Regulation and Function of Thioredoxin Interacting Protein (Txnip) in Nonalcoholic Steatohepatitis (NASH) - PROJECT SUMMARY The worldwide epidemic of nonalcoholic fatty liver disease (NAFLD) has become a severe and costly threat to public health. The current therapeutic options for NAFLD are exceedingly limited, especially for its severe form - nonalcoholic steatohepatitis (NASH), which has no FDA-approved therapy. There is an urgent need to identify novel therapeutic targets for NASH treatment. Thioredoxin interacting protein (Txnip) is a stress-induced gene, and it has been implicated in NASH. However, the role of Txnip in NASH is controversial, which may be attributed to the following two issues. Firstly, there are two genes in the Txnip gene locus: Txnip and Txnip antisense long non-coding RNA Gm15441. Genetic deletion of Txnip also deletes part of Gm15441. Secondly, Txnip plays critical roles in other metabolic organs, which interferes with its function in the liver. Therefore, previous studies using Txnip global knockout mice were not able to reveal the liver-specific role of Txnip in NASH. Our preliminary data demonstrate that Txnip protein is abnormally accumulated in NASH mouse livers. Our preliminary studies also suggest that Txnip may promote hepatocyte apoptosis. Given that excessive hepatocyte apoptosis drives NASH development, therefore, we propose a central hypothesis that inhibition of hepatic Txnip alleviates NASH. In Aim 1, an antisense RNA based Txnip translational inhibitor will be developed for NASH treatment. In Aim 2, we will dissect the functional role and mechanism of Txnip in NASH mouse liver. In Aim 3, we will investigate a novel mechanism that causes Txnip protein accumulation in NASH mouse liver. Completion of this proposal will provide critical insights into the functions and mechanisms of Txnip in NASH development. These studies will also lead to the development of novel therapeutic strategies for NASH treatment.
