FoxO1 antagonist suppresses autophagy and lipid droplet growth in adipocytes

Liu, Longhua; Zheng, Louise; Zou, Peng; Brooke, Joseph; Smith, Cayleen; Long, Yun; Almeida, Fabio A.; Liu, Dongmin; Cheng, Zhiyong

doi:10.1080/15384101.2016.1192732

Cited by 51 publications

(57 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…FOXO1 is an intracellular super transcription factor which modulates numerous cell activities, such as metabolism, apoptosis, and cell circle arrest and maintains tissue homeostasis and changes in response to various stimulations [38,39]. Recent study revealed that FOXO1 positively regulated intracellular lipid droplet formation and growth [40]. Here in our present study, it can be found out that FOXO1 level rose remarkably as lipid droplet accumulated in TECs of SAKI rat model.…”

Section: Discussionsupporting

confidence: 58%

MiR-21-3p Plays a Crucial Role in Metabolism Alteration of Renal Tubular Epithelial Cells during Sepsis Associated Acute Kidney Injury via AKT/CDK2-FOXO1 Pathway

Lin

Liu

Wang

et al. 2019

BioMed Research International

View full text Add to dashboard Cite

Objective. Sepsis and associated acute kidney injury (SAKI) are determined to be closely related to poor prognosis. Because the metabolic alterations of tubular epithelial cells (TECs) are crucial for the occurrence and development of SAKI, we carried out this present study to identify the metabolism changes of TECs during SAKI and relevant mechanisms. Methods. Rat SAKI model and rat tubular epithelial cell line were used in our study. ELISA was used to determine the serum cytokines levels. Protein expressions were examined with Western-Blotting and the transcriptions of RNAs were determined with qRT-PCR. ADP/ATP assay and Oil Red O staining were used to examine the energy and lipid metabolism, respectively. Dual-luciferase reporter assay was carried out to determine the interactions between miRNA and specific proteins. Cell cycle arrest and apoptosis were determined with flow cytometry. Results. Sepsis and AKI were induced 12 h after CLP. Energy and lipid metabolism reduced significantly while FOXO1 levels increased remarkably in TECs during SAKI. The expressions of both AKT and CDK2 and the transcriptions of relevant mRNAs reduced significantly in TECs during SAKI while miR-21-3p expression increased remarkably. Both AKT and CDK2 were determined as the direct targets of miR-21-3p. Furthermore, by in vitro experiments, it was demonstrated that FOXO1 levels were regulated by miR-21-3p in TECs via AKT/CDK2 and AKT/CDK2-FOXO1 pathway was crucial in the regulations of miR-21-3p on lipid metabolism, cell cycle arrest, and apoptosis of TECs. Conclusions. MiR-21-3p mediates metabolism and cell fate alterations of TECs via manipulating AKT/CDK2-FOXO1 pathway, and that is crucial in the regulation of energy metabolism of TECs during SAKI.

show abstract

Section: Discussionsupporting

confidence: 58%

MiR-21-3p Plays a Crucial Role in Metabolism Alteration of Renal Tubular Epithelial Cells during Sepsis Associated Acute Kidney Injury via AKT/CDK2-FOXO1 Pathway

Lin

Liu

Wang

et al. 2019

BioMed Research International

View full text Add to dashboard Cite

show abstract

“…Regulation of the expression and transcriptional activity of FOXO1 is involved in promoting cellular autophagy [7, 30]. In our study, SS condition could upregulate the expression of FOXO1,which regulate both basal and SS-induced autophagy in QBC939 cells.…”

Section: Discussionmentioning

confidence: 57%

FOXO1, a Potential Therapeutic Target, Regulates Autophagic Flux, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis in Human Cholangiocarcinoma QBC939 Cells

