Taking KLF9 to “Cort” for crimes against metabolism

Sweet, David R; Fan, Liyan; Jain, Mukesh K.

doi:10.1172/jci128481

Cited by 7 publications

(3 citation statements)

References 26 publications

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“…Similarly, krüppel-like factor 9 (KLF9) was among the highest-ranked transcription factors. KLF9 promotes the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), resulting in hepatic gluconeogenesis, and it is involved in glucocorticoid-induced hyperglycemia and diabetes (Cui et al, 2019; Sweet et al, 2019). Given the involvement of these transcription factors in key processes associated with AD, their potential as therapeutic targets warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic and Network Analysis Highlight the Association of Diabetes at Different Stages of Alzheimer’s Disease

Santiago¹,

Bottero

Potashkin

2019

Front. Neurosci.

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Alzheimer’s disease (AD) and type 2 diabetes (T2D) are among the most prevalent chronic diseases affecting the aging population. Extensive research evidence indicates that T2D is a well-established risk factor for AD; however, the molecular mechanisms underlying this association have not been fully elucidated. Furthermore, how T2D may contribute to the progression of AD is a subject of extensive investigation. In this study, we compared the blood transcriptome of patients with mild cognitive impairment (MCI), AD, and advanced AD to those afflicted with T2D to unveil shared and unique pathways and potential therapeutic targets. Blood transcriptomic analyses revealed a positive correlation between gene expression profiles of MCI, AD, and T2D in seven independent microarrays. Interestingly, gene expression profiles from women with advanced AD correlated negatively with T2D, suggesting sex-specific differences in T2D as a risk factor for AD. Network and pathway analysis revealed that shared molecular networks between MCI and T2D were predominantly enriched in inflammation and infectious diseases whereas those networks shared between overt AD and T2D were involved in the phosphatidylinositol 3-kinase and protein kinase B/Akt (PI3K-AKT) signaling pathway, a major mediator of insulin signaling in the body. The PI3K-AKT signaling pathway became more significantly dysregulated in the advanced AD and T2D shared network. Furthermore, endocrine resistance and atherosclerosis pathways emerged as dysregulated pathways in the advanced AD and T2D shared network. Interestingly, network analysis of shared differentially expressed genes between children with T2D and MCI subjects identified forkhead box O3 (FOXO3) as a central transcriptional regulator, suggesting that it may be a potential therapeutic target for early intervention in AD. Collectively, these results suggest that T2D may be implicated at different stages of AD through different molecular pathways disrupted during the preclinical phase of AD and more advanced stages of the disease.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic and Network Analysis Highlight the Association of Diabetes at Different Stages of Alzheimer’s Disease

Santiago¹,

Bottero

Potashkin

2019

Front. Neurosci.

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“…Hence, GC-induced stimulation of gluconeogenesis involves stimulation of the cascade of KLF9-PGC1α-GRU-containing genes. 40 Elevated glucagon levels are observed as a result of GC treatment. 41,42 Increased glucagon in the presence of elevated insulin levels is often found in patients with type 2 diabetes (T2DM).…”

Section: Glucocorticoid Stimulation Of Gluconeogenesis and The Role Omentioning

confidence: 99%

<p>Glucocorticoid-Induced Fatty Liver Disease</p>

Rahimi

Rajpal

Ismail‐Beigi

2020

DMSO

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Glucocorticoids (GCs) are commonly used at high doses and for prolonged periods (weeks to months) in the treatment of a variety of diseases. Among the many side effects are increased insulin resistance with disturbances in glucose/insulin homeostasis and increased deposition of lipids (mostly triglycerides) in the liver. Here, we review the metabolic pathways of lipid deposition and removal from the liver that become altered by excess glucocorticoids. Pathways of lipid deposition stimulated by excess glucocorticoids include 1) increase in appetite and high caloric intake; 2) increased blood glucose levels due to GC-induced stimulation of gluconeogenesis; 3) stimulation of de novo lipogenesis that is augmented by the high glucose and insulin levels and by GC itself; and 4) increased release of free fatty acids from adipose stores and stimulation of their uptake by the liver. Pathways that decrease hepatic lipids affected by glucocorticoids include a modest stimulation of verylow-density lipoprotein synthesis and secretion into the circulation and inhibition of βoxidation of fatty acids. Role of 11β-hydroxysteroid dehydrogenases-1 and-2 and the reversible conversion of cortisol to cortisone on intracellular levels of cortisol is examined. In addition, GC control of osteocalcin expression and the effect of this bone-derived hormone in increasing insulin sensitivity are discussed. Finally, research focused on gaining a better understanding of the dose and duration of treatment with glucocorticoids, which leads to increased triglyceride deposition in the liver, and the reversibility of the condition is highlighted.

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“…Krüppel-like factor 9 (KLF9) is a basic transcription element-binding protein (27,28). An increasing number of studies have shown that KLF9 exerts regulatory roles in the pathogenesis of several cancer types (29,30).…”

Section: Long Non-coding Rna Dancr Represses the Viability Migration ...mentioning

confidence: 99%

Long non‑coding RNA DANCR represses the viability, migration and invasion of multiple myeloma cells by sponging miR‑135b‑5p to target KLF9

Xia

Jiang

et al. 2021

Mol Med Rep

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Multiple myeloma (MM) is a malignancy of plasma cells that leads to marrow failure and bone lesions. Numerous studies have verified the link between long non-coding RNAs (lncRNAs) and MM. The present study aimed to examine the role and underlying mechanism of differentiation antagonizing non-protein coding RNA (DANCR) in MM cells. The relative expression levels of DANCR, microRNA (miR)-135b-5p and Krüppel-like factor 9 (KLF9) were examined using reverse transcription-quantitative PCR. Cell viability was assessed using the MTT assay, while relative cell migration and invasion were evaluated using Transwell assays. Moreover, the dual-luciferase reporter assay was used to examine the interplay between DANCR, miR-135b-5p and KLF9. Western blotting was performed to determine the expression level of KLF9. It was found that lncRNA DANCR and KLF9 were downregulated, while miR-135b-5p was upregulated in the serum of patients with MM and in MM cells compared with the controls. Overexpressing DANCR or knocking down miR-135b-5p reduced the viability of the MM cells, as well as restrained MM cells from migrating and invading. Furthermore, DANCR directly targeted miR-135b-5p and was negatively correlated with miR-135b-5p. It was also found that KLF9 was targeted by miR-135b-5p and was inversely correlated with miR-135b-5p expression. The impact of lncRNA DANCR-mediated suppression on cell viability, invasion and migration was partially abolished by short hairpin RNA KLF9 or miR-135b-5p mimics transfection in MM cells. Thus, it was suggested that lncRNA DANCR repressed the viability, migration and invasion of MM cells by sponging miR-135b-5p to target KLF9.

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Taking KLF9 to “Cort” for crimes against metabolism

Cited by 7 publications

References 26 publications

Transcriptomic and Network Analysis Highlight the Association of Diabetes at Different Stages of Alzheimer’s Disease

Transcriptomic and Network Analysis Highlight the Association of Diabetes at Different Stages of Alzheimer’s Disease

<p>Glucocorticoid-Induced Fatty Liver Disease</p>

Long non‑coding RNA DANCR represses the viability, migration and invasion of multiple myeloma cells by sponging miR‑135b‑5p to target KLF9

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