Triclosan-induced abnormal expression of miR-30b regulates fto-mediated m6A methylation level to cause lipid metabolism disorder in zebrafish

Y Chronic exposure of triclosan (TCS) to zebrafish triggers high incidence of fatty liver and hepatitis; however, the underlying molecular mechanisms remain unclear. Herein, we identified miR-30b as a sensitive biomarker to TCS stress, reflecting in that its decreased expression caused metabolic toxicity, abnormal development and behavior, and lipid-metabolism disorder. By microinjecting the inhibitor and mimic experiments, miR-30b was proved to regulate lipid metabolism by its main target gene fto. Over-expression of FTO resulted in fat accumulation, elevation of the TG and TC levels and up-regulation of the PPAR gamma and CEBP alpha, as well as decrease of the global m(6)A level in larvae. On the contrary, the knock-down of FTO using MO caused the anti-lipogenic effect, decrease of the TG and T-CHO levels, and abnormal changes of cebp gamma, acsl5, fasn, ppap2c and ppar gamma etc. Further fortification tests of cycloleucine and betaine evidenced that the toxic effect was strongly dependent on regulation of the m(6)A level. The toxicity effects in the treatments of methylated donors and receptors were consistent with the changes in physiological functions of FTO knockdown and overexpression. The effects of cycloleucine on m6A level and lipid metabolism generally consisted with those of FTO, but this was not the case for betaine, reflecting in increased m(6)A level and lipid accumulation in larval liver. Consequently, we posit that TCS exposure caused zebrafish lipid-metabolism disorder by decreasing miR-30b expression to regulate fto-mediated m(6)A methylation level. These findings contribute to our deep understanding of the underlying molecular mechanisms regarding contaminant-originating fatty liver and hepatocellular carcinoma, and also have practical significance in pollution warning and target therapy for related diseases. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

Chronic exposure to triclosan in zebrafish leads to fatty liver and hepatitis, with miR-30b identified as a sensitive biomarker reflecting metabolic toxicity and lipid-metabolism disorder. The regulation of fto-mediated m(6)A methylation level by decreasing miR-30b expression is crucial in causing lipid-metabolism disorder in zebrafish.