miR-18a-5p/PXR/SREBP2 Was Involved in MAFLD Associated With Methyl Tert-Butyl Ether Among Petrol Station Workers

Background: Metabolic associated fatty liver disease (MAFLD), previously defined as non-alcoholic fatty liver disease (NAFLD), has been shown to be closely related to many environmental pollutants. Lately, we found methyl tert-butyl ether (MTBE), a new environmental pollutant, could increase NAFLD risk in American adults, which still needs more population epidemiological studies to verify, and its pathogenic mechanism is not yet clear.

Methods: We conducted a cross-sectional study among petrol station workers, diagnosed their MAFLD according to internationally recognised diagnostic criteria, assessed the potential association of MTBE exposure with MAFLD risk, and explored the miR-18a-5p/PXR/SREBP2 pathway as possible pathogenic mechanisms in male Wistar rats and HepaRG cells treated with MTBE.

Results: Blood MTBE levels were found to be significantly correlated with an increased risk of MAFLD, and MAFLD risk increased by 24.3% for every 0.1 μg/L increase in blood MTBE. Consistently, we found that MTBE exposure could induce MAFLD in rats and HepaRG cells, and activate pregnane X receptor (PXR) by inhibiting miR-18a-5p to upregulate the expression of sterol regulatory element-binding protein 2 (SREBP2) and its nuclear translocation, thereby upregulating the expression of its downstream target genes.

Conclusions: Our study demonstrated that MTBE exposure might be a significant risk factor for MAFLD, and MTBE could promote liver Cholesterol synthesis and lipid deposition by activating the miRNA-18a-5p/PXR/SREBP2 pathway.

MAFLD; Pregnane X receptor (PXR); methyl tert‐butyl ether (MTBE); miRNA‐18a‐5p; sterol regulatory element‐binding protein 2 (SREBP2).