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

PPARA, a key regulator of global lipid homeostasis, modulates fasting-induced lipid accumulation and hepatosteatosis in mice (Brocker et al., 2018) . Lipid droplets appeared in livers of fasted Gm15441 +/+ mice but were more widely distributed in livers of fasting Gm15441 LSL mice compared to fasting Gm15441 +/+ mice. Histological lipid staining revealed considerably larger amounts of lipid accumulation in livers of fasted Gm15441 LSL mice than in fasted Gm15441 +/+ . CC-BY-NC-ND 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/675785 doi: bioRxiv preprint livers. Serum and liver TG levels and liver CHOL levels were significantly elevated by fasting in Gm15441 LSL mouse livers. RNA-sequencing analysis revealed that liver damage, inflammation, and fatty accumulation biomarkers such as Apoa4, Bhmt, Lcn2, Orm2, Saa1, and Saa2 mRNAs showed significantly higher expression under fasting-induced metabolic stress in Gm15441 LSL compared to Gm15441 +/+ mouse liver. LCN2 is marker for liver damage and inflammation (Asimakopoulou et al., 2016; Moschen et al., 2017) . Hepatic Lcn2 and Orm2 mRNAs are both upregulated in the liver in response to IL1B (Sai et al., 2014; Zhang et al., 2014) . Saa1 and Saa2 mRNAs are acute phase response proteins and biomarkers of inflammation and their protein products become major components high density lipoprotein (HDL) regulated by IL1B (Leclerc et al., 2019; Lindhorst et al., 1997; Olteanu et al., 2014) . Moreover, SAA1 and SAA2 potentiate NLRP3 inflammasome activation, which would act as a feed forward much further increasing IL1B cleavage/maturation/inflammation (Chiba et al., 2009; Zhou et al., 2016) . APOA4 plays a role in hepatic TG secretion and is upregulated in response to lipid accumulation (Qin et al., 2016; Zhang et al., 2017b) . Notably, APOA4 is a regulator of fasting lipid that is associated with TG secretion and HDL cholesterol in type 2 diabetes (Delgado-Lista et al., 2010; Qi et al., 2007) .