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

During fasting, hepatic PPARA facilitates the metabolic remodeling that promotes use of lipids as an alternate energy source (Brocker et al., 2018) . Fasting is also associated with many anti-inflammatory effects (Corrales et al., 2019) . To determine whether Gm15441 regulates inflammasome activation during physiological fasting, Gm15441 +/+ and Gm15441 LSL mice were fasted for 24 hours. Serum ALT and AST were not changed between Gm15441 +/+ and Gm15441 LSL mice, both with and without WY-14643 treatment ( Figure 6A ). Fasting decreased serum glucose levels in both Gm15441 +/+ and Gm15441 LSL mice, but the decrease was greater in Gm15441 LSL mice ( Figure 6A) . Expression of Acadm, Cyp4a14, and Txnip mRNAs was significantly increased by fasting in both Gm15441 +/+ and Gm15441 LSL mice ( Figure S2A ). Gm15441 was significantly induced by fasting, although to a much lower degree than with WY-14643 treatment ( Figure S2A ). Expression of Txnip mRNA was increased to the same level in livers of fasted Gm15441 LSL mice as in fasted Gm15441 LSL mice ( Figure S2A ). Fasting also increased TXNIP, CASP1, and IL1B protein levels in Gm15441 LSL mice, in contrast to either a modest increase (TXNIP) or no increase (CASP1, IL1B) in Gm15441 +/+ mice ( Figure S2B , Figure S2C ). Fasting markedly promotes lipid accumulation in mouse liver (Brocker et al., 2018) . Lipid droplet accumulation was also observed and more widespread in fasting Gm15441 LSL mice than fasting Gm15441 +/+ mice ( Figure S2D ). ORO staining was performed to validate the lipid accumulation response to fasting in Gm15441 LSL mice. A greater amount of lipid accumulation was observed in fasting Gm15441 LSL liver than in fasting Gm15441 +/+ mice liver ( Figure 6B ).