BMAL1: A Novel Regulator For Inflammatory Liver Injury

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DESCRIPTION (provided by applicant): Caused by excessive alcohol drinking, alcoholic liver disease (ALD) is one of the leading chronic liver diseases worldwide. ALD includes a spectrum of liver disorders ranging from simple fatty liver to alcoholic hepatitis, cirrhosis, and liver faiure. Current treatment for severe ALD such as alcoholic hepatitis is limited and lacks long-term efficacy. Therefore, there is an urgent need for developing new therapeutics to block or delay the eventual organ failure and reduce the huge medical costs. One of the main pathological features in ALD is the presence of prolonged and low-grade inflammatory response within liver. Activation of hepatic macrophages (Kupffer cells) by elevated endotoxin levels generates oxidative stress and produces a variety of pro-inflammatory cytokines, which result in increased apoptosis of hepatocytes, excessive production of extracellular matrix proteins, and fibrosis. Thus, a complex interaction between macrophages and hepatocytes might promote unsolved inflammation in the presence of chronic ethanol consumption. A better understanding of how to restrain inflammation and apoptosis in the liver will shed light on developing effective treatment and prevention of ALD. As a key circadian clock protein, highly expressed in hepatocytes, BMAL1 regulates oscillations of circadian genes as well as genes involved in lipid and glucose metabolism. We discovered that Bmal1 deficiency exacerbates liver injury induced by either lipopolysaccharide (LPS) or acute alcohol intoxication in mice. The severity of liver injury in Bmal1-/- mice is associated with increased inflammation and cell apoptosis, suggesting that normal BMAL1 protein expression or function is required to protect hepatocytes from apoptosis and suppress inflammation in response to liver injury treatment. Based on these novel preliminary data, we hypothesize that BMAL1 plays a critical role during the progression of alcohol liver disease by promoting hepatocyte survival and alleviating chronic hepatic inflammation. We will test the hypothesis in two specific aims. In Aim 1, we will determine whether hepatocyte-specific Bmal1 deficiency is sufficient to enhance liver inflammation and injury during alcohol feeding. In Aim 2, we will determine whether BMAL1 deficiency sensitizes hepatocyte to ethanol-induced apoptosis via activating pro-apoptotic transcription factor FOXO1. We will determine the effects of inhibition of FOXO1 on liver injury in Bmal1-/- knockout mice. Successful completion of the application will yield new insights on alcohol-induced liver injury and identify new strategies for the treatment of ALD.