The fibrosis progression, and treatment of the NCU-G1gt/gt mouse model

Abstract

Hepatic fibrogenesis is a wound healing response to continuous or chronic insults to the liver. The fibrotic stimuli are often based on disease, genetic disorders, abuse of alcohol and drugs or physical injury to the liver. The stimuli activate hepatic stellate cells (HSC) and other fibrogenic cell types, which induce up-regulation of the expression of pro-fibrotic factors and extracellular matrix (ECM) components leading to an alternated ECM. The matrix metalloproteinases (MMPs) and their inhibitors tissue inhibitors of metalloproteinases (TIMPs) are the main ECM remodelers, and an imbalance in their expression may lead to fibrosis. If left untreated, it may develop to its severe form, cirrhosis. Liver fibrosis is a dynamic process that can be reversed both spontaneously, by removal of the causative agent, and therapeutically by the aid of anti-fibrotic drugs. NCU-G1 (kidney predominant protein) is a protein consisting of 404 amino acids, in mice, with a predicted molecular weight of 43.8 kDa. It is highly conserved among species. Ncug1 is highly expressed in liver, kidney and prostate. NCU-G1 has been shown to be a nuclear protein functioning as a co-activator for peroxisome proliferator activated receptor α (PPAR-α), and a higly glycosylated lysosomal membrane protein. A NCU-G1gt/gt mouse has been developed, and it is shown to successfully lack the expression of Ncug1. The NCU-G1 gt/gt mice are fertile and grow normally, but spontaneously develop liver fibrosis. This study investigates the fibrosis progression in the NCU-G1 gt/gt mice with gene expression, protein and liver component analyses. A pilot study was conducted to investigate the applicability of the NCU-G1 gt/gt mice as a fibrosis model organism, with treatment with the anti-fibrotic agent sodium hydrogen sulfide (NaHS). The fibrosis in the NCU-G1 gt/gt mice liver increase until the mice reaches 4.5 months of age, after 4.5 months the fibrotic state revert to some degree. Treatment with NaHS attenuated the fibrotic state to some degree in the NCU-G1 gt/gt mice.