Subcellular redistribution of protein kinase C isozymes is associated with rat liver cirrhotic changes induced by carbon tetrachloride or thioacetamide

Abstract

Background and Aims: Protein kinase C (PKC) plays a key role in the alteration of signal transduction in the liver, which may contribute to the development of liver cirrhosis. The aim of the present study was to examine the subcellular redistribution of PKC isozymes in rat liver cirrhosis, which is induced by two different cirrhotic chemical agents, carbon tetrachloride (CCl4) and thioacetamide (TAA). Methods and Results: Thioacetamide and CCl4 were administered to rats for 8 and 30 weeks, respectively before rats were killed and autopsies performed at 9, 20 and 30 weeks later. The TAA induced a fibrotic pattern in the liver that differed from that produced by CCl4, notably in the formation of fibrous connective tissue and the proliferation of bile ductule cells. Cholangiofibrosis and clear‐cell foci were also observed in TAA‐treated rats at 30 weeks. Histological examination revealed that severe cirrhotic changes were present 9 weeks after the commencement of CCl4 treatment and 30 weeks after TAA treatment. Discussion: When the subcellular redistribution of PKC isozymes (PKCα, ‐β1, ‐δ, and ‐ɛ) was examined, all the PKC isozymes in CCl4‐treated rats were found to be translocated to the membrane fraction, which may mean PKC activation, and then downregulated by proteolytic degradation after 9 weeks of treatment, which coincided with peak cirrhotic changes. All rats treated with CCl4 recovered to the control level after 20 weeks of treatment. In the case of TAA‐treated rats, PKC isozymes were translocated to the particulate fraction of the liver after 9 weeks of treatment and this persisted in most of the rats for the duration of the experiment. Conclusions: From these results, it would appear that PKC translocation preceded morphologic changes, and that an altered subcellular distribution of the PKC isozyme may be associated with the response to liver damage and carcinogenesis.

Carbon tetrachloride-induced hepatic injury through formation of oxidized diacylglycerol and activation of the PKC/NF-κB pathway

“…These findings indicate that this reagent Using immunohistochemistry and subcellular fractionation, we found that PKCa, bI, bII and d were translocated to the plasma membrane in the CCl 4 -treated rats. Membrane localization of PKCa, bI, d and e has been previously reported in cirrhotic livers of chronically CCl 4 -treated rats, 30 but for CCl 4 -induced acute liver injury, the present study is the first to demonstrate selective activation of PKCa, bI, bII and d as evidenced by their membrane localization. PKCa, bI and bII are conventional PKC isoforms that require both DAG and Ca 2 þ ions for activation, while PKC d and e are 'novel PKC' that need only DAG.…”

“…30 Immunohistochemistry with isoform-specific anti-PKC antibodies localized intense PKCa expression to the plasma membrane of hepatocytes around the centrilobular vein at 2 and 6 h following CCl 4 administration ( Figure 3a). PKCbI, bII and d were also localized to the membrane of hepatocytes at 2 and 6 h, respectively.…”

Butterfat fatty acids differentially regulate growth and differentiation in Jurkat T‐cells

“…PKC is a group of serine/threonine kinases involved in cell-signaling pathways regulating fundamental cellular functions including proliferation, death, differentiation, tumorigenesis, and stress responses [Buckner, 2001;Jeong et al, 2001]. Several n-3, n-6 PUFA [Nishikawa et al, 1988;Huang et al, 1997] have been demonstrated to modulate PKC activity and superoxide production in vitro and a-Toc was previously shown to impair the NADPH oxidase by decreasing PKC activity [Cachia et al, 1998].…”

Altered Endothelin-1 Signaling in Production of Thromboxane A2 in Kupffer Cells from Bile Duct Ligated Rats

“…PKC has been reported to play significant roles in the early stages of fibrosis and development of cirrhosis, and mediating the activation of cPLA 2 and release of AA in response to ET-1 (72)(73)(74). Mustafa et al demonstrated that either 4-bromophenacyl bromide, a nonspecific PLA 2 inhibitor, or PTX inhibited the ET-1 induced synthesis of platelet activating factor (PAF) in KCs.…”

“…In addition, the pretreatment with staurosporine, a PKC inhibitor, attenuated the release of PAF in response to ET-1 (72,75). In the CCl 4 model of fibrosis, Jeong et al demonstrated the increased activity of PKC preceded the morphologic changes of the liver architecture (73). KCs express the Ca 2+ dependent  and Ca 2+ independent  isoforms of PKC, both of which have been implicated in the activation of cPLA 2 and release of AA (74).…”