Long non-coding RNA GAS5 contributes to the progression of nonalcoholic fatty liver disease by targeting the microRNA-29a-3p/NOTCH2 axis

Abstract

Long non-coding RNAs (lncRNAs) have been widely recognized as critical players in the development of nonalcoholic fatty liver disease (NAFLD), one of the most prevalent liver diseases globally. In this study, we established a HFD-induced NAFLD mouse model and explored the role of lncRNA GAS5 in NAFLD progression and its possible underlying mechanisms. We showed that NAFLD activity score was elevated in the HFD mice. GAS5 knockdown attenuated HFD-induced hepatic steatosis and lipid accumulation and reduced NAFLD activity score in HFD mice. In addition, GAS5 knockdown reduced serum triglyceride cholesterol levels and inhibited alanine aminotransferase and aspartate aminotransferase activities in HFD mice. Moreover, GAS5 overexpression enhanced NOTCH2 levels in liver cells and promoted NAFLD progression by sponging miR-29a-3p in vivo . Furthermore, miR-29a-3p inhibited NAFLD progression by targeting NOTCH2 in vivo . Overall, our results indicated that GAS5 acts as a sponge of miR-29a-3p to increase NOTCH2 expression and facilitate NAFLD progression by targeting the miR-29a-3p/NOTCH2 axis and demonstrated a new GAS5-mediated mechanism underlying NAFLD development, suggesting that GAS5 could be a potential therapeutic target of NAFLD. Abbreviations: Alanine aminotransferase: ALT; Aspartate aminotransferase: AST; Enzyme linked immunosorbent assay: ELISA; Hepatocellular carcinoma: HCC; High-fat diet: HFD; Long non-coding RNA: Lnc RNA; Long non-coding RNA GAS5: GAS5; MicroRNAs: MiRNAs; Nonalcoholic fatty liver disease: NAFLD; Quantitative reverse transcription PCRs: RT-qPCRs; siRNA negative control: si-NC; Total cholesterol: TC; Triglyceride: TG

MicroRNA-379-5p regulates free cholesterol accumulation and relieves diet induced-liver damage in db/db mice via STAT1/HMGCS1 axis

“…However, its level in the liver has not been mentioned. Since only hepatic miRNAs profile can reflect their function in the liver [ 17 ], we examined its expression firstly in the liver from clinical database. As shown in Fig.…”

Systems biology approach reveals a common molecular basis for COVID-19 and non-alcoholic fatty liver disease (NAFLD)

“…For risk stratification of NASH patients, Harrison et al devised a non-invasive diagnostic approach containing mir-34a-5p [91]. GAS5 operated as a miR-29a-3p sponge, promoting NAFLD progression by targeting the miR-29a-3p/NOTCH2 axis, according to Cui et al [92]. We also found five miRNAs linked with COVID-19 (mir-26b-5p, mir-21-5p, mir-34a-5p, mir-4659a-3p, mir-142-5p).…”

The Implications of Noncoding RNAs in the Evolution and Progression of Nonalcoholic Fatty Liver Disease (NAFLD)-Related HCC

“…Recently, many findings emerged supporting the implication of miRNAs and lncRNAs in the pathogenesis of NAFLD-related HCC [ 124 , 125 ]. Dysregulated expression profiles of such ncRNAs could improve our understanding of this complex disease and hopefully provide the means for the development of noninvasive and cost-effective methods of diagnosis.…”

“…Moreover, GAS5 knockdown caused a reduction in serum triglyceride cholesterol levels while inhibiting alanine aminotransferase and aspartate aminotransferase activities in vivo. Their results suggest that GAS5 is a potent regulator of the miR-29a-3p/NOTCH2 axis while actively involved in NAFLD progression, which recommends it as a potential therapeutic target against NAFLD [ 125 ]. These findings reflect a possible role of GAS5 in the progression of NAFLD to HCC, but extensive research and validation are required.…”