CRISPR/Cas9-based screening identifies potential therapies for non-alcoholic fatty liver disease NAFLD LiverHealth Innovation NRF2Activation OxidativeStress CRISPR AntioxidantResponse Research Therapeutics antioxidants_OA
By Dr. Priyom Bose, Ph.D.Jul 3 2023Reviewed by Benedette Cuffari, M.Sc. Non-alcoholic fatty liver disease is characterized by an excessive accumulation of lipids in hepatocytes in non-alcoholic individuals. NAFLD progressively changes from fatty liver to non-alcoholic steatohepatitis , cirrhosis, fibrosis, and, in some cases, hepatocellular carcinoma.
Background The Western diet, which is high in fat and sugar, exacerbates the incidence of obesity, which indirectly increases the prevalence of NAFLD. The two-hit hypothesis proposes insulin resistance to be responsible for this association, as it is superseded by oxidative stress that ultimately leads to NAFLD.
Potential NRF2 activators are discovered based on two approaches. The first approach includes the investigation of compounds that can alter interactions between the protein Kelch-like ECH-associated protein 1 and NRF2. The newly developed cell line contains endogenous HMOX1 tagged with Nanoluc luciferase , which enables efficient physiological identification of potential NRF2 inducers. To assess the suitability of this cell line for high-throughput screening campaigns, 1,200 FDA-approved compounds were tested.
The identified compounds were validated for their capacity to activate HMOX1 expression. In both the validation assay and dose-response assay , powdered compounds were used in the HMOX1-Nanoluc cell line. The combined use of Thimerosal and Vorinostat at a high dose exhibited a detrimental effect on protection against H2O2. However, such effects were not observed when independent compounds were used.
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