Previous studies have shown that

Previous studies have shown that ox-LDL-induced hepatic sinus dysfunction is the result of multiple pathways, multi-factorial regulation, and in the present study, we reported for the first time that ox-LDL regulates the basement membrane protein VN through the integrin αvβ5 pathway under high glucose conditions. We have found that high glucose and ox-LDL can not only increase the expression of integrin αvβ5 and basement membrane protein VN in LSECs, but also can increase their expression in the coexistence of high glucose and ox-LDL. Conditions of liver sinusoidal cell dysfunction, and both have a synergistic effect. This is similar to the results of previous studies [9], just the factors and subunits affecting hepatic sinusoidal capillaries are different in different studies. In addition, studies have also shown that the combination of ox-LDL and LOX-1 leads to increased expression of oxidative stress product ROS [20], which induces oxidative stress injury and inflammatory response, further leads to changes in the structure and function of LSECs, and ultimately promotes the expression of integrin αvβ5 and VN. Combined with our results, we found that high glucose and ox-LDL can increase the expression of integrin αvβ5 and VN and induce LSECs dysfunction, promoting hepatic sinusoidal capillarization. Therefore, we hypothesize that integrin αvβ5 plays an important role in diabetic hepatic sinusoid dysfunction in fatty liver disease. It is worth noting that VN is a known ligand for the integrin αvβ5 [21]. The interaction between integrin αvβ5 and laminin is crucial for cell survival through focal adhesion kinase (FAK) signaling. Integrin/FAK signaling pathway can promote the activation of liver endothelial SC-514 through multiple pathways, aggravating the process of transformants growth factor beta (TGF-β)-induced fatty liver [22]. FAK is an important signaling molecule that mediates the adhesion of cells to the ECM [23]. The cell signal-regulated kinase (ERK) mitogen-activated protein kinase pathway, also known as the MEK/ERK1/2 kinase cascade [24], involves the regulation of lipid metabolism and fatty liver disease Yousefi B studies have shown that the ERK1/2 signaling pathway [25]. Hepatic lipid metabolism has a potential regulatory role. It can be activated by a series of extracellular signals such as stress and inflammatory cytokines, and is involved in many physiological and pathological processes such as cell growth, differentiation, and metabolism. Some studies have found that FAK/ERK is an important signaling molecule in the inflammatory response, and they are closely related to non-alcoholic fatty liver sinusoid dysfunction [26]. FAK/ERK binds to integrins, causing a series of cascaded amplification reactions that ultimately regulate cell function. In addition, one study showed that adhesion of cancer cells to ECM activates the intracellular signaling cascade through integrin-β1/FAK/ERK signaling to proliferate and invade cells [13]. However, in the process of hepatic sinusoid capillarization of fatty liver in diabetics, the mutual regulation between integrin αvβ5/VN and FAK/ERK has not been reported at home and abroad. The present study shows that the combination of high glucose and ox-LDL can significantly increase the expression of αvβ5, FAK, ERK and VN in liver sinusoidal endothelial cells. The inhibitors of αvβ5 inhibit the expression of FAK, ERK and VN to some extent, and add FAK inhibitors. After that, ERK and VN were inhibited, but the effect of this inhibitory effect on integrin αvβ5 was not obvious. Further, after adding ERK inhibitors, we found that only the expression of VN was reduced and the expression of αvβ5 and FAK did not decrease. The results showed that in the state of high glucose/ox-LDL, integrin αvβ5 successively passed through the FAK in the upstream, and the ERK signaling pathway increased the expression of its ligand VN, and finally mediated hepatic sinusoidal capillarization.