Polycyclic aromatic hydrocarbon aggravates high-fat diet-induced metabolic dysfunction-associated steatotic liver disease through disturbing hepatocyte sphingolipid metabolism.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic liver condition, with polycyclic aromatic hydrocarbons (PAHs) as a potential risk factor; however, the regulatory mechanisms remain unclear. PAH exposure oxidizes sphingosine-1-phosphate (S1P) lyase (S1PL) at position 317, reducing lyase activity and increasing S1P levels which is linked to MASLD progression. This study investigates how PAH exposure influences MASLD development and explores the role of S1PL and S1P in this process. C57BL/6J wild-type (WT) and mutant Sgpl1-knock-in (KI) (C317A, rendering resistance to oxidation) were fed either control diet (CD) or high-fat diet (HFD) for 8 weeks. Mice were treated with 500 μg/kg indeno(1,2,3-cd)pyrene (IP) every three days by oral gavage. Hepatocytes were isolated using classic two-step collagenase perfusion method and treated with IP or S1P. Increased lipid accumulation and upregulated S1P levels were observed in the MPH upon IP treatment. Reduced weight gain, fatty liver, and serum S1P levels were observed in Sgpl1-KI mice compared to those of WT mice upon HFD and IP treatments. Inhibition of S1PL increased lipid accumulation and S1P levels in Sgpl1-KI MPHs, whereas pharmacological inhibition of sphingosine kinase 1 (SPHK1), not SPHK2, decreased IP-induced lipid accumulation and S1P levels in WT MPH. S1P receptor 2 (S1pr2)-null MPHs developed alleviated IP-induced lipid accumulation as compared with WT MPHs. PAH elevated S1P via SphK1- and S1PL-mediated pathways, thereby increasing lipid accumulation through the S1P/S1PR2 axis in hepatocytes, worsening HFD-induced MASLD.