We then explored the possible mechanisms by which integrin w

We then explored the possible mechanisms by which integrin α5β1 was involved in the PHEV proliferation process. Normally, the virus activates integrin and induces its downstream protein activation to promote its own invasion and proliferation. Human papillomavirus type 16 (HPV16) binds to heparan sulfate and then activates FAK via integrins to promote infection (Abban and Meneses, 2010). Kaposi's sarcoma-associated herpesvirus (KSHV) induces activation of the integrin-dependent FAK-Src-PI-3 K-Rho GTPase kinase pathway. These signaling pathways play an important role in host cell endocytosis and cytoplasmic transport (Kerur et al., 2010). Previous studies have confirmed that PHEV promotes its entry into N2a cells by activating the integrinα5β1-FAK signaling pathway (Lv et al., 2019). Therefore, this study detected whether the signaling pathway was activated in the HBC tissue of PHEV-infected mice. Western blotting and GST pull-down results indicated that each molecule of the signaling pathway was activated. The activation of this pathway was inhibited after ATN-161 treatment, suggesting that PHEV also promoted its invasion and proliferation through the integrin α5β1-FAK signaling pathway in vivo.
Competing interests
Introduction Type 2 diabetes mellitus (T2DM) has been represented a major global health problem, which also be potentially complicated by hepatic microangiopathy and liver inflammation and is an independent risk factor for the formation and development of non-alcoholic fatty liver disease (NAFLD) [1]. The prevalence of NAFLD in T2DM patients is 42.6%–76% according to the latest study [2]. However, the cause–effect relationship between these conditions is complex and difficult to decipher. The occurrence of NAFLD is associated with hepatic sinusoidal dysfunction [3]. While the liver dysfunction consist of hepatic sinusoidal endothelial dysfunction, hepatic sinusoidal contractile dysfunction and hepatic sinusoidal capillarization which caused by hepatic sinusoidal structure and dysfunction as well as blood flow abnormalities [4]. Hepatic sinusoidal capillarization is a pathological manifestation of hepatic sinusoidal dysfunction, mainly characterized by phenotypic changes of LSECs, permanent reduction or disappearance of fenestration. Besides, increasing of vitronectin (VN) and type IV collagen. The sinusoidal capillarization enhances the damage of free radicals to the liver, and reduces the ability of taking up metabolic substances and oxygen, causing metabolic disorders and internal environment disorders, leading to the development of fatty liver disease. Hepatic sinusoidal dysfunction can influence on liver lipid metabolism and accelerate the formation of fatty liver [5]. Under the condition of diabetes, the damage of liver and liver microcirculation dysfunction caused by the toxicity of glycolipids and the occurrence and development of fatty liver must have an inevitable correlation [6]. As one of the factors which can lead to oxidative stress and inflammatory response, oxidized low-density lipoprotein (ox-LDL) is shown to be over-oxidated of a large number of polyunsaturated fatty acids in low-density lipoprotein (LDL) under the action of Numerous basic and is a well-recognized proatherogenic particle that functions in atherosclerosis [7]. Studies have shown that ox-LDL can cause endothelial diastolic Dysfunction and depolarization of LSECs through the LOX-1/ROS/NF-κB pathway, leading to sinusoidal endothelial dysfunction [8]. However, the effect of inhibition only responsible for about 30% after knocking out the LOX-1 gene, suggesting that impaired hepatic sinusoidal function and liver microcirculatory disturbance may have other factors and pathways involved in regulation [9]. VN is a major component of the basement membrane, excessively deposited in LSECs gap, reducing endothelial cell permeability and causing hepatic sinusoidal capillarization [10]. The integrin family is a group of transmembrane glycoproteins for ligands in the extracellular matrix. Integrin αvβ5, the receptor of VN, is a member of the integrin family and only binds to VN, and highly expressed in endothelial cells of angiogenic vessels, mediating cell-matrix adhesion, migration, cytoskeleton formation, and cell proliferation [11].