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Prolonged exposure to arsenic can cause nonalcoholic steatohepatitis (NASH). The NOD-like receptor protein 3 (NLRP3) inflammasome plays an essential role in the process of NASH. However, the mechanism by which arsenic promotes NLRP3 expression remains unclear. Three-month NaAsO2 gavage led to the nuclear factor-κB (NF-κB) signaling pathway activation and NASH. Additionally, NaAsO2 upregulated the level of Filamin A (FLNA) and pyroptosis, thereby activating the NLRP3 inflammasome in SD rat liver. Using FLNA siRNA, NASH-associated inflammation and pyroptosis were clearly mitigated by reducing activation of the NLRP3 inflammasome. Furthermore, arsenic treatment facilitated activation of the NF-κB signaling pathway and promoted p-p65 translocation into the nucleus. Chromatin immunoprecipitation (Ch-IP) assay indicated that FLNA promoted p65 binding to the NLRP3 gene and upregulated the transcription of NLRP3, ultimately leading to pyroptosis and NASH. Our findings indicate that FLNA and pyroptosis are strongly associated with NASH induced by NaAsO2. Collectively, the findings of this study indicated that FLNA mediates NF-κB signaling pathway-induced activation of the NLRP3 inflammasome and ultimately activates pyroptosis and NASH upon NaAsO2 exposure. This information may be useful for improving therapeutic strategies against arsenic-induced NASH. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) messenger RNA methylation is the most widespread gene regulatory mechanism affecting liver functions and disorders. However, the relationship between m6A methylation and arsenic-induced hepatic insulin resistance (IR), which is a critical initiating event in arsenic-induced metabolic syndromes such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), remains unclear. Here, we showed that arsenic treatment facilitated methyltransferase-like 14 (METTL14)-mediated m6A methylation, and that METTL14 interference reversed arsenic-impaired hepatic insulin sensitivity. We previously showed that arsenic-induced NOD-like receptor protein 3 (NLRP3) inflammasome activation contributed to hepatic IR. However, the regulatory mechanisms underlying the role of arsenic toward the post-transcriptional modification of NLRP3 remain unclear. Here, we showed that NLRP3 mRNA stability was enhanced by METTL14-mediated m6A methylation during arsenic-induced hepatic IR. Furthermore, we demonstrated that arsenite methyltransferase (AS3MT), an essential enzyme in arsenic metabolic processes, interacted with NLRP3 to activate the inflammasome, thereby contributing to arsenic-induced hepatic IR. Also, AS3MT strengthened the m6A methylase association with NLRP3 to stabilize m6A-modified NLRP3. In summary, we showed that AS3MT-induced m6A modification critically regulated NLRP3 inflammasome activation during arsenic-induced hepatic IR, and we identified a novel post-transcriptional function of AS3MT in promoting arsenicosis. [ABSTRACT FROM AUTHOR]

The activation of hepatic stellate cells (HSCs) is a key event during the progression of liver fibrosis (LF). We have previously indicated that NLRP3 inflammasome plays a crucial role in arsenic-induced HSCs activation. However, the mechanism of cascade responses between NLRP3 inflammasome and HSCs activation is unclear. Here, we showed that the transcription and protein level of Hsp47 was upregulated after 4 μM arsenic treatment, both in vivo and in vitro. Additionally, arsenic-induced HSCs activation was remarkably alleviated by the interference of Hsp47. Furthermore, blockage of NLRP3 significantly mitigated the activation of the NLRP3 inflammasome and decreased the expression of Hsp47, thereby attenuating the arsenic-induced HSCs activation. However, the ablation of Hsp47 did not affect the activation of the NLRP3 inflammasome. Notably, the protein-protein interaction between NLRP3 and Hsp47 was observed both in vivo and in vitro , and the target amino acid sequences were further identified. In summary, the present study indicated that NaAsO 2 induced HSCs activation via the NLRP3 inflammasome-Hsp47 pathway. These findings provide direct evidence that Hsp47 may be a potential therapeutic target for arsenic-induced LF. [Display omitted] • Hsp47 plays a critical role in HSCs activation and iAs-induced liver fibrosis. • iAs treatment upregulates Hsp47 via promoting NLRP3 inflammasome activation. • NLRP3 interacts with Hsp47 during the activation of HSCs by iAs. [ABSTRACT FROM AUTHOR]

Hepatic insulin resistance (IR) is the primary pathology of type 2 diabetes (T2D). The role of the NOD-like receptor protein 3 (NLRP3) inflammasome in arsenic-induced hepatic IR has been previously demonstrated. However, the mechanism of the arsenic-induced activation of the NLRP3 inflammasome is still unclear. Here, we demonstrate that NaAsO 2 downregulated the mRNA and protein level of Annexin A1 (AnxA1), an anti-inflammatory factor, in rat livers and L-02 cells. Moreover, AnxA1 overexpression significantly alleviated arsenic-induced NLRP3 inflammasome activation and IR in L-02 cells. Importantly, Co-immunoprecipitation (Co-IP) results showed that AnxA1 1–190 peptide could bind to the domain encompassing amino acids 1–210 and 211–550 of NLRP3. In conclusion, our experiments demonstrated that arsenic exposure could activate the NLRP3 inflammasome and IR by inhibiting the AnxA1 activity. These findings suggest that AnxA1 may be a promising therapeutic target of arsenicosis. [Display omitted] • NaAsO 2 decreased the expression of AnxA1 in hepatocytes. • NaAsO 2 -activated NLRP3 inflammasome was inhibited by AnxA1 overexpression. • AnxA1 target-binding of NLRP3 specially inhibited the expression of NLRP3. [ABSTRACT FROM AUTHOR]