Heavy alcohol drinking results in liver steatohepatitis and fibrosis, and ultimately leads to cirrhosis. Liver cirrhosis is the 12th leading cause of death in the United States and alcohol abuse accounts for around 50% of cirrhosis cases. Currently, there is no curative pharmacologic treatment for alcoholic steatohepatitis and fibrosis. Thus, finding therapeutic targets in the progression from steatosis to steatohepatitis and fibrosis would lead to a reduction in the number of patients with cirrhosis, as well as lower medical costs. This exploratory proposal stems from our unexpected findings on lysophosphatidic acid (LPA) in alcoholic steatosis and fibrosis. Extracellular LPA is present in serum at low concentrations as an albumin-bound form and elicits its biological effects via LPA receptors. We found that antagonism of LPA receptor 1 (LPAR1) reduces de novo lipogenesis in alcoholic steatosis in mice. Our preliminary data suggest that LPA induces the expression of mature sterol regulatory element binding transcription factor 1 (SREBP1), a main driver for de novo lipogenesis, in hepatocytes via atypical protein kinase C (PKC?/?). Furthermore, we found that antagonism of LPAR1 suppresses the activation of hepatic stellate cells, which are major source of myofibroblasts in liver fibrosis. Mechanistically, LPA/LPAR1 signaling stimulates the nuclear localization of WW domain-containing transcription regulator protein 1 (TAZ), a downstream effector of the Hippo signaling, and induces the expression of ?-smooth muscle actin in activation of hepatic stellate cells. Based on our preliminary data, we hypothesize that LPA/LPAR1 pathway mediates de novo lipogenesis in hepatocytes via PKC?/? and SREBP1 in alcohol-induced steatosis. Furthermore, LPA/LPAR1 signaling also induces the activation of hepatic stellate cells via TAZ in liver fibrosis.
In Aim 1, we will examine roles of LPA/LPAR1 in alcoholic steatohepatitis using a new Lpar1-flox mice we have generated.
In Aim 2, we will determine if LPAR1 signaling is required to induce the activation of hepatic stellate cells in alcoholic liver fibrosis via TAZ. Our preliminary data suggest that LPA/LPAR1 signaling is a new therapeutic target for suppression of alcoholic steatosis and fibrosis. The outcome of this proposal will be applicable to new drug therapies for suppression of alcoholic liver disease by targeting LPA/LPAR1 signaling.
Chronic alcohol abuse causes liver steatosis and promotes the progression to steatohepatitis, fibrosis, and cirrhosis which is the 12th leading cause of death in the United States. Currently, no curative pharmacologic treatment is available for alcoholic steatohepatitis, fibrosis, and cirrhosis. This proposal will determine whether lysophosphatidic acid signaling could be a novel therapeutic target for the suppression of alcoholic liver disease.
