Hepatic Injury Due to Combined Choline-Deprivation and Thioacetamide Administration: An Experimental Approach to Liver Diseases

Abstract

Long-term combined dietary CD and TAA administration could be a more realistic experimental approach to human liver diseases involving severe steatosis, fibrosis, stellate cell activation and significant regenerative hepatocellular response.

“Extracellular matrix remodelling in the liver of rats subjected to dietary choline deprivation and/or thioacetamide administration”

“…We believe that the increased expression of TIMP‐1 in all studied groups throughout the experiment indicates the activation of the ECM turnover mechanism in the presence of excessive MMP‐9, which is in agreement with previous studies showing that TIMPs arise when the ECM regulation balance has been disturbed . Moreover, in the TAA and the combination group, the moderate gradual increased expression of TIMP‐1 as compared to the respective sharp and intense expression observed in the control and CDD group, could indicate that the augmented/enhanced extracellular matrix degradation under the concomitant TAA and CDD exposure might accelerate the changes of liver architecture, leading to ECM remodelling that inevitably leads to the development of hepatic fibrosis …”

“…In a previous study of ours, we have demonstrated that concomitant exposure to TAA with CDD over a period of time (30, 60 and 90 days) induces a state of progressive hepatic steatosis and fibrosis along with hepatic stellate cell activation and significant regenerative hepatocellular response with a progressive increase in liver enzymes. This model is compatible with the “two hit” theory in the liver pathology for studying the changes of a prolonged period of time similar to liver‐associated human diseases in clinical practice like chronic liver disease, nonalcoholic steatohepatitis and cirrhosis.…”

“…We have established that prolonged exposure to CDD and/or concomitant exposure to TAA causes progressive hepatic inflammation and fibrosis in rats . This type of hepatic injury includes gradual and progressive steatosis, stellate cell activation, fibrosis and a significant regenerative hepatocellular response that could simulate nonalcoholic fatty liver diseases .…”

“…We have established that prolonged exposure to CDD and/or concomitant exposure to TAA causes progressive hepatic inflammation and fibrosis in rats . This type of hepatic injury includes gradual and progressive steatosis, stellate cell activation, fibrosis and a significant regenerative hepatocellular response that could simulate nonalcoholic fatty liver diseases . Combining the toxic effect of TAA with the detrimental dietary choline deprivation leads to progressive liver enzymes' stimulation and more severe liver damage, including cellular necrosis and apoptosis, followed by a significant regenerative response (with increasing mitotic figures to compensate cellular loss) .…”

“…This type of hepatic injury includes gradual and progressive steatosis, stellate cell activation, fibrosis and a significant regenerative hepatocellular response that could simulate nonalcoholic fatty liver diseases . Combining the toxic effect of TAA with the detrimental dietary choline deprivation leads to progressive liver enzymes' stimulation and more severe liver damage, including cellular necrosis and apoptosis, followed by a significant regenerative response (with increasing mitotic figures to compensate cellular loss) . Hepatic stellate cell activation is considered the main source of inflammatory mediators, including MMPs and their inhibitors, which have an important role in triggering fibrogenesis and inhibition of adequate nourishment to the newly regenerating cells, thus producing a picture of a micro‐ and macronodular fibrosis and, ultimately, cirrhosis …”