Abstract
BackgroundNon-alcoholic steatohepatitis (NASH) is a key stage in leading development of non-alcoholic simple fatty liver (NAFL) into cirrhosis and even liver cancer. This study aimed at exploring the lncRNAs expression profile in NASH and the biological function of a novel LncRNA-gm9795.MethodsMicroarray analysis was performed to compare the expression profiles of lncRNAs in the liver of NASH, NAFLD and normal mice (5 mice for each group). Methionine-choline-deficient Medium (MCD) with Lipopolysaccharide (LPS) or palmitic acid (PA)were used to built NASH cell models. The role and mechanism of LncRNA-gm9795 in NASH were explored by knocking down or over-expressing its expression.ResultsA total of 381 lncRNAs were found to be not only highly expressed in NAFLD, but also is going to go even higher in NASH. A novel LncRNA-gm9795 was significantly highly expressed in liver tissues of NASH animal models and NASH cell models. By staining with Nile red, we found that gm9795 did not affect the fat accumulation of NASH. However, gm9795 in NASH cell models significantly promoted the expression of TNF alpha {}, IL-6, IL-1beta {}, the important inflammatory mediators in NASH. At the same time, we found that gm9795 upregulated the key molecules in endoplasmic reticulum stress (ERS), while NF-kappa {}B/JNK pathways were also activated. When ERS activator Thapsigargin (TG) was introduced in cells with Ggm9757 si-RNA, NF-kappa {}B and JNK pathways were activated. Conversely, ERS inhibitor Tauroursodeoxycholic acid (TUDCA) inhibited NF-kB and JNK pathways in cells with gm9795 overexpression plasmid.ConclusionLncRNA-gm9795 promotes inflammatory response in NASH through NF-kB and JNK pathways by ERS, which might provide theoretical basis for revealing the pathogenesis of NASH and discovering new therapeutic targets
Highlights
Non-alcoholic steatohepatitis (NASH) is a key stage in leading development of non-alcoholic simple fatty liver (NAFL) into cirrhosis and even liver cancer
Pathological sections showed that fat accumulation was significantly increased in DB/ DB mice fed with normal diet(NAFLD model) compared with the control group, while DB/DB mice fed with Methioninecholine-deficient medium (MCD) diet(NASH model) showed significant inflammatory cell infiltration, indicating the success of the model building (Fig. 1a)
The results of Microarray showed that a total of 3111 long noncoding RNAs (lncRNAs) (1915 upregulated and 1196 downregulated) were differentially expressed between the non-alcoholic fatty liver disease (NAFLD) and control groups
Summary
Non-alcoholic steatohepatitis (NASH) is a key stage in leading development of non-alcoholic simple fatty liver (NAFL) into cirrhosis and even liver cancer. Ye et al J Transl Med (2021) 19:101 non-alcoholic simple fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), and to non-alcoholic cirrhosis (NAC) and even to liver cancer [4]. Insulin resistance (Insulin to hold, IR) is the core link This theory cannot fully explain the development of lipid deposition in liver cells during steatohepatitis, liver fibrosis and other NAFLD processes. Oxidative stress, exogenous substances, and the accumulation of unfolded proteins in the endoplasmic reticulum can all disrupt the endoplasmic reticulum balance, leading to ERS, liver lipid metabolism disorder, hepatocyte inflammatory necrosis and apoptosis, and the development of NASH [6, 7]. It is not difficult to notice the important role of inflammatory response and endoplasmic reticulum stress in NASH, so inhibiting inflammation and endoplasmic reticulum stress may be a strategy for treating NASH
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