Mechanotransduction in Liver Diseases

Abstract

Chronic liver diseases, such as fibrosis and cancer, lead to a rigid or stiff liver because of perpetual activation of hepatic stellate cells or portal fibroblasts into matrix-producing myofibroblasts. Mechanical forces, as determined by the mechanical properties of extracellular matrix or pressure of circulating blood flow/shear stress, are sensed by mechanoreceptors at the plasma membrane and transmitted into a cell to impact cell function. This process is termed as mechanotransduction. This review includes basic knowledge regarding how external forces are sensed, amplified, and transmitted into the interior of a cell as far as the nucleus to regulate gene transcription and generate biological responses. It also reviews literatures to highlight the mechanisms by which mechanical forces in a normal or diseased liver influence the phenotype of hepatocytes, hepatic stellate cells, portal fibroblasts, and sinusoidal endothelial cells, and these cells in turn participate in the initiation and progression of liver diseases.

Overlooked subclinical portal hypertension in non-cirrhotic NAFLD: Is it real and how to measure it?

“…Resistance to these forces is quantified in pascals (Pa), allowing liver tissue stiffness measurements by various elastography techniques widely used today in noninvasive fibrosis assessment. The molecular network of mechanosensing ('mechanosome') links extracellular physical signals to the cytoskeleton and nucleus [37]. Mechanical forces may cause deformation of plasma membrane lipid rafts and caveolae, expose new protein binding sites, alter the activity of transmembrane receptors and adhesion molecules, or change ion channel conductivity.…”

“…Flow-responsive transcriptional regulators include the Kruppel-like factor (KLF) family, the Hippo-regulated YAP/TAZ pathway and the pleiotropic nuclear factor κB (NFκB) that modulate endothelial responses such as barrier function, contractility, hemostasis and angiogenesis [38,39]. Aberrant activation of mechanosignaling pathways and their associated genetic programs may occur in LSECs, hepatic stellate cells and parenchymal liver cells due to increased stiffness of the cell culture matrix in vitro or the liver tissue in vivo, profoundly altering the function of these cells and their interactions with each other [37,40,41]. Experimental observations indicate that accumulation of lipid droplets and nuclear dislocation is associated with YAP activation in cultured hepatocytes, offering a molecular mechanism that may be relevant to early mechanotransduction events in NAFLD [42].…”

Mechano-Signaling Aspects of Hepatocellular Carcinoma

“…Several adaptor proteins such as paxillin, vinculin and talin facilitate the connection of integrin to the actin cytoskeleton, translating the mechanosensitive information into changes in cell contractility and mechanoresponsive signals. Strain stiffening driven by cell contractility of ECM causes elevated levels of integrin activation, leading, e.g., to phosphorylation of the kinases Src and FAK, and thus their activation [41][42][43]. Increased stiffness stimulates HCC proliferation by inducing resistance towards Sorafenib through activation of β1 integrin/FAK signaling and enhancing nuclear translocation of YAP1.…”

An engineered mayhem: YAP/TAZ mechanosignaling and hepatocarcinogenesis in NAFLD

“…It is now clear that mechanical cues from cell density, polarity and other structural properties of the cellular microenvironment are critically important in Hippo-dependent and Hippo-independent regulation of YAP/TAZ activation, and this response may be modulated by inflammatory and metabolic changes in the regenerating liver [7,8]. Mechanotransduction is the umbrella term for cellular responses to physical stimuli detected by mechanosensors and transmitted into biochemical signals [20]. YAP/TAZ have a fundamental role in mechanocrine signaling pathways, governing the interaction of various liver cells with each other and with the extracellular matrix (ECM) [18].…”