Alcoholic liver disease (ALD) is a significant cause of liver-related death in the United States. The disease covers a spectrum of disorders ranging from steatosis to alcoholic hepatitis and may progress to cirrhosis and hepatocellular carcinoma. While the majority of heavy drinkers develop fatty liver, only a minority will progress to alcoholic hepatitis, and 10-15% develop cirrhosis. Despite the significant public health burden, there is currently no FDA-approved pharmacotherapy for ALD indicating the urgent need to develop new therapies. Protein tyrosine phosphatase 1B (PTP1B; encoded by Ptpn1) is a widely expressed phosphatase and an established metabolic regulator. Given the beneficial effects of PTP1B deficiency and pharmacological inhibition it is an attractive therapeutic target for metabolic diseases. To investigate the role of PTP1B in ALD we will use a loss-of-function approach to investigate the contribution of PTP1B in hepatocytes and hepatic stellate cells. Also, we will determine the molecular mechanisms underlying hepatic PTP1B action and explore the potential preventative and therapeutic value of PTP1B inhibition in ALD. Preliminary data demonstrated that liver- specific PTP1B disruption attenuated ethanol-induced steatosis and inflammation in the chronic plus binge mouse model of ALD. Moreover, hepatic PTP1B deficiency attenuated ethanol- induced oxidative stress and inflammation. Together, these findings suggest that PTP1B impacts hepatic function in ALD and that PTP1B pharmacological inhibition may present a therapeutic approach in disease management.
Alcoholic liver disease (ALD) is a major cause of liver-related death in the United States. The disease includes a spectrum of clinical disorders that range from steatosis to alcoholic hepatitis. Currently, there is no FDA-approved pharmacotherapy for any stage of ALD. The proposed studies will deploy advanced genetic, pharmacological and biochemical approaches to investigate the cell-specific role of hepatic protein tyrosine phosphatase 1B in ALD. The objective is to identify and validate molecular targets that may develop into novel therapies for this disease.
