Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress

Chad N. Brocker; Donghwan Kim; Tisha Melia; Kritika Karri; Thomas J. Velenosi; Shogo Takahashi; Jessica A. Bonzo; David J. Waxman; Frank J. Gonzalez

A strand-specific Gm15441 knockout mouse was developed to assess lncRNA function without impacting regulation of its antisense protein-coding partner Txnip. In contrast, previous knockout mouse models developed to evaluate TXNIP function disrupt both Txnip and Gm15441 and therefore abolish the unique regulatory loop that exists between these two genes. Txnip-null mice show a higher incidence of hepatocellular carcinoma, with approximately 40% of male mice developing hepatic tumors (Kwon et al., 2010; Sheth et al., 2006) . However, the Txnip-null mice lack exons 1-4, and thus Gm15441 is also ablated (Oka et al., 2006) . Conditional Txnip-floxed mice were developed that target exon 1, which results in deletion of Gm15441 exon 3 (Oka et al., 2009 ). However, in another study, the ubiquitously-expressed protamine-Cre mouse was employed to generate a Txnip conditional-null mouse line (Yoshioka et al., 2007) . Hepatocytespecific Txnip-null mice also used an exon 1 floxed allele which results in the removal of Gm15441 exon 2 (Chutkow et al., 2008) . TXNIP expression in vitro inhibited hepatocellular carcinoma cell proliferation and induced apoptosis (Liu et al., 2017) . Thus, prolonged Gm15441-mediated suppression of TXNIP may contribute to PPARA agonist induced hepatocellular carcinoma (Cho et al., 2019; Gunes et al., 2018) .