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REV-ERB agonism improves liver pathology in a mouse model of NASH.

ABSTRACT: 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.

SUBMITTER: Griffett K

PROVIDER: S-EPMC7529425 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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REV-ERB agonism improves liver pathology in a mouse model of NASH.

Griffett Kristine K Bedia-Diaz Gonzalo G Elgendy Bahaa B Burris Thomas P TP

PloS one 20201001 10

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 ...[more]

PMID: 33002003

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Regulation of circadian behaviour and metabolism by REV-ERB-? and REV-ERB-?.

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| S-EPMC3367514 | biostudies-literature

Rev-erb? and Rev-erb? coordinately protect the circadian clock and normal metabolic function.

Project description:The nuclear receptor Rev-erb? regulates circadian rhythm and metabolism, but its effects are modest and it has been considered to be a secondary regulator of the cell-autonomous clock. Here we report that depletion of Rev-erb? together with closely related Rev-erb? has dramatic effects on the cell-autonomous clock as well as hepatic lipid metabolism. Mouse embryonic fibroblasts were rendered arrhythmic by depletion of both Rev-erbs. In mouse livers, Rev-erb? mRNA and protein levels oscillate with a diurnal pattern similar to that of Rev-erb?, and both Rev-erbs are recruited to a remarkably similar set of binding sites across the genome, enriched near metabolic genes. Depletion of both Rev-erbs in liver synergistically derepresses several metabolic genes as well as genes that control the positive limb of the molecular clock. Moreover, deficiency of both Rev-erbs causes marked hepatic steatosis, in contrast to relatively subtle changes upon loss of either subtype alone. These findings establish the two Rev-erbs as major regulators of both clock function and metabolism, displaying a level of subtype collaboration that is unusual among nuclear receptors but common among core clock proteins, protecting the organism from major perturbations in circadian and metabolic physiology.

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Project description:Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease with large unmet need. Non-alcoholic steatohepatitis (NASH), a progressive variant of NAFLD, can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. To identify potential new therapeutics for NASH, we used a computational approach based on Connectivity Map (CMAP) analysis, which pointed us to bromodomain and extra-terminal motif (BET) inhibitors for treating NASH. To experimentally validate this hypothesis, we tested a small-molecule inhibitor of the BET family of proteins, GSK1210151A (I-BET151), in the STAM mouse NASH model at two different dosing timepoints (onset of NASH and progression to fibrosis). I-BET151 decreased the non-alcoholic fatty liver disease activity score (NAS), a clinical endpoint for assessing the severity of NASH, as well as progression of liver fibrosis and interferon-? expression. Transcriptional characterization of these mice through RNA-sequencing was consistent with predictions from the CMAP analysis of a human NASH signature and pointed to alterations in molecular mechanisms related to interferon signaling and cholesterol biosynthesis, as well as reversal of gene expression patterns linked to fibrotic markers. Altogether, these results suggest that inhibition of BET proteins may present a novel therapeutic opportunity in the treatment of NASH and liver fibrosis.

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A functional Rev-erb alpha responsive element located in the human Rev-erb alpha promoter mediates a repressing activity.

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| S-EPMC39648 | biostudies-other

Sinapic Acid Ameliorates REV-ERB α Modulated Mitochondrial Fission against MPTP-Induced Parkinson's Disease Model.

Project description:Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, and accumulating evidence indicates that mitochondrial dysfunction is associated with progressive deterioration in PD patients. Previous studies have shown that sinapic acid has a neuroprotective effect, but its mechanisms of action remain unclear. The neuroprotective effect of sinapic acid was assayed in a PD mouse model generated by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as well as in SH-SY5Y cells. Target protein expression was detected by western blotting. Sinapic acid treatment attenuated the behavioral defects and loss of dopaminergic neurons in the PD models. Sinapic acid also improved mitochondrial function in the PD models. MPTP treatment increased the abundance of mitochondrial fission proteins such as dynamin-related protein 1 (Drp1) and phospho-Drp1 Ser616. In addition, MPTP decreased the expression of the REV-ERB α protein. These changes were attenuated by sinapic acid treatment. We used the pharmacological REV-ERB α inhibitor SR8278 to confirmation of protective effect of sinapic acid. Treatment of SR8278 with sinapic acid reversed the protein expression of phospho-Drp1 Ser616 and REV-ERB α on MPTP-treated mice. Our findings demonstrated that sinapic acid protects against MPTP-induced PD and these effects might be related to the inhibiting abnormal mitochondrial fission through REV-ERB α.

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Altered Sleep Homeostasis in Rev-erb? Knockout Mice.

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| S-EPMC4763348 | biostudies-other

Rev-erb Agonist Inhibits Chikungunya and O'nyong'nyong Virus Replication.

Project description:Chikungunya virus (CHIKV), an alphavirus spread by Aedes spp. mosquitos, causes severe inflammation and joint pain, progressing to a chronic arthralgic state in a subset of patients. Due to recent global epidemics of CHIKV and the potential for related viruses to cause outbreaks, multiple approaches to combat these pathogens are of interest. We report that SR9009, a synthetic agonist of nuclear receptors Rev-erb ?/?, inhibits replication of multiple alphaviruses (CHIKV and O'nyong'nyong virus) mainly by suppressing structural protein synthesis, although viral RNA accumulation is relatively unimpeded. Furthermore, SR9009 reduces the inflammatory response in cultured murine macrophages exposed to alphavirus-infected cells.

| S-EPMC6293476 | biostudies-literature

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