RNA Sequencing Analysis of Control and Blnc1 liver specific knockout mice (LKO) Liver Transcriptomes after 24 weeks NASH diet feeding

ABSTRACT: Hepatic lipogenesis is a central aspect of the feeding response and is aberrantly induced in the progression of fatty liver disease. Liver X receptors (LXRs) and sterol regulatory element-binding protein 1c (SREBP1c) are potent activators of the lipogenic gene program that promote triglyceride synthesis and hepatic steatosis in the insulin-resistant state. To date, key protein components of the LXR-SREBP1c axis have been uncovered that mediate transcriptional activation of SREBP1c by LXRs and nutrient and hormonal regulation. However, whether this regulatory pathway interfaces with long noncoding RNAs (lncRNAs) remains largely unexplored. Here we show that hepatic expression of Blnc1, a regulator of brown adipocyte development, is strongly associated with adiposity and liver fat content in mice. Blnc1 is required for the induction of SREBP1c and hepatic lipogenic genes in response to LXR activation. CRISPR/Cas9-mediated liver-specific inactivation of Blnc1 abrogates high fat diet-induced hepatic steatosis and insulin resistance. We further observed that liver Blnc1 expression is elevated in a mouse model of nonalcoholic steatohepatitis (NASH). Mice lacking Blnc1 in the liver are protected from diet-induced NASH and exhibit attenuated liver injury, inflammation and liver fibrosis. At the molecular level, proteomic analysis of the Blnc1 ribonucleoprotein complex in the liver identified endothelial differentiation related factor 1 (EDF1) as a component of the LXR transcriptional complex that acts in concert with Blnc1 to stimulate SREBP1c expression. These findings uncover a lncRNA ribonucleoprotein complex that licenses obesity-linked activation of hepatic lipogenesis and NAFLD pathogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE108609 | GEO | 2018/12/21

REPOSITORIES: GEO