UCSF

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.