Protection against Glucolipotoxicity by High Density Lipoprotein in Human PANC-1 Hybrid 1.1B4 Pancreatic Beta Cells: The Role of microRNA

Abstract

High-density lipoproteins provide protection against the damaging effects of glucolipotoxicity in beta cells, a factor which sustains insulin secretion and staves off onset of type 2 diabetes mellitus. This study examines epigenetic changes in small non-coding microRNA sequences induced by high density lipoproteins in a human hybrid beta cell model, and tests the impact of delivery of a single sequence in protecting against glucolipotoxicity. Human PANC-1.1B4 cells were used to establish Bmax and Kd for [3H]cholesterol efflux to high density lipoprotein, and minimum concentrations required to protect cell viability and reduce apoptosis to 30mM glucose and 0.25 mM palmitic acid. Microchip array identified the microRNA signature associated with high density lipoprotein treatment, and one sequence, hsa-miR-21-5p, modulated via delivery of a mimic and inhibitor. The results confirm that low concentrations of high-density lipoprotein can protect against glucolipotoxicity, and report the global microRNA profile associated with this lipoprotein; delivery of miR-21-5p mimic altered gene targets, similar to high density lipoprotein, but could not provide sufficient protection against glucolipotoxicity. We conclude that the complex profile of microRNA changes due to HDL treatment may be difficult to replicate using a single microRNA, findings which may inform current drug strategies focused on this approach.

Homo Sapiens (Hsa)-microRNA (miR)-6727-5p Contributes to the Impact of High-Density Lipoproteins on Fibroblast Wound Healing In Vitro

“…However, hsa-miR-6727-5p was confirmed to be up-regulated in HDFn, and downregulated in HDFa, by treatment with HDL (Figure 5); intriguingly, this was not one of the sequences identified as regulated by HDL or apoA-I in human PANC-1 hybrid 1.1B4 pancreatic beta cells under equivalent conditions [28]. Only one published report exists on this sequence, indicating that it promotes the proliferation, migration and invasion of cervical cancer cell lines [60] suggesting a possible role in mediating the impact of HDL in wound healing.…”

“…The ability of HDL to modulate the expression within, and secretion of, selected small non-coding microRNA sequences in cells is well established, achieving regulation of expression of networks of genes, including those involved in lipoprotein metabolism and intercellular communication [25][26][27][28]. Equally, microRNA sequences have been shown to modulate the process of wound healing [29][30][31][32], but insights into the genetic mechanism(s) by which HDL promote this process are lacking are present.…”

Clustering patterns of metabolic syndrome: A cross-sectional study in children and adolescents in Kyiv

“…Aliusef et al 10.3389/fped.2022.972975 significantly higher than HOMA-2 IR, so by determining only the HOMA-1 IR we may lose some patients, on the other hand determining insulin resistance with HOMA-2 IR may be a more sensitive method and represent data from the current population. However, further studies of the MetS with a control group of healthy children are necessary.…”

“…Studies demonstrate that LDL-C inhibits glucose-stimulated insulin secretion and β -cell proliferation via LDL receptor mechanisms. Also, high levels of LDL-C (>6 mmol/L) cause β -cell apoptosis ( 10 ). Given the pathogenetic links between the processes outlined above, we suggested that beta cell activity and insulin sensitivity may be prognostic criteria for severity of the MetS.…”

MicroRNA Sequences Modulated by Beta Cell Lipid Metabolism: Implications for Type 2 Diabetes Mellitus

“…Notably, ABCA1 is also regulated by exposure to elevated levels of glucose: miR-145 increases the total level of islet cholesterol [200], while miR-383 targets the anti-inflammatory Toll-like receptor 4 [201], which has also been linked with altered expression of ABCA1 [182]. More complex relationships between miRs and HDL emerge from Table 1: Tarlton et al (2021) showed that miR-21-5p could mimic the effects of HDL on targets STAT3 and SMAD7, but could not provide equivalent protection against glucolipotoxicity in human PANC hybrid 1.1B4 cells [202], while HDL increases the export of miR-375-3p, a feature which correlates inversely with insulin secretion in murine MIN6 cells [203]. Cholesterol exposure also enhances the expression of miR-24a, which impacts on the transcription factor Sp1 to alter the expression of secretagogin and reduce insulin secretion [204].…”