Complementary gene regulation by NRF1 and NRF2 protects against hepatic cholesterol overload

Hepatic cholesterol overload promotes steatohepatitis. Insufficient understanding of liver stress defense im-pedes therapy development. Here, we elucidate the role of stress defense transcription factors, nuclear fac-tor erythroid 2 related factor-1 (NRF1) and-2 (NRF2), in counteracting cholesterol-linked liver stress. Using a diet that increases liver cholesterol storage, expression profiles and phenotypes of liver from mice with he-patocyte deficiency of NRF1, NRF2, or both are compared with controls, and chromatin immunoprecipitation sequencing is undertaken to identify target genes. Results show NRF1 and NRF2 co-regulate genes that elim-inate cholesterol and mitigate inflammation and oxidative damage. Combined deficiency, but not deficiency of either alone, results in severe steatohepatitis, hepatic cholesterol overload and crystallization, altered bile acid metabolism, and decreased biliary cholesterol. Moreover, therapeutic effects of NRF2-activating drug bardoxolone require NRF1 and are supplemented by NRF1 overexpression. Thus, we discover complemen-tary gene programming by NRF1 and NRF2 that counteract cholesterol-associated fatty liver disease progression.

Automated summary

Hepatic cholesterol overload promotes steatohepatitis, and insufficient understanding of liver stress defense impedes therapy development. In this study, the role of stress defense transcription factors NRF1 and NRF2 in counteracting cholesterol-linked liver stress is elucidated.