Bis(2-Ethylhexyl)-2,3,4,5-Tetrabromophthalate Promotes NASH Progression through Disrupting Endoplasmic...

Area of Science:

• Environmental Health
• Hepatology
• Toxicology

Background:

• Environmental pollutants are linked to chronic liver diseases.
• Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH), a brominated flame retardant, is detected in human tissues, but its liver disease role is unclear.

Purpose of the Study:

• To investigate the impact of TBPH exposure on nonalcoholic steatohepatitis (NASH) progression and mechanisms using mouse and liver organoid (LO) models.

Main Methods:

• Diet-induced NASH mouse model and liver organoid (LO) model.
• Lipidomic analysis to identify metabolic changes.
• Investigation of Mitofusin2 (MFN2) expression and endoplasmic reticulum-mitochondria (ER-Mito) contacts.
• Treatment with MFN2 agonist M1 in LOs.

Main Results:

• TBPH exposure exacerbated hepatic steatosis, inflammation, and fibrosis in mice.
• TBPH disrupted phospholipid metabolism, reducing cardiolipin (CL) and phosphatidylserine (PS).
• TBPH decreased MFN2, impairing ER-Mito contacts, phospholipid transfer, and mitochondrial function, triggering UPR^mt and ER stress.
• MFN2 activation in LOs ameliorated TBPH-induced NASH phenotypes by restoring ER-Mito contacts and bioenergetics.

Conclusions:

• TBPH is identified as an environmental risk factor contributing to NASH progression.
• The study highlights the critical role of MFN2-mediated ER-Mito contacts in lipid metabolism and liver health.
• Findings offer new perspectives for evaluating the health risks associated with brominated flame retardants.