Model organisms for investigating the functional involvement of NRF2 in non-communicable diseases.

Non-communicable chronic diseases (NCDs) are most commonly characterized by age-related loss of homeostasis and/or by cumulative exposures to environmental factors, which lead to low-grade sustained generation of reactive oxygen species (ROS), chronic inflammation and metabolic imbalance. Nuclear factor erythroid 2-like 2 (NRF2) is a basic leucine-zipper transcription factor that regulates the cellular redox homeostasis. NRF2 controls the expression of more than 250 human genes that share in their regulatory regions a cis-acting enhancer termed the antioxidant response element (ARE).

Electrophilic metabolites targeting the KEAP1/NRF2 partnership.

Numerous electrophilic metabolites are formed during cellular activity, particularly under conditions of oxidative, inflammatory and metabolic stress. Among them are lipid oxidation and nitration products, and compounds derived from amino acid and central carbon metabolism. Here we focus on one cellular target of electrophiles, the Kelch-like ECH associated protein 1 (KEAP1)/nuclear factor erythroid 2 p45-related factor 2 (NRF2) partnership.

Oncogenic KEAP1 mutations activate TRAF2-NFκB signaling to prevent apoptosis in lung cancer cells.

The Kelch-like ECH-associated protein 1 (KEAP1) - Nuclear factor erythroid 2 -related factor 2 (NRF2) pathway is the major transcriptional stress response system in cells against oxidative and electrophilic stress. NRF2 is frequently constitutively active in many cancers, rendering the cells resistant to chemo- and radiotherapy. Loss-of-function (LOF) mutations in the repressor protein KEAP1 are common in non-small cell lung cancer, particularly adenocarcinoma.

Metabolic effects of nuclear receptor activation in vivo after 28-day oral exposure to three endocrine-disrupting chemicals.

Environmental exposure to endocrine-disrupting chemicals (EDCs) can lead to metabolic disruption, resulting in metabolic complications including adiposity, dyslipidemia, hepatic lipid accumulation, and glucose intolerance. Hepatic nuclear receptor activation is one of the mechanisms mediating metabolic effects of EDCs. Here, we investigated the potential to use a repeated dose 28-day oral toxicity test for identification of EDCs with metabolic endpoints.

Genetic variation is a key determinant of chromatin accessibility and drives differences in the regulatory landscape of C57BL/6J and 129S1/SvImJ mice.

Most common genetic variants associated with disease are located in non-coding regions of the genome. One mechanism by which they function is through altering transcription factor (TF) binding. In this study, we explore how genetic variation is connected to differences in the regulatory landscape of livers from C57BL/6J and 129S1/SvImJ mice fed either chow or a high-fat diet.