Study On The Function Of Wnt Signaling Pathway On Regulating Hepatointestinal Diseases And The Mechanism Of Berberin In Preventing Liver Injury

Background:The canonical Wnt/?-catenin signaling pathway has played a key role in embryonic development,tumor formation,and stem cells.Studies have also shown that the Wnt/?-catenin signaling pathway could regulate liver development,cancerogeneis,and metabolism,but its mechanism remains unclear.The liver is an important digestive and metabolic organ in the human body.When type 2 diabetes and other metabolic disorders occur,the liver will have "selective insulin resistance".There are many factors regulating the insulin signaling pathway,and the role of the Wnt / ?-catenin signaling pathway on insulin signaling in hepatocytes is still unclear.At the same time,based on the theory of "hepatic intestinal axis",intestinal barrier and intestinal flora are closely related to many liver diseases.It is still unclear whether the Wnt/?-catenin signaling pathway in intestinal epithelial cells can regulate the effect of intestinal flora on liver function by affecting the intestinal barrier.Pre-clinical and clinical evidence indicate that persistent endoplasmic reticulum stress(ERS)results in increasing the risk of metabolic diseases including diabetes,obesity and dyslipidemia.However,it is not clear whether there is an interaction between Wnt / ?-catenin signaling pathway and endoplasmic reticulum stress in regulating hepatocytes metabolism.Because persistent endoplasmic reticulum stress in the liver can cause liver damage and abnormal liver metabolism,which can lead to cirrhosis,liver cancer,and even death,it is necessary to find drugs for endoplasmic reticulum stress-induced liver injury.In recent years,many studies have found that the Chinese medicine component berberine has the pharmacological effect of lowering blood sugar and blood fat,but its specific molecular biological mechanism is not completely clear.In this article,we will use Hep G2 hepatocellular carcinoma model and C57 BL / 6 mouse model to explore the role and mechanism of Wnt/?-catenin signaling in hepatocyte metabolism and intestinal barrier,and at the same time berberine could improve liver injury by inhibiting endoplasmic reticulum stress.Purposes:1.To investigate the function of Wnt/?-catenin signaling pathway on the metabolism of hepatocytes;2.To find out the molecular mechanism by which the Wnt/?-catenin signaling pathway affects the metabolism of hepatocytes through endoplasmic reticulum stress;3.To investigate the function of Wnt/?-catenin signaling pathway on intestinal inflammation and its molecular mechanism;4.To explore the protective effect of berberine on liver injury and its molecular mechanism.Methods:1.HepG2 cells were used as the model to explore the mechanism of excessive activation of Wnt/?-catenin signaling pathway in hepatic metabolism;2.Mice administrated with intraperitoneal injection of lithium chloride were used to explore the role of Wnt/?-catenin signaling pathway in the development of liver injury and colonic inflammation;3.Mice intraperitoneally injected with tunicamycin were used as models to investgate the role and mechanism of berberine in preventing liver injury caused by ERS.Results:1.Excessive activation of Wnt signaling pathway would lead to abnormal metabolism of liver cells,and inhibition of endoplasmic reticulum stress could improve abnormal metabolism of hepatocytes caused by excessive activation of Wnt signaling pathway;2.Intraperitoneal injection of LiCl could activate the Wnt signaling pathway cause liver injury ? colonic inflammation and intestinal flora disturbance;3.The possible mechanism of colitis caused by intraperitoneal injection of Li Cl:(1)Lithium chloride could activate F4/80 macrophages to secrete pro-inflammatory cytokines,such as TNF? and IL-1?;(2)Lithium chloride could inhibit the transcription of IgA encoding genes in plasma cells;(3)Lithium chloride could inhibit the expression of pigr and claudin-15 in colonic epithelial cells.4.Berberine prevents endoplasmic reticulum stress-induced liver injury by improving the unfolded protein response pathway and regulating intestinal flora.Conclusions:Excessive activation of the Wnt signaling pathway resulted in endoplasmic reticulum stress and abnormal hepatocytes metabolism;meanwhile,excessive activation of the Wnt signaling pathway could cause colon inflammation and intestinal flora disturbance;berberine could prevent endoplasmic reticulum stress-induced liver damage.