Burris, T. P. | bioRxiv Science

bioRxiv2020

REV-ERB Agonism Improves Liver Pathology in a Mouse Model of NASH

Non-alcoholic fatty liver disease (NAFLD) affects a significant number of people worldwide and currently there are no pharmacological treatments. NAFLD often presents with obesity, insulin resistance, and in some cases cardiovascular diseases. There is a clear need for treatment options to alleviate this disease since it often progresses to much more the much more severe non-alcoholic steatohepatitis (NASH). The REV-ERB nuclear receptor is a transcriptional repressor that regulates physiological processes involved in the development of NAFLD including lipogenesis and inflammation. We hypothesized that pharmacologically activating REV-ERB would suppress the progression of fatty liver in a mouse model of NASH. Using REV-ERB agonist SR9009 in a mouse NASH model, we demonstrate the beneficial effects of REV-ERB activation that led to an overall improvement of hepatic health by suppressing hepatic fibrosis and inflammatory response.

pharmacology and toxicology↗

bioRxiv2019

Rev-erba heterozygosity produces a dose-dependent phenotypic advantage in mice

Numerous mutational studies have demonstrated that circadian clock proteins regulate behavior and metabolism. Nr1d1(Rev-erb) is a key regulator of circadian gene expression and a pleiotropic regulator of skeletal muscle homeostasis and lipid metabolism. Loss of Rev-erb expression induces muscular atrophy, high adiposity, and metabolic syndrome in mice. Here we show that, unlike knockout mice, Nr1d1 heterozygous mice are not susceptible to muscular atrophy and in fact paradoxically possess larger myofiber diameters and improved neuromuscular function, compared to wildtype mice. Heterozygous mice lacked dyslipidemia, a characteristic of Nr1d1 knockout mice and displayed increased whole-body fatty-acid oxidation during periods of inactivity (light cycle). Heterozygous mice also exhibited higher rates of glucose uptake when fasted, and had elevated basal rates of gluconeogenesis compared to wildtype and knockout littermates. Rev-erb ablation suppressed glycolysis and fatty acid-oxidation in white-adipose tissue (WAT), whereas partial Rev-erb loss, curiously stimulated these processes. Our investigations revealed that Rev-erb dose-dependently regulates glucose metabolism and fatty acid oxidation in WAT and muscle.

molecular biology↗