Regulation of Benzo[a]pyrene-Induced Hepatic Lipid Accumulation through CYP1B1-Induced mTOR-Mediated Lipophagy

• Published in: International journal of molecular sciences 2024-01, Vol.25 (2), p.1324
• Main Authors: Bu, Kyung-Bin, Kim, Min, Shin, Min Kyoung, Lee, Seung-Ho, Sung, Jung-Suk
• Format: Article
• Language: English
• Subjects: Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Benzo(a)pyrene - toxicity; benzo[a]pyrene; Benzopyrene; Cell cycle; Cell growth; CYP1B1; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1B1 - genetics; Cytochrome P-450 Enzyme System; Enzymes; Genes; Hydrocarbons; Lipids; lipophagy; Liver; Liver - metabolism; Liver diseases; Metabolism; mTOR; non-alcoholic fatty liver disease; Proteins; Receptors, Aryl Hydrocarbon - metabolism; TOR Serine-Threonine Kinases - genetics; Type 2 diabetes
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25021324

Metabolic dysfunction-associated steatotic liver disease (MASLD) is caused by lipid accumulation within the liver. The pathogenesis underlying its development is poorly understood. Benzo[a]pyrene (B[a]P) is a polycyclic aromatic hydrocarbon and a group 1 carcinogen. The aryl hydrocarbon receptor activation by B[a]P induces cytochrome P450 (CYP) enzymes, contributing to hepatic lipid accumulation. However, the molecular mechanism through which the B[a]P-mediated induction of CYP enzymes causes hepatic lipid accumulation is unknown. This research was conducted to elucidate the role of CYP1B1 in regulating B[a]P-induced lipid accumulation within hepatocytes. B[a]P increased hepatic lipid accumulation, which was mitigated by CYP1B1 knockdown. An increase in the mammalian target of rapamycin (mTOR) by B[a]P was specifically reduced by CYP1B1 knockdown. The reduction of mTOR increased the expression of autophagic flux-related genes and promoted phagolysosome formation. Both the expression and translocation of TFE3, a central regulator of lipophagy, were induced, along with the expression of lipophagy-related genes. Conversely, enhanced mTOR activity reduced TFE3 expression and translocation, which reduced the expression of lipophagy-related genes, diminished phagolysosome production, and increased lipid accumulation. Our results indicate that B[a]P-induced hepatic lipid accumulation is caused by CYP1B1-induced mTOR and the reduction of lipophagy, thereby introducing novel targets and mechanisms to provide insights for understanding B[a]P-induced MASLD.