P53/PANK1/miR‐107 signalling pathway spans the gap between metabolic reprogramming and insulin resistance induced by high‐fat diet

Abstract

High‐fat diet (HFD) leads to obesity, type II diabetes mellitus (T2DM) and increases the coincidence of cardiovascular diseases and cancer. Insulin resistance (IR) is considered as the ‘common soil’ of those diseases. Furthermore, people on HFD showed restrained glycolysis and enhanced fatty acid oxidation, which is the so‐called metabolic reprogramming. However, the relationship between metabolic reprogramming and IR induced by HFD is still unclear. Here, we demonstrate that PANK1 and miR‐107 were up‐regulated in the liver tissue of mice on HFD for 16 weeks and involved in metabolic reprogramming induced by palmitate acid (PA) incubation. Importantly, miR‐107 within an intron of PANK1 gene facilitated IR by targeting caveolin‐1 in AML12 cells upon PA incubation. Moreover, we identify that HFD enhanced P53 expression, and activation of P53 with nutlin‐3a induced PANK1 and miR‐107 expression simultaneously in transcriptional level, leading to metabolic reprogramming and IR, respectively. Consistently, inhibition of P53 with pifithrin‐α hydrobromide ameliorated PA‐induced metabolic reprogramming and IR. Thus, our results revealing a new mechanism by which P53 regulate metabolism. In addition, the results distinguished the different roles of PANK1 and its intron miR‐107 in metabolic regulation, which will provide more accurate intervention targets for the treatment of metabolic diseases.

p53 Promotes Ferroptosis in Macrophages Treated with Fe3O4 Nanoparticles

“…To further investigate Fe 3 O 4 NP-induced ferroptosis of macrophages and whether p53 was involved in this process, we used PFT, a known p53 inhibitor . PFT exhibited inhibitory effects after co-incubation with NP-treated Ana-1 cells for 48 h. AM/PI staining was used for cell viability assay; PFT (Figure a) was found to reduce the death of NP-treated macrophages.…”

“…To further investigate Fe 3 O 4 NP-induced ferroptosis of macrophages and whether p53 was involved in this process, we used PFT, a known p53 inhibitor. 42 PFT exhibited inhibitory effects after co-incubation with NP-treated Ana-1 cells for 48 h. AM/PI staining was used for cell viability assay; PFT (Figure 7a) was found to reduce the death of NP-treated macrophages. The values were approximately 30−35% higher than those in the 48 h group, although they were slightly lower than those in the control group, indicating that PFT could reduce cell death in macrophages induced by NPs.…”

Multi‐ancestry genome‐wide association study of asthma exacerbations

“…Bioproducts from bacterial infections, such as LPS, can trigger an inflammatory response and increase airway hyperresponsiveness and risk of asthma exacerbations 47,48 . Moreover, p53 can regulate cell cycle progression via upregulation of PANK1 after DNA damage 49 and metabolism 50 …”

Genome-wide microRNA profiles identify miR-107 as a top miRNA associating with expression of the CYP3As and other drug metabolizing cytochrome P450 enzymes in the liver

“…miR-107 belongs to a highly conserved miR-15/miR-107 gene family that shares a common “AGCAGC” sequence near the end of the mature miRNAs’ 5′UTR ( Finnerty et al, 2010 ). miR-107 is transcribed from the host gene PANK1 , which is broadly expressed in many tissues and has been implicated in cancers ( Turco et al, 2020 ), chemosensitivity ( Chen et al, 2021 ), ischemic stroke ( Yang et al, 2014 ), insulin resistance ( Yang et al, 2020 ), and neuronal differentiation ( Croizier et al, 2018 ). Dysregulation of miR-107 is associated with diverse pathways, including: obesity and diabetes ( Foley and O'Neill, 2012 ), Alzheimer’s disease ( Chang et al, 2017 ), cancers ( Turco et al, 2020 ; Chen et al, 2021 ), and drug treatment and environmental exposure ( Chou et al, 2017 ; Chen et al, 2020 ).…”