Lo Chia-Wen, Yen Chih-Ching, Chen Chun-You, Chen Haw-Wen, Lii Chong-Kuei
Department of Nutrition, China Medical University, Taichung 406, Taiwan.
Department of Respiratory Therapy, China Medical University, Taichung 404, Taiwan; Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan.
Toxicol Appl Pharmacol. 2023 Mar 1;462:116424. doi: 10.1016/j.taap.2023.116424. Epub 2023 Feb 10.
The NLRP3 inflammasome plays an important role in the pathogenesis of numerous inflammation-related diseases. Benzyl isothiocyanate (BITC) is rich in cruciferous vegetables and possesses potent antioxidant, anti-inflammatory, anti-cancer, and anti-obesogenic properties. In this study, we investigated the role of the NLRP3 inflammasome in the protection by BITC against steatohepatitis and insulin resistance. A mouse model of high-fat/cholesterol/cholic acid diet (HFCCD)-induced steatohepatitis, LPS/nigericin-stimulated primary Kupffer cells, and IL-1β treated primary hepatocytes were used. BITC attenuated LPS/nigericin-induced activation of the NLRP3 inflammasome by enhancing protein kinase A-dependent NLRP3 ubiquitination, which increased the degradation of NLRP3 and reduced IL-1β secretion in Kupffer cells. In hepatocytes, BITC pretreatment reversed the IL-1β-induced decrease in the phosphorylation of IR, AKT, and GSK3β in response to insulin. After 12 weeks of HFCCD feeding, increases in blood alanine aminotransferase (ALT) and glucose levels were ameliorated by BITC. Hepatic IL-1β production, macrophage infiltration, and collagen expression induced by HFCCD were also mitigated by BITC. BITC suppresses activation of the NLRP3 inflammasome in Kupffer cells by enhancing the PKA-dependent ubiquitination of NLRP3, which leads to suppression of IL-1β production and subsequently ameliorates hepatic inflammation and insulin resistance.
NLRP3炎性小体在众多炎症相关疾病的发病机制中起重要作用。异硫氰酸苄酯（BITC）富含于十字花科蔬菜中，具有强大的抗氧化、抗炎、抗癌和抗肥胖特性。在本研究中，我们探究了NLRP3炎性小体在BITC对脂肪性肝炎和胰岛素抵抗的保护作用中的角色。使用了高脂/胆固醇/胆酸饮食（HFCCD）诱导的脂肪性肝炎小鼠模型、脂多糖/尼日利亚菌素刺激的原代库普弗细胞以及白细胞介素-1β处理的原代肝细胞。BITC通过增强蛋白激酶A依赖性的NLRP3泛素化作用，减弱了脂多糖/尼日利亚菌素诱导的NLRP3炎性小体的激活，这增加了NLRP3的降解并减少了库普弗细胞中白细胞介素-1β的分泌。在肝细胞中，BITC预处理逆转了白细胞介素-1β诱导的胰岛素刺激下胰岛素受体（IR）、蛋白激酶B（AKT）和糖原合成酶激酶3β（GSK3β）磷酸化的降低。在HFCCD喂养12周后，BITC改善了血液中丙氨酸氨基转移酶（ALT）和葡萄糖水平的升高。BITC还减轻了HFCCD诱导的肝脏白细胞介素-1β产生、巨噬细胞浸润和胶原蛋白表达。BITC通过增强NLRP3的蛋白激酶A依赖性泛素化作用，抑制库普弗细胞中NLRP3炎性小体的激活，这导致白细胞介素-1β产生的抑制，随后改善肝脏炎症和胰岛素抵抗。
