Rat Liver Enzyme Release Depends on Blood Flow‐Bearing Physical Forces Acting in Endothelium Glycocalyx rather than on Liver Damage

Abstract

We have found selective elevation of serum enzyme activities in rats subjected to partial hepatectomy (PH), apparently controlled by hemodynamic flow-bearing physical forces. Here, we assess the involvement of stretch-sensitive calcium channels and calcium mobilization in isolated livers, after chemical modifications of the endothelial glycocalyx and changing perfusion directionality. Inhibiting in vivo protein synthesis, we found that liver enzyme release is influenced by de novo synthesis of endothelial glycocalyx components, and released enzymes are confined into a liver “pool.” Moreover, liver enzyme release depended on extracellular calcium entry possibly mediated by stretch-sensitive calcium channels, and this endothelial-mediated mechanotransduction in liver enzyme release was also evidenced by modifying the glycocalyx carbohydrate components, directionality of perfusing flow rate, and the participation of nitric oxide (NO) and malondialdehyde (MDA), leading to modifications in the intracellular distribution of these enzymes mainly as nuclear enrichment of “mitochondrial” enzymes. In conclusion, the flow-induced shear stress may provide fine-tuned control of released hepatic enzymes through mediation by the endothelium glycocalyx, which provides evidence of a biological role of the enzyme release rather to be merely a biomarker for evaluating hepatotoxicity and liver damage, actually positively influencing progression of liver regeneration in mammals.

Critical Role of LSEC in Post-Hepatectomy Liver Regeneration and Failure

“…Mechanoreceptors transform this mechanical signal into a biological one [ 46 , 47 ]. Intracellular pathways activated by shear stress include stimulation of transmembrane proteins, activation of ion channels, intracellular calcium mobilization, Notch1 signaling, activation of the transcription factor KLF2, expression of vascular cell adhesion molecule 1 (VCAM-1) and CD44, as well as c-fos, c-myc and c-jun [ 26 , 48 , 49 , 50 , 51 ]. These molecular responses are crucial to ‘prime’ the hepatocytes for liver regeneration [ 5 ].…”

Cyanidin 3-glucoside targets a hepatic bilirubin transporter in rats

“…Once the need for oxygen delivery to the liver was overcome, perfusion flow was maintained at 0.9 mL min − 1 g − 1 liver weight (6 mL min − 1 ), which is within the range that ensures normal portal pressure and perfusion flow in the isolated rat liver [30], and is close to physiological portal blood flow in the rat (1.25 mL min − 1 g − 1 liver weight) [31]. These conditions preserve the sinusoidal endothelium from shear stress [32], which can trigger the release of hepatic enzymes [33]. The bile duct was not cannulated, as recommended, to avoid accidental cholestasis and its unpredictable influence on the kinetics of hepatic BR uptake [34].…”

“…The tests were performed as described in detail [22]. Liver perfusion effluent was assayed for a marker of membrane lipid oxidation (malondialdehyde), which was undetectable in contrast to oxygenated liver perfusion [33]. There was no apparent membrane permeabilization (ATP release) or cytolysis (LDH release) (Suppl.…”

Clinico-toxicological effects of ceftriaxone after intramuscular administration of graded doses in Basenji dogs

“…Studies have shown that elevated activities of these cytosolic enzymes indicate hepatocyte or other cell type damage [15]. However, the ALT is more specific to liver and better use in the diagnosis of liver injury particularly in dogs and cats [16].…”