Sub-chronic exposure to lanthanum chloride induces hepatic steatosis via AMPK-dependent lipophagic defects in male zebrafish.
Chronic exposure to lanthanum chloride can cause significant liver injury and steatosis in zebrafish, with potential implications for environmental health risks. AICAR showed promise in restoring certain cellular pathways in vitro.
Where it sits
this study against the rest of the aicar (acadesine) corpusSummary and findings
This study investigated the effects of lanthanum chloride (LaCl3) on hepatic steatosis in male zebrafish exposed from 2 hours post-fertilization to 120 days post-fertilization. The study found that exposure to LaCl3 at concentrations of 0.1 and 1 μM resulted in significant liver injury and steatosis. AICAR was noted to restore certain signaling pathways in HepG2 cells, but no specific therapeutic claims are made.
Abstract
Lanthanum (La), one of the most widely used rare earth elements (REEs), is inevitably released into the environment, raising concerns about its potential health risks. Epidemiological evidence has linked La exposure to liver injury, but the mechanisms underlying chronic hepatotoxicity remain poorly understood. Here, zebrafish were exposed to environmentally relevant concentrations of LaCl<sub>3</sub> (0.1 and 1 μM) from 2 hours post-fertilization (hpf) to 120 days post-fertilization (dpf), and integrated histological, biochemical, metabolomic, and transcriptomic analyses to examine LaCl<sub>3</sub>-induced hepatic responses. We found that chronic LaCl<sub>3</sub> exposure caused marked hepatic steatosis and liver injury in male zebrafish, and these effects persisted after a 30-day depuration period. Multi-omics analyses revealed that LaCl<sub>3</sub> drives glycolysis-dependent metabolic reprogramming, which subsequently suppresses the AMPK-ULK1-LC3B axis, thereby impairing lipophagy and leading to abnormal lipid droplet accumulation. In HepG2 cells, pharmacological inhibition of glycolysis with 2-DG or activation of AMPK with AICAR effectively restored AMPK-ULK1-LC3B signaling and attenuated LaCl<sub>3</sub>-induced lipid accumulation. Collectively, our findings provide a previously underrecognized mechanism underlying LaCl<sub>3</sub>-disrupted hepatic lipid homeostasis, offering novel insights into REEs-related hepatotoxicity and supporting environmental health risk assessment.
Background
This paper addresses the potential health risks associated with lanthanum chloride (LaCl3), a rare earth element released into the environment. Previous epidemiological studies have linked La exposure to liver injury, but the underlying mechanisms remain unclear. Understanding these mechanisms is crucial for assessing environmental health risks and potential impacts on human health.
Methods
Zebrafish were exposed to environmentally relevant concentrations of LaCl3 (0.1 and 1 μM) from 2 hours post-fertilization to 120 days post-fertilization. The study utilized integrated histological, biochemical, metabolomic, and transcriptomic analyses to examine hepatic responses. Primary outcomes included the assessment of hepatic steatosis and liver injury.
Results
Chronic exposure to LaCl3 resulted in marked hepatic steatosis and liver injury in male zebrafish. The study reported that these effects persisted even after a 30-day depuration period. Multi-omics analyses indicated that LaCl3 exposure drives glycolysis-dependent metabolic reprogramming, which suppresses the AMPK-ULK1-LC3B axis, impairing lipophagy.
Interpretation
The findings suggest that LaCl3 disrupts hepatic lipid homeostasis through a previously unrecognized mechanism. While the study provides insights into the effects of La exposure, the clinical significance of the findings is uncertain due to the use of a zebrafish model. The limitations include the potential lack of direct applicability to human health and the need for further research to validate these mechanisms in human systems.
Key findings
- Chronic LaCl3 exposure caused marked hepatic steatosis and liver injury in male zebrafish.
- Effects persisted after a 30-day depuration period.
- LaCl3 drives glycolysis-dependent metabolic reprogramming.
- Inhibition of glycolysis with 2-DG or activation of AMPK with AICAR restored AMPK-ULK1-LC3B signaling.
- LaCl3 exposure led to abnormal lipid droplet accumulation.
Limitations
- Zebrafish model may not fully replicate human responses.
- Effects may not translate directly to clinical relevance in humans.
- No human data reported.
- Short follow-up period of 30 days post-exposure.