Processed Buthus martensii Karsch scorpions ameliorate diet-induced NASH in mice by attenuating Kv1.3-mediated macrophage activation

Ethnopharmacological relevance Processed Buthus martensii Karsch (BmK) scorpion, also known as Quan-Xie, is a traditional Chinese medicine clinically used to for the treatment of NAFLD due to its Tong-Luo-San-Jie effects. Our previous study showed that aqueous extract of the processed BmK scorpion venom gland (pVg AE) inhibited macrophage inflammation by targeting Kv1.3 and identified the thermostable peptide BmKK2 as a potent Kv1.3 blocker. Aim of the study This study examined the therapeutic effects of processed BmK scorpions on NASH, specifically focusing on the involvement of their anti-inflammatory effects mediated by macrophage-expressed Kv1.3 in NASH. Materials and methods In the present study, the anti-NASH effects of pVg AE were evaluated in high-fat diet (HFD)-induced NASH mouse models. Additionally, the in vitro anti-inflammatory mechanisms of pVg AE and BmKK2 were assessed using a palmitic acid (PA)-induced mouse bone marrow-derived macrophages (BMDMs) inflammation model. Protein and cytokine expression related to the Kv1.3-NF-κB pathway was analyzed by real-time PCR, immunoblotting and ELISA. The effect of pVg AE and BmKK2 on potassium channels were detected by whole-cell voltage-clamp recordings on transfected HEK293 cells or mouse BMDMs. Calcium ion imaging was used to evaluate intracellular calcium signaling. Furthermore, the study utilized Kv1.3 siRNA and a BMDMs and hepatocytes co-culture model were used to investigate the specific role of Kv1.3 in mediating the effects of pVg AE and BmKK2. Results Lipid accumulation upregulated Kv1.3 expression in macrophages both in vivo and in vitro . However, pVg AE significantly reduced Kv1.3 expression and Kv1.3-positive macrophage infiltration. Treatment with pVg AE improved obesity, insulin resistance (IR), hepatic steatosis (HS), inflammation, and fibrosis in HFD-fed mice. Mechanistically, pVg AE and BmKK2 inhibited macrophage inflammation by targeting Kv1.3, which reduced PA-induced intracellular Ca 2+ levels, resulting in the inhibition of the NF-κB pathway and TNFα release. Conclusions This study demonstrates that Kv1.3-mediated macrophage inflammation is involved in the pathogenesis and treatment of NASH. pVg AE effectively alleviates metabolic stress-induced NASH by inhibiting this inflammation.

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