Abstract
Abnormal expression of circRNAs (circular RNAs), a subclass of non-coding RNAs, has been documented in numerous human diseases. Herein, we explored whether circRNAs act as ceRNAs (competing endogenous RNAs) to modulate the pathological process-insulin resistance, as well as dyslipidemia of MetS (Metabolic Syndrome). The profile of circRNAs in serume of MetS and control samples was characterized by circRNA deep sequencing. We identified circRNF111 as a key downregulated circRNA involved in MetS. The decreased expression of circRNF111 in the serum samples of MetS was directly linked to excessive insulin resistance and dyslipidemia. Loss-of-function experiments showed that circRNF111 knockdown inhibited the glucose uptake and the Akt signaling pathway, meanwhile increased the deposition of triglycerides in adipogenic differentiated hADSCs (human adipose-derived stem cells). Mechanistically, circRNF111 sponged miR-143-3p and functioned via targeting miR-143-3p along with its downstream target gene IGF2R. The role along with the mechanism of circRNF111 sponging miR-143-3p in MetS was also explored in obese mice triggered by high-fat die. Therefore, our data suggest a protective role of the novel circRNA-circRNF111 in MetS progression. CircRNF111 inhibition enhances insulin resistance and lipid deposition in MetS through regulating miR-143-3p-IGF2R cascade. This provides a promising therapeutic approach for MetS.
Highlights
Metabolic syndrome (MetS) is a group of predisposing factors, consisting of low high-density lipoprotein content, high glucose, hypertension, obesity along with high triglyceride contents (Rodríguez-Monforte et al, 2019)
We further investigated circRNAs’ number in their host genes and the results illustrated that one gene could generate numerous circRNAs as indicated in Supplementary Figure 1F
We identified and characterized one potential protective function of hsa_circ_0001982, which is produced by the circularization of exon 2 of RNF111 gene, thereafter termed circRNF111 (Supplementary Figure 1I)
Summary
Metabolic syndrome (MetS) is a group of predisposing factors, consisting of low high-density lipoprotein content, high glucose, hypertension, obesity along with high triglyceride contents (Rodríguez-Monforte et al, 2019). Patients with MetS have a relatively increased risk of about twofold of developing cardiovascular disease in a period of 5–10 years and at least 5-fold for. CircRNF111 Sponging miR-143-3p Regulating IGF2R developing type-2 diabetes, and an approximately 1.6fold increased risk of mortality (Kaur, 2014). A population-based pooled assessment involving 2416 studies consisting of 128.9 million children, adolescents, as well as adults from the Lancet showed that China has the largest number of obese and severely obese people in the world, to 1st rank for both men and women in 2014 (NCD Risk Factor Collaboration (NCD-RisC), 2016). Insulin resistance and obesity-induced dyslipidemia are recognized as the primary causes of most MetS cases (Gobato et al, 2014). It is necessary to design improved approaches of averting insulin resistance, enhancing MetS prognosis
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