Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes

Abstract

Previous studies have demonstrated in hepatocytes that deoxycholic acid (DCA) promotes inactivation of protein tyrosine phosphatases (PTPases) and activation of ERBBl and the extracelMar-regulated kinase (ERK) 1/2 pathway. The present studies have determined the biochemical mechanism(s) through which these events occur. DCA and taurodeovcholic acid (TDCA) (100 pmoYL) caused activation of ERBB1, insulin receptor, and the ERK1/2 and AKT pathways in primary rodent hepatocytes. DCA-and TDCA-induced receptor and signaling pathway activations were blocked by the reactive oxygen species (ROS) scavengers N-acetyl cysteine (NAC) and Trolox (TX), as well as by cyclosporin A (CsA) and bongkrekic acid (BKA). DCA ile acids are detergent molecules that are released into the gut upon feeding and are essential for digestion. Postfeeding, bile acids re-enter the liver via the portal vein together with digested nutrients and are

GCDCA down-regulates gene expression by increasing Sp1 binding to the NOS-3 promoter in an oxidative stress dependent manner

“…Similarly, MitoQ reduced the expression and/or activation of Sp1 and induced the pNOS-3 activity, which was related to the NOS-3 expression/activity increase and the cell survival [9]. This is consistent with a model of gene expression regulation by oxidative stress instead of direct interaction with TFs [31], and agrees with the MAPKs regulation mechanism through oxidative stress induced by bile acids [32].…”

α-Lipoic Acid as a Directly Binding Activator of the Insulin Receptor: Protection from Hepatocyte Apoptosis

“…Other antioxidants, among them Trolox, were even shown to abolish ROS-induced insulin receptor activation (37). Such observations are usually explained by the fact that oxidants FIGURE 5: Computer modeling of binding of LA to the insulin receptor tyrosine kinase domain.…”

Bone marrow mononuclear cell transplantation improves mitochondrial bioenergetics in the liver of cholestatic rats

“…However, the oxidative damage is associated with the balance disruption, being incompatible with cell viability [50]. Mitochondria plays a key role in liver fibrosis progression, because it produces ROS that regulate the inflammatory cytokines expression and promote cell death, leading to maintenance of the pathological process [24,17,51]. ROS also induce lipid peroxidation of membrane phospholipids, which causes hepatocyte death and synthesis of apoptotic body, and consequently activate fibrogenic cells [56,22,49].…”

“…Some of the adverse effects of bile acids on mitochondrial bioenergetics could be related to the disturbance in the composition of the mitochondrial membrane, since they can be incorporated and reduce its phospholipid component [27], changing the fluidity and the mitochondrial membrane potential (Ψ m ), ATP levels, and ROS production, leading to apoptosis rate increase [24,30,17,3].…”