Profile analysis and functional modeling identify circular RNAs in nonalcoholic fatty liver disease as regulators of hepatic lipid metabolism

Yang Xie; Yi Cao; Can-Jie Guo; Xing-Ya Guo; Ya-Fang He; Qing-Yang Xu; Feng Shen; Qin Pan

doi:10.3389/fgene.2022.884037

Profile analysis and functional modeling identify circular RNAs in nonalcoholic fatty liver disease as regulators of hepatic lipid metabolism

Front Genet. 2022 Sep 15:13:884037. doi: 10.3389/fgene.2022.884037. eCollection 2022.

Authors

Yang Xie¹, Yi Cao², Can-Jie Guo³, Xing-Ya Guo⁴, Ya-Fang He⁵, Qing-Yang Xu¹, Feng Shen⁶, Qin Pan^{7

1}

Affiliations

¹ Department of Gastroenterology, School of Medicine, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, China.
² Department of Pediatric Digestion and Nutrition, School of Medicine, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, China.
³ Department of Gastroenterology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
⁴ Department of Gastroenterology, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
⁵ Department of Pediatric Respiratory, School of Medicine, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, China.
⁶ Endoscopy Center, School of Medicine, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, China.
⁷ Research Center, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, China.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, associated with an outcome of hepatic fibrosis/cirrhosis and hepatocellular carcinoma. However, limited exploration of the underlying mechanisms hinders its prevention and treatment. To investigate the mechanisms of epigenetic regulation in NAFLD, the expression profile of circular RNA (circRNA) of rodents in which NAFLD was induced by a high-fat, high-cholesterol (HFHC) diet was studied. Modeling of the circRNA-microRNA (miRNA) -mRNA regulatory network revealed the functional characteristics of NAFLD-specific circRNAs. The targets and effects in the liver of such NAFLD-specific circRNAs were further assessed. Our results uncovered that the downregulation of 28 annotated circRNAs characterizes HFHC diet-induced NAFLD. Among the downregulated circRNAs, long intergenic non-protein coding RNA, P53 induced transcript (LNCPINT) -derived circRNAs (circ_0001452, circ_0001453, and circ_0001454) targeted both miR-466i-3p and miR-669c-3p. Their deficiency in NAFLD abrogated the circRNA-based inhibitory effect on both miRNAs, which further inactivated the AMPK signaling pathway via AMPK-α1 suppression. Inhibition of the AMPK signaling pathway promotes hepatic steatosis, depending on the transcriptional and translational upregulation of lipogenic genes, such as those encoding sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN) in hepatocytes. The levels of LNCPINT-derived circRNAs displayed a negative association with hepatic triglyceride (TG) concentration. These findings suggest that loss of LNCPINT-derived circRNAs may underlie NAFLD via miR-466i-3p- and miR-669c-3p-dependent inactivation of the AMPK signaling pathway.

Keywords: AMPK; circular RNA; microRNA; nonalcoholic fatty liver disease; signaling pathway.