Frequent fried food intake fuels incidence of metabolic associated fatty liver disease attributed to acrylamide-induced hepatic lipid disorders through arachidonic acid-PGE2-PPARα axis

INTRODUCTION: Fried food and hazard factors, particularly acrylamide, have been implicated in adverse health outcomes. However, how fried food consumption fuels the development of metabolic associated fatty liver disease (MAFLD) remains poorly understood. OBJECTIVES: We investigated fried food consumption in relation to MAFLD risk, which may be driven by acrylamide-induced hepatic lipid metabolism disorders. METHODS: UK Biobank data (n = 208,673) were analyzed to assess the association between fried food consumption and incident MAFLD using Cox proportional hazards models. In vivo, mice were exposed to dietary acrylamide for 14 weeks, followed by measurement of serum and hepatic lipid parameters. Transcriptomics and untargeted lipidomics were performed to elucidate the mechanisms underlying acrylamide-induced lipid dysregulation. The role of PGE2 was further validated via molecular docking analysis. RESULTS: Frequent consumption of fried foods, particularly fried potatoes, was linked with a 15% higher MAFLD risk, which was predominantly mediated by body mass index, serum triglycerides, C-reactive protein, and high-density lipoprotein cholesterol. Furthermore, long-term dietary exposure to acrylamide, a characteristic hazardous compound in fried food, significantly deteriorates lipid deposition, ultimately leading to impaired liver function and oxidative stress in liver of mice. Exposure to acrylamide inhibits the browning of white adipose and disturbs energy metabolism via downregulating uncoupling protein 1 and transcriptional regulators Prdm16, Pgc1α, Cebpβ, and Pparγ. Notably, acrylamide disrupts arachidonic acid metabolism and promotes the production of prostaglandin E2 (PGE2) driven by the upregulation of cyclooxygenase-2 and microsomal prostaglandin E synthase, which subsequently triggers hepatic inflammatory responses. Moreover, PGE2 interacts with PGE receptor Ptger3 or Ptger4 to inhibit PPARα activity, thus disrupting lipid oxidation and contributing to hepatic lipid dysfunction following long-term exposure to acrylamide. CONCLUSION: Both epidemiological and molecular evidence link acrylamide exposure to a higher MAFLD risk through the arachidonic acid-PGE2-PPARα axis, underscoring the importance of minimizing fried food consumption to preserve liver health.