Pharmacological IKK2 inhibition blocks liver steatosis and initiation of non-alcoholic steatohepatitis.

BACKGROUND: Non-alcoholic-steatohepatitis (NASH) leading to fibrosis, end-stage cirrhosis and hepatocellular carcinoma is an increasing health problem in the Western world. Thus, the need for new therapeutic approaches is increasing. IKK2 plays a key role in the development of NASH by mediating inflammation and insulin resistance. AIM: Here the beneficial effects of a pharmacological IKK2 inhibitor (AS602868) on initial stages of NASH progression were tested. METHODS: Mice were fed with a high sucrose diet (HSD) and daily-administered AS602868 and vehicle. The impact of AS602868 on NASH progression was studied using biochemical, histological and molecular markers. RESULTS: AS602868 treatment prevented HSD-induced weight gain and visceral fat accumulation. In adipose tissue, AS602868-treated mice exhibited a lower degree of infiltrated macrophages along with reduced proinflammatory cytokine production. Further analysis demonstrated that AS602868 treatment efficiently inhibited nuclear factor (NF)-kappaB activation in liver non-parenchymal cells and as a consequence attenuated the inflammatory response in the liver. Accordingly, in HSD/AS602868 mice, liver and adipose tissue adiponectin levels remained at levels comparable with those of control chow-fed mice, while they were decreased in HSD/vehicle animals. Additionally, AS602868 improved lipid beta-oxidation mediated by peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma. Systemic pharmacological IKK2 inhibition by AS602868 treatment efficiently prevented liver steatosis and inflammation, and improved antioxidant response. All this contributed to attenuation of NASH progression as evidenced by lower hepatocyte apoptosis and early stages of liver fibrosis. CONCLUSION: The data demonstrate that AS602868-mediated IKK2 inhibition represents a new therapeutic approach to prevent dietary-induced NASH progression.

Unr, a cytoplasmic RNA-binding protein with cold-shock domains, is involved in control of apoptosis in ES and HuH7 cells.

Unr (upstream of N-ras) is a cytoplasmic RNA-binding protein involved in the regulation of messenger RNA stability and internal initiation of translation. We have used Unr-deficient murine embryonic stem (ES) cells to analyse Unr role in cell proliferation and response to stress. Disruption of both unr gene copies had no effect on ES cell proliferation. However, after ionizing radiation (IR), clonogenic survival of unr(-/-) ES cells was approximately 3-fold enhanced as compared to unr(+/+) cells. We further determined that IR-induced apoptosis was decreased in unr(-/-) ES cells, and that reintroduction of the unr gene in unr(-/-) cells restored normal IR-induced apoptosis. Three pro-apoptotic genes, p53, caspase-3 and Gadd45gamma, were downregulated in unr(-/-) ES cells, indicating that Unr, as other cytoplasmic RNA-binding proteins, regulates a complex genetic program, promoting cell death after IR. In contrast, in the human hepatoma cell line HuH7, Unr knockdown using unr-specific small interfering RNAs induced apoptosis, both in untreated and gamma-irradiated cells. Thus, our results establish that Unr acts as a positive or negative regulator of cell death, depending on the cell type. Manipulating the level of Unr may constitute a specific approach to sensitize cancer cells to anticancer treatments.