Honokiol Inhibits The Inflammatory Response And Lipid Metabolism Disorder By Inhibiting P38α In Alcoholic Liver Disease

Objective: Alcoholic liver disease（ALD）is one of the major causes of morbidity and mortality in liver disease worldwide,but there is still no effective treatment for ALD.ALD is a chronic liver disease accompanied by inflammatory response and lipid metabolism disorder.Honokiol is a lignin-type natural compound isolated from the leaves and bark of Magnolia plants.Because of its beneficial effects of a variety of chronic diseases,honokiol has been widely studied.A growing number of studies show that natural lignin,including honokiol,has a potential effect on the treatment of ALD.But the mechanism of honokiol in ALD still needs further discussion.Alcohol directly activates liver cells to produce inflammatory cytokines,including tumor necrosis factor-α（TNF-α）,interleukin-6（IL-6）and interleukin-1β（IL-1β）,causing liver damage.Alcohol consumption also affects liver lipid metabolism.PPAR-α（Peroxisome proliferator-activated receptor α）,a member of the ligand activated transcription factor nuclear receptor superfamily,plays an important role in regulating liver fatty acid homeostasis and inflammatory control.There is good evidence that ethanol downregulated PPAR-α in mouse liver.SREBP-1c（Sterol regulatory element-binding protein1c）is a key regulator of lipid accumulation,and ethanol can promote the synthesis of fatty acids by upregulating SREBP-1c.p38α is an intracellular signal transduction factor involved in the biosynthesis of inflammatory cytokines（TNF-α,IL-6 and IL-1β）and induces the production of inflammatory proteins such as NF-κB.In addition,alcohol stimulates the activation of NF-κB pathway,inducing the expression of TNF-α,IL-6and IL-1β.Inhibition of inflammatory cytokines and lipid metabolism mediators seem to be useful in the treatment of ALD.There is less research on how honokiol ameliorates ALD by regulating inflammatory cytokines and lipid metabolites.In order to better explore the mechanism of honokiol in the treatment of ALD,this experiment was conducted.Our experiment through animal experiments and cell experiments to study honokiol in the improvement of ALD,and the effect of honokiol on inflammatory factors inhibition and lipid metabolism index improvement in ALD.Methods: C57BL/6J male mice were randomly divided into control group,alcoholic liver model group,honokiol low-dose group（25mg/kg）,honokiol medium-dose group（50mg/kg）,honokiol high-dose group（100mg/kg）and silibinin group（100mg/kg）.Alcoholic liver model was established by Gaobin method and corresponding drugs were given intragastric administration in the blank control group.At the same time,equal volume of normal saline were given intragastric administration in the alcoholic liver model group.After the modeling,blood and liver tissue were collected under anesthesia The body weight and liver weight of mice were tested,and the levels of serum ALT,AST and inflammatory factors were detected.Liver tissue was stained with HE to observe the liver tissue injury.Immunohistochemistry was used to detect the expression of inflammatory factors and lipid metabolism indexes and p38α in liver tissue.Western blotting and RT-q PCR were used to detect the expression levels of related indexes.In vitro,AML-12 cells were induced with Et OH.After p38α was silenced and overexpressed,the expression levels of inflammatory factors（TNF-α,IL-6,IL-1β）,lipid metabolism indexes（SREBP-1c,PPAR-α）,p38α,NF-κB-p IKKα and other related indexes were detected by Western blotting and RT-q PCR,respectively.Results: This study confirmed that honokiol has a protective effect on ALD,because it significantly inhibited the expression levels of inflammatory cytokines（TNF-α,IL-6,IL-1β）in alcohol-fed mice and alcohol-induced AML-12 cells.At the same time,the expression of lipid metabolism parameter SREBP-1c decreased,and the expression of PPAR-α increased.p38α is considered to be one of the key intracellular signaling regulators involved in the biosynthesis of inflammatory cytokines and lipid metabolites.The results showed that honokiol significantly inhibited the expression of p38α in vivo and in vitro,and p38α regulated the expression of inflammatory factors and lipid metabolism indicators.In AML-12 cells treated with honokiol,inhibition of p38α inhibited the expression of TNF-α,IL-6,IL-1β and SREBP-1c,but promoted the expression of PPAR-α.Compared with p38α silencing,p38α overexpression and honokiol treatment groups had opposite effects on inflammatory cytokines and lipid metabolism indices.In addition,the activation pattern of p38α is related to NF-κB activation.In this study,honokiol significantly inhibited p38α-mediated NF-κB-p IKK αactivation.In conclusion,honokiol may effectively regulate NF-κB signaling pathway by inhibiting p38α,thereby reducing the inflammatory response and lipid metabolism disorder of ALD.Conclusion: These experimental results suggest that honokiol inhibits the inflammatory response and lipid metabolism disorder of alcoholic liver disease by regulating p38α.