A novel pathway controls liver injury in NASH

Project Summary Nonalcoholic fatty liver disease (NAFLD) has become a prevalent health risk. Nonalcoholic steatohepatitis (NASH), featured by hepatic steatosis, inflammation, liver injury, and fibrosis, could lead to the occurrence of cirrhosis and liver cancer, both of which require liver transplantation. Although NASH is reversible, there is no therapeutics that have been approved by FDA. The pathogenesis for this devastating disease remains poorly understood. Therefore, investigating the molecular mechanism underlying NASH pathogenesis and identifying potential therapeutic targets are of great significance. Liver injury caused by hepatocellular death is a cardinal feature of NASH and is typically characterized by the presence of ballooned hepatocytes on liver biopsy examination. In normal liver, hepatocyte apoptosis plays a key role in liver homeostasis, maintaining equilibrium between hepatocyte loss and replacement. However, pathological conditions including alcoholic or nonalcoholic steatohepatitis lead to extensive hepatocyte death and liver injury. Numerous studies suggest that hepatocellular death is the key event triggering the progression of NAFLD and the development of cirrhosis and liver cancer. Thus, understanding the molecular mechanisms by which hepatocellular death is controlled may lead to new treatments for NASH. Metabolic stress, such as overnutrition, is a major pathogenic factor promoting the development of NASH. However, it is still unclear whether and how metabolic stress directly regulates NASH- associated liver injury. Our recent study found that the intracellular energy sensor AMP-activated protein kinase (AMPK) senses metabolic stress and controls liver injury in NASH. The repression of AMPK during overnutrition and obesity promotes NASH-associated liver injury and fibrosis. Moreover, we identified that AMPK directly phosphorylates zymogen procaspase-6 and prevents its cleavage and activation in livers. Furthermore, preliminary studies suggest that active caspase-6 cleaves Bcl-2 family protein BID to mediate a feedforward pathway in the apoptotic caspase cascade. These findings indicate that a novel AMPK-caspase-6-BID axis may control liver injury and subsequent fibrosis in NASH. We hypothesize that AMPK senses metabolic stress and controls caspase-6 activation, which in turn mediates NASH-associated liver injury via cleaving BID in hepatocytes. We will explore this hypothesis with the following aims. Specific Aim 1 will delineate the regulation and function of caspase-6 in NASH pathophysiology. Using existing and new transgenic mouse models, including global and conditional knockout mice, we will thoroughly evaluate the role of caspase-6 in the pathogenesis of NASH, and examine whether BID mediates the deleterious function of caspase-6. Specific Aim 2 will elaborate the molecular mechanism by which the AMPK-caspase-6-BID axis regulates hepatocyte death. The findings from proposed studies will unravel a novel mechanism underlying NASH-associated liver injury and identify potential targets for the development of new therapy.