride levels, increased hepatic triglyceride content, and higher hepatic levels of 9-HODE and 13-HODE, as compared to control mice exposed to filtered air. A direct effect of DE exposure on hepatocytes was demonstrated by treatment of HepG2 cells with a methanol extract of DE particles followed by loading with oleic acid. As observed in vivo, this led to increased triglyceride content and significant downregulation of ACAD9 mRNA expression. Treatment of HepG2 cells with DE particles and oleic acid did not alter de novo lipogenesis but inhibited total, mitochondrial, and ATP-linked oxygen consumption rate, indicative of mitochondrial dysfunction. Treatment of isolated mitochondria, prepared from mouse liver, with DE particles and oleic acid also inhibited mitochondrial complex activity and β-oxidation.

Conclusions

DE exposure leads to dyslipidemia and liver steatosis in ApoE knockout mice, likely due to mitochondrial dysfunction and decreased lipid catabolism.