RESUMEN
Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease (MAFLD). However, there are few reported lipotoxicity inhibitors. Here, we identified a natural anti-lipotoxicity candidate, HN-001, from the marine fungus Aspergillus sp. C1. HN-001 dose- and time- dependently reversed palmitic acid (PA)-induced hepatocyte death. This protection was associated with IRE-1α-mediated XBP-1 splicing inhibition, which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation. Knockdown of XBP-1s attenuated lipotoxicity, but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes. Notably, the ER stress and lipotoxicity amelioration was associated with PLA2. Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity, reduced lysophosphatidylcholine (LPC) level, subsequently ameliorated lipotoxicity. In contrast, overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001. Additionally, HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway. In vivo, chronic administration of HN-001 (i.p.) in mice alleviated all manifestations of MAFLD, including hepatic steatosis, liver injury, inflammation, and fibrogenesis. These effects were correlated with PLA2/IRE-1α/XBP-1s axis and JNK signaling suppression. These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity, and provide a natural structural basis for developing anti-MAFLD candidates.
RESUMEN
ObjectiveTo observe the effect of probucol combined with atorvastatin in treatment of stenosis carotid atherosclerosis.MethodsEighty-six patients with stenosis carotid atherosclerosis were separated into two groups with 43 cases each by random digits table.The patients were treated with probucol combined with atorvastatin in observation group and atorvastatin only in control group.The changes of arteriosclerotic plaque and blood fat pre- and poet-treatment were observed.Results There was no significant difference in the levels of lumen area (LN) and intima-media thickness (IMT) pre-treatment between two groups (P＞ 0.05).Compared with pre-treatment,the levels of LN and IMT post-treatment were significantly decreased in observation group(P ＜ 0.05 ),while no significant difference in control group (P ＞0.05).There was significant difference in the levels of LN and IMT post-treatment between two groups [(0.59 ±0.19) cm2 vs.(0.72 ±0.28) cm2,(2.76 ±0.41 ) mm vs.(3.27 ±0.57) mm](P＜ 0.05).There was no significant difference in the levels of total cholesterol (TC),triacylglycerol (TG),low density lipoprotein cholesterol (LDL-C),high density lipoprotein cholesterol (HDL-C) pre-treatment between two groups (P ＞0.05).Compared with pre-treatment,the levels of TC,TG,LDL-C post-treatment were decreased,HDL-C was increased,there were significant differences (P ＜ 0.05 ).Post-treatment,the levels of TC,TG,LDL-C in observation group were lower and HDL-C was higher than those in control group (P ＜ 0.05).Conclusion Probucol combined with atorvastatin in treatment of stenosis carotid atherosclerosis can improve arteriosclerotic plaque and low blood fat,which can be applied in clinic.