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Recombinant FGF21 Attenuates Polychlorinated Biphenyl-Induced NAFLD/NASH by Modulating Hepatic Lipocalin-2 Expression
Hye Young Kim1, Young Hyun Yoo1
1Department of Anatomy and Cell Biology and BK21 Program, Department of Translational Biomedical Science, Dong-A University College of Medicine, Busan 49201, Korea.
Abstract:
Although recent studies have demonstrated that polychlorinated biphenyls (PCB) exposure leads to toxicant-associated steatohepatitis, the underlying mechanism of this condition remains unsolved. Male C57Bl/6 mice fed a standard diet (SD) or 60% high fat diet (HFD) were exposed to the nondioxin-like PCB mixture Aroclor1260 or dioxin-like PCB congener PCB126 by intraperitoneal injection for a total of four times for six weeks. We observed hepatic injury, steatosis, inflammation, and fibrosis in not only the Aroclor1260-treated mice fed a HFD but the PCB126-treated mice fed either a SD or a HFD. We also observed that both types of PCB exposure induced hepatic iron overload (HIO). Noticeably, the expression of hepatic lipocalin-2 (LCN2) was significantly increased in the PCB-induced nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) models. The knockdown of LCN2 resulted in improvement of PCB-induced lipid and iron accumulation in vitro, suggesting that LCN2 plays a pivotal role in PCB-induced NAFLD/NASH. We observed that recombinant FGF21 improved hepatic steatosis and HIO in the PCB-induced NAFLD/NASH models. Importantly, recombinant FGF21 reduced the PCB-induced overexpression of hepatic LCN2 in vivo and in vitro. Our findings indicate that recombinant FGF21 attenuates PCB-induced NAFLD/NASH by modulating hepatic lipocalin-2 expression. Our data suggest that hepatic LCN2 might represent a suitable therapeutic target for improving PCB-induced NAFLD/NASH accompanying HIO.
Insights
Polychlorinated biphenyls (PCB) exposure causes liver damage, fat accumulation, and iron overload. Fibroblast growth factor 21 (FGF21) may treat this by reducing lipocalin-2 (LCN2) levels in PCB-induced nonalcoholic fatty liver disease.
Area of Science:
- Toxicology
- Hepatology
- Endocrinology
Background:
- Polychlorinated biphenyls (PCBs) are environmental toxicants linked to steatohepatitis.
- The precise mechanisms underlying PCB-induced liver injury, including nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), require further elucidation.
Purpose of the Study:
- To investigate the role of lipocalin-2 (LCN2) in PCB-induced NAFLD/NASH.
- To evaluate the therapeutic potential of fibroblast growth factor 21 (FGF21) in mitigating PCB-induced liver pathology.
Main Methods:
- Mice were fed standard or high-fat diets and exposed to Aroclor1260 or PCB126.
- Hepatic injury, steatosis, inflammation, fibrosis, and iron overload were assessed.
- Lipocalin-2 (LCN2) expression was analyzed, and its function was studied using knockdown techniques.
- The effects of recombinant FGF21 were evaluated in vivo and in vitro.
Main Results:
- PCB exposure induced hepatic injury, steatosis, inflammation, fibrosis, and hepatic iron overload (HIO) in mice.
- Increased hepatic LCN2 expression was observed in PCB-induced NAFLD/NASH models.
- LCN2 knockdown ameliorated PCB-induced lipid and iron accumulation.
- Recombinant FGF21 improved hepatic steatosis and HIO, and reduced LCN2 overexpression.
Conclusions:
- Lipocalin-2 (LCN2) plays a critical role in the pathogenesis of PCB-induced NAFLD/NASH.
- FGF21 demonstrates therapeutic potential by attenuating PCB-induced liver injury through modulation of LCN2.
- Hepatic LCN2 may serve as a therapeutic target for PCB-induced NAFLD/NASH with hepatic iron overload.
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