N-acetylcysteine (NAC) possesses a strong capability to ameliorate high-fat diet (HFD)-induced nonalcoholic-fatty liver disease (NAFLD) in mice, but the underlying mechanism is still unknown. Our study aimed to clarify the involvement of long noncoding RNAs (lncRNAs) in the beneficial effects of NAC on HFD-induced NAFLD. C57BL/6J mice were fed a normal-fat diet (10% fat), a HFD (45% fat), or a HFD plus NAC (2 g/L in the drinking water). After 14-week of intervention, NAC obviously rescued the deleterious alterations induced by HFD, including the changes in body and liver weights, hepatic triglycerides (TGs), plasma alanine aminotransferase (ALT), plasma aspartate transaminase (AST), and liver histomorphology (H&E and Oil red O staining). Through whole-transcriptome sequencing, 52167 (50758 known and 1409 novel) hepatic lncRNAs were detected. Our cross-comparison data revealed the expression of 175 lncRNAs were significantly changed by HFD but reversed by NAC. Five of those lncRNAs, lncRNA-NONMMUT148902.1 (NO_902.1), lncRNA-XR_001781798.1 (XR_798.1), lncRNA-NONMMUT141720.1 (NO_720.1), lncRNA-XR_869907.1 (XR_907.1), and lncRNA-ENSMUST00000132181 (EN_181) were selected based on an absolute log2 fold change (FC) value of greater than 4, P-value &lt; 0.01, and P-adjusted value &lt; 0.01. Further qRT-PCR analysis showed that the levels of lncRNA-NO_902.1, lncRNA-XR_798.1, and lncRNA-EN_181 were dramatically decreased by HFD but restored by NAC, consistent with the RNA-sequencing. Finally, we constructed a ceRNA network containing lncRNA-EN_181, 3 miRNAs, and 13 mRNAs, which was associated with the NAC-ameliorated NAFLD. Overall, lncRNA-EN_181 might be a potential target in NAC-ameliorated NAFLD. This finding enhanced our understanding of the biological mechanisms underlying the beneficial role of NAC.

Long noncoding RNA-EN_181 potentially contributes to the protective effects of N-acetylcysteine against non-alcoholic fatty liver disease in mice

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