Zhang

Lei

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Autophagy is an evolutionarily conserved catabolic mechanism to maintain energy homeostasis and to remove damaged cellular components, which plays an important role in the survival of various cells. Inhibiting autophagy is often applied as a new strategy to halt the growth of cancer cells. Methods: The effect of FOXO1 gene on cellular function and apoptosis and its underlying mechanisms were investigated in cultured QBC939 cells by the methylthiazoletetrazolium (MTT) assay, western blot, DCFDA mitochondrial membrane potential, and ATP content measurement. FOXO1 siRNA was applied to down-regulate FOXO1 expression in QBC939 cells. Results: Here we reported that FOXO1, acetylation of FOXO1 (Ac-FOXO1) and the following interaction between Ac-FOXO1 and Atg7 regulated the basal and serum starvation (SS)-induced autophagy as evidenced by light chain 3 (LC3) accumulation and p62 degration. Either treatment with FOXO1 siRNA or resveratrol, a sirt1 agonist, inhibited autophagic flux, resulting in oxidative stress, mitochondrial dysfunction (MtD) and apoptosis in QBC939 cells, which were attenuated by enhancing autophagy with rapamycin. On the contrary, inhibiting autophagic flux with 3-MA worsened all these effects in QBC939 cells. Conclusions: Taken together, our study for the first time identified FOXO1 as a potential therapeutic target to cure against human cholangiocarcinoma via regulation of autophagy, oxidative stress and MtD.

show abstract

“…FoxO1‐specific inhibitor AS1842856 (no. 344355; Sigma‐Aldrich) () was added to a final concentration of 1 u M , and cells were incubated for 24 hours. Cells were then synchronized with 100 n M dexamethasone (no.…”

Section: Methodsmentioning

confidence: 99%

Genome‐Wide Occupancy Profiling Reveals Critical Roles of FoxO1 in Regulating Extracellular Matrix and Circadian Rhythm Genes in Human Chondrocytes

Duffy

Bekki

Lotz

2020

Arthritis & Rheumatology

View full text Add to dashboard Cite

Objective Osteoarthritis (OA) is the most common age‐related joint disease. With aging and in OA, the expression of FoxO transcription factors is reduced, diminishing their chondroprotective actions. In order to elucidate the molecular mechanisms by which FoxO1 protects chondrocytes, we sought to identify the genome‐wide occupancy profile of FoxO1. Methods We performed FoxO1 chromatin immunoprecipitation followed by high‐throughput sequencing (ChIP‐Seq) on human primary chondrocytes. ChIP‐Seq data were integrated with RNA sequencing (RNA‐Seq) data sets. Bioinformatics results were confirmed in primary chondrocytes that were treated with a FoxO1 inhibitor. Results Analysis of FoxO1 ChIP‐Seq on human primary chondrocytes showed that pathways implicated in OA pathogenesis are mainly regulated by FoxO1 binding to tissue‐specific enhancers with suboptimal binding sites (20% of the peaks), while more ubiquitous FoxO1 pathways are regulated at the promoter level through interaction with its canonical binding motif (7% of the peaks). Integrating FoxO1 occupancy data with RNA‐Seq data comparing OA and healthy human cartilage revealed 428 putative FoxO1 target genes that are dysregulated in OA. Pathway analysis showed enrichment for genes belonging to the senescence pathway (logP = −6.73), extracellular matrix (ECM) pathway (logP = −12.97), and circadian clock pathway (logP = −6.30), which suggests that FoxO1 dysregulation plays an important role in their abnormal expression in OA. Using an inhibitor of FoxO1, we confirmed that FoxO1 regulates these pathways in cultured human chondrocytes. Conclusion FoxO1 regulates ubiquitous and cartilage‐specific genes in chondrocytes by using different mechanisms. The FoxO1 transcriptional network is a key player in regulating homeostasis, ECM, and circadian clock genes and plays an important role in the abnormal expression of these pathways observed in OA pathogenesis.

show abstract

FoxO1 antagonist suppresses autophagy and lipid droplet growth in adipocytes

Cited by 51 publications

References 50 publications

MiR-21-3p Plays a Crucial Role in Metabolism Alteration of Renal Tubular Epithelial Cells during Sepsis Associated Acute Kidney Injury via AKT/CDK2-FOXO1 Pathway

MiR-21-3p Plays a Crucial Role in Metabolism Alteration of Renal Tubular Epithelial Cells during Sepsis Associated Acute Kidney Injury via AKT/CDK2-FOXO1 Pathway

FOXO1, a Potential Therapeutic Target, Regulates Autophagic Flux, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis in Human Cholangiocarcinoma QBC939 Cells

Genome‐Wide Occupancy Profiling Reveals Critical Roles of FoxO1 in Regulating Extracellular Matrix and Circadian Rhythm Genes in Human Chondrocytes

Contact Info

Product

Resources

About