Emergent Roles of Circular RNAs in Metabolism and Metabolic Disorders

Abstract

Circular RNAs (circRNAs) are an emerging group of long non-coding RNAs (lncRNAs) and have attracted attention again according to the progress in high-throughput sequencing in recent years. circRNAs are genome transcripts produced from pre-messenger (m)RNA regions in a specific process called "back-splicing," which forms covalently closed continuous loops. Due to their lack of a 5' cap and 3' poly-adenylated tails, circRNAs are remarkably more stable than linear RNAs. Functionally, circRNAs can endogenously sponge to microRNAs, interact with RNA-binding proteins (RBPs), or translate themselves. Moreover, circRNAs can be expressed in cell type- or tissue-specific expression patterns. Therefore, they are proposed to play essential roles in fine-tuning our body's homeostasis by regulating transcription and translation processes. Indeed, there has been accumulating emergent evidence showing that dysregulation of circRNAs can lead to metabolic disorders. This study explored the current knowledge of circRNAs that regulate molecular processes associated with glucose and lipid homeostasis and related pathogeneses of metabolic disorders. We also suggest the potential role of circRNAs as disease biomarkers and therapeutic targets.

Keywords: NAFLD; NASH; circRNA; diabetes; obesity.

Figure 1

Biogenesis and potential biological functions of circular (circ)RNAs. (A) Back-splicing model: pre-mRNA is spliced in a non-canonical manner of “back-splicing” by (1) inverted repeat elements in long flanking intron pairs, such as Alu elements, or (2) dimerization of RNA-binding proteins (RBPs). During back-splicing, an upstream branch point attacks a downstream splice donor site to form exonic circRNAs or exon–intron circRNAs. (B) Lariat precursor model: pre-mRNA undergoes canonical splicing to generate a linear mRNA and a lariat precursor. (3) The lariat precursors with exon components might be generated from exon-skipping events and then further back-spliced to exonic circRNAs. Alternatively, (4) the intronic lariat precursors escape from the debranching step of canonical linear splicing to form intronic circRNAs. Exonic circRNAs are transported from the nucleus to the cytoplasm to function as miRNA sponges to inhibit miRNA activity; protein sponges (such as RBPs) affect protein functions and translocation or protein-coding to further translation. Exon–intron circRNAs and intronic circRNAs can interact with transcription complexes to regulate transcription in the nucleus.

Figure 2

The potential role of circular (circ)RNAs in pancreatic β-cells. circHIPK3 and ciRS-7/CDR1a are exonic circRNAs mainly localized in the cytoplasm which act as miRNA sponges to enhance insulin secretion. ciRS-7/CDR1a also enhances insulin expression by the mi7 sponge. circTulp4 is also an exonic circRNA that sequesters miR-7222-3p to promote β-cell proliferation. circAFF1 is an exonic circRNA that inhibits β-cell apoptosis through an unknown mechanism. ci-Ins2 is an intronic circRNA mainly localized in the nucleus that interacts with the RNA-binding protein, TDP-43. The interaction between ci-Ins2 and TDP-43 promotes expression of the insulin secretory machinery. Pax6, paired box 6; SLc2a2, solute carrier family 2 member 2; Akt1, AKT serine/threonine kinase 1; Mtpn, myotrophin; Myrip, myosin VIIA and Rab interacting protein; Cacna1d, calcium voltage-gated channel subunit alpha1 D; TDP-43, TAR DNA-binding protein 43.