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.
Highlights
Among the metabolic disorders, non-alcoholic fatty liver disease (NAFLD) is considered a hepatic manifestation of metabolic syndrome (MetS) and it is one of the prominent health challenges of the twenty-first century as NAFLD is the most prevalent liver disease worldwide affecting 25–30% of the general population and its prevalence could reach 70–90% in specific populations with comorbidities such as morbid obesity or type 2 diabetes mellitus [1, 2]
non-alcoholic steatohepatitis (NASH) has been mainly associated with higher morbidity and mortality than other diseases in the NAFLD spectrum and, there are pharmacological therapies under clinical investigation for treatment of NASH [2], no drugs are approved by the Federal Drug Administration (FDA) or the European Medicines Agency (EMA) for the NASH treatment [3]
Given that REV-ERBs have been demonstrated to play a regulatory role in hepatic lipid metabolism [18] as well as inflammation [16, 18, 19], we sought to examine the effects of pharmacologically activating REV-ERB in a mouse model of NASH and determine whether REV-ERB
Summary
Non-alcoholic fatty liver disease (NAFLD) is considered a hepatic manifestation of metabolic syndrome (MetS) and it is one of the prominent health challenges of the twenty-first century as NAFLD is the most prevalent liver disease worldwide affecting 25–30% of the general population and its prevalence could reach 70–90% in specific populations with comorbidities such as morbid obesity or type 2 diabetes mellitus [1, 2]. NAFLD can often progress to non-alcoholic steatohepatitis (NASH), which is associated with progressive liver disease [1]. NASH has been mainly associated with higher morbidity and mortality than other diseases in the NAFLD spectrum and, there are pharmacological therapies under clinical investigation for treatment of NASH [2], no drugs are approved by the Federal Drug Administration (FDA) or the European Medicines Agency (EMA) for the NASH treatment [3]. Nuclear receptors (NRs) are transcription factors generally activated by ligands and involved in diverse biological processes such as cell growth and differentiation, apoptosis, gene expression during tumor formation and metabolism. They bind to specific sequences of DNA allowing them to regulate the expression of adjacent genes. Many diseases including NASH are directly or indirectly related to nuclear receptor signaling and many NRs have become
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