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

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

  • Environ Pollut. 2025 Jul 16:383:126846. doi: 10.1016/j.envpol.2025.126846.
Hui-Ru Kuo 1,  Yu-Fen Chung 2,  Li-Ting Wang 3,  Chih-Wen Wang 4,  Shih-Hsien Hsu 5,  Li-Chen Chen 6,  Ming-Hong Lin 7,  Shau-Ku Huang 8,  Kwei-Yan Liu 9
Affiliations

Affiliations

  • 1 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan.
  • 2 National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan.
  • 3 Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
  • 4 Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, Division of Hepatobiliary, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 5 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 6 Department of Pediatrics, Municipal TuCheng Hospital, Chang Gung Memorial Hospital, New Taipei City, Taiwan; Chang Gung University, College of Medicine, Taoyuan, Taiwan.
  • 7 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Microbiology and Immunology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: mhlin@kmu.edu.tw.
  • 8 National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan; Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: skhuang@nhri.edu.tw.
  • 9 National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan. Electronic address: a52t5213b@hotmail.com.
PMID: 40681076 DOI: 10.1016/j.envpol.2025.126846
Abstract

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.

Keywords

Metabolic dysfunction-associated steatotic liver disease; Polycyclic aromatic hydrocarbon; Sphingosine-1-phosphate; Sphingosine-1-phosphate lyase; Sphingosine-1-phosphate receptor 2.

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