Loss of miR-23b/27b/24-1 Cluster Impairs Glucose Tolerance via Glycolysis Pathway in Mice

Abstract

Alterations in miRNAs are associated with many metabolic disorders, such as type 2 diabetes (T2DM). The miR-23b/27b/24-1 cluster contains miR-23b, miR-27b, and miR-24-1, which are located within 881 bp on chromosome 9. Studies examining the roles of miR-23b, miR-27b, and miR-24-1 have demonstrated their multifaceted functions in variable metabolic disorders. However, their joint roles in metabolism in vivo remain elusive. To investigate this subject, we constructed miR-23b/27b/24-1 cluster knockout (KO) mice. Compared with wild-type (WT) mice, the KO mice exhibited impaired glucose tolerance, which was accompanied by a reduction in the respiratory exchange rate (RER). These alterations were more noticeable after a high-fat diet (HFD) induction. Hepatic metabolomic results showed decreased expression of reduced nicotinamide adenine dinucleotide (NADH), nicotinamide adenine dinucleotide (NAD), phosphoenolpyruvic acid (PEP), and phosphoric acid, which are involved in the glycolysis pathway. The transcriptomic results indicated that genes involved in glycolysis showed a downregulation trend. qPCR and Western blot revealed that pyruvate kinase (PKLR), the key rate-limiting enzyme in glycolysis, was significantly reduced after the deletion of the miR-23b/27b/24-1 cluster. Together, these observations suggest that the miR-23b/27b/24-1 cluster is involved in the regulation of glucose homeostasis via the glycolysis pathway.

Suicide Related Phenotypes in a Bipolar Sample: Genetic Underpinnings

“…These miRNAs are highly expressed in vascularized tissues [60]. In addition, miR-27b was shown to target the NOTCH ligand Delta-like ligand 4 (Dll4) [55]. To note, the NOTCH pathway was enriched in our pathway analysis.…”

“…The role of these miRNAs has not been fully elucidated, however studies examining the roles of miR-23b, miR-27b and miR-24-1 have demonstrated their multiple functions, ranging from metabolic disorders to proliferation and development disorders [55][56][57][58][59][60]. These miRNAs are highly expressed in vascularized tissues [60].…”

Transcript Expression Profiles and MicroRNA Regulation Indicate an Upregulation of Processes Linked to Oxidative Stress, DNA Repair, Cell Death, and Inflammation in Type 1 Diabetes Mellitus Patients

“…Overexpression of miR-27b was found to inhibit NRF2 activation, a master regulator of antioxidant response [54], and suppress NFKB activation [55]. Furthermore, mir-27b upregulation has been associated with the onset of retinopathy [56], while its downregulation has been implicated in glucose tolerance impairment [57] and nephropathy [58]. The upregulation of mir-148a has been consistently found in T1D patients [59,60].…”

The Role of miR-23b in Cancer and Autoimmune Disease

“…Small endogenous regulatory RNAs, also known as short-strand ribonucleic acid microRNAs (miRNAs), are critical posttranscriptional regulators of gene expression and were first identified in C. elegans [19][20][21]. ere are many kinds of miRNAs, among which miRNA-23b belongs to miR-23b/27b/24-1 cluster [22]. miR-23b possessed regulatory roles, especially in the development of cancer and autonomic immune diseases [23].…”