Saturated fatty acids-induced miR-424–5p aggravates insulin resistance via targeting insulin receptor in hepatocytes

Min, Kyung-Ho; Yang, Won-Mo; Lee, Wan

doi:10.1016/j.bbrc.2018.07.084

Cited by 33 publications

(27 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The experiments have shown that INSR expression can be directly targeted by several miRNAs, such as miR-424-5p, miR-15b, miR-1271, miR-195, miR-497 and miR-96 in HepG2 or other type cells [36–38]. In addition, gene expression may also be regulated indirectly by miRNAs.…”

Section: Discussionmentioning

confidence: 99%

NR6A1 regulates lipid metabolism through mammalian target of rapamycin complex 1 in HepG2 cells

et al. 2019

View full text Add to dashboard Cite

Background Lipogenesis is required for the optimal growth of many types of cancer cells, it is shown to control the biosynthesis of the lipid bilayer membrane during rapid proliferation and metastasis, provides cancer cells with signaling lipid molecules to support cancer development and make cancer cells more resistant to oxidative stress-induced cell death. Though multiple lipogenic enzymes have been identified to mediate this metabolic change, how the expression of these lipogenic enzymes are transcriptionally regulated remains unclear. Methods Gain- and loss-of-function experiments were conducted to assess the role of transcriptional repressor, nuclear receptor sub-family 6, group A, member 1 (NR6A1) in HepG2 cells. RT-qPCR method was performed to investigate target gene of NR6A1. Western blot was employed to determine the mechanisms by which NR6A1 regulates lipid accumulation in HepG2 cells. Results We provide evidence that NR6A1 is a novel regulator of lipid metabolism in HepG2 cells. NR6A1 knockdown can increase lipid accumulation as well as insulin-induced proliferation and migration of HepG2 cells. The lipogenic effect correlated well with the expression of lipogenic genes, including fatty acid synthase (FAS), diglyceride acyltransferase-2 (DGAT2), malic enzyme 1 (ME1), microsomal triglyceride transfer protein (MTTP) and phosphoenolpyruvate carboxykinase (PEPCK). NR6A1 knockdown also increased the expression of carnitine palmitoyltransferase 1A (CPT1a), the rate-limiting enzyme in fatty acid oxidation. Furthermore, NR6A1 knockdown induced lipid accumulation through mammalian target of rapamycin complex 1 (mTORC1), but not mTORC2. Moreover, siRNA-mediated knockdown of NR6A1 increased expression of insulin receptor (INSR) and potentitated insulin-induced phosphorylation of mTOR and AKT partly via miR-205-5p in HepG2 cells. Conclusions These findings provide important new insights into the role of NR6A1 in the lipogenesis in HepG2 cells. Graphical abstract . Electronic supplementary material The online version of this article (10.1186/s12964-019-0389-4) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

NR6A1 regulates lipid metabolism through mammalian target of rapamycin complex 1 in HepG2 cells

et al. 2019

View full text Add to dashboard Cite

show abstract

“…A recent report demonstrated the direct interaction of miR-424-5p with INSR mRNA 3′UTR sequence in human hepatocytes cell line HepG2 [80], showing that overexpression of miR-424-5p induced a reduction of INSR mRNA and protein levels. Additionally, it provided evidence that HepG2 cells treated with saturated fatty acids, as well as liver from high fat diet (HFD) mice, retained a reduced expression of INSR and IRS1 paralleled by an increased expression of miRNA miR-424-5p.…”

Section: Mirnas As Rheostats Of Insulin and Igf-1signalingmentioning

confidence: 99%

“…These data suggest that miR-424-5p hyperexpression was potentially driven by an acute lipotoxic stress and lipid accumulation leading to downregulation of INSR. Although the transcriptional activation mechanism and expression regulation of miR-424-5p is largely unknown, it is likely that its hyperexpression upon fatty acids treatment can be partly attributed to the activation of TGFβ-SMAD3 signaling [81], suggested by the presence of several SMAD3 binding sites within miR-424-5p human promoter region [80].…”

Section: Mirnas As Rheostats Of Insulin and Igf-1signalingmentioning

confidence: 99%

MicroRNAs as Regulators of Insulin Signaling: Research Updates and Potential Therapeutic Perspectives in Type 2 Diabetes

Nigi

Grieco

Ventriglia

et al. 2018

IJMS

View full text Add to dashboard Cite

The insulin signaling pathway is composed of a large number of molecules that positively or negatively modulate insulin specific signal transduction following its binding to the cognate receptor. Given the importance of the final effects of insulin signal transduction, it is conceivable that many regulators are needed in order to tightly control the metabolic or proliferative functional outputs. MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively modulate gene expression through their specific binding within the 3′UTR sequence of messenger RNA (mRNA), thus causing mRNA decoy or translational inhibition. In the last decade, miRNAs have been addressed as pivotal cellular rheostats which control many fundamental signaling pathways, including insulin signal transduction. Several studies demonstrated that multiple alterations of miRNAs expression or function are relevant for the development of insulin resistance in type 2 diabetes (T2D); such alterations have been highlighted in multiple insulin target organs including liver, muscles, and adipose tissue. Indirectly, miRNAs have been identified as modulators of inflammation-derived insulin resistance, by controlling/tuning the activity of innate immune cells in insulin target tissues. Here, we review main findings on miRNA functions as modulators of insulin signaling in physiologic- or in T2D insulin resistance- status. Additionally, we report the latest hypotheses of prospective therapies involving miRNAs as potential targets for future drugs in T2D.

show abstract

“…In this paper, the authors used a myoblast DM without insulin supplement, differing from our culture conditions. According to references, miR-322/-503 was reported to interact with insulin involved pathways 38,51 , and directly regulate insulin resistance 52 . Therefore, the difference in DM might bias the role of miR-322/-503 in myoblast differentiation.…”

Section: Discussionmentioning

confidence: 99%

miR-322/-503 rescues myoblast defects in myotonic dystrophy type 1 cell model by targeting CUG repeats

Shen

Feng

et al. 2020

Cell Death Dis

View full text Add to dashboard Cite

Myotonic dystrophy type 1 (DM1) is the most common type of adult muscular dystrophy caused by the expanded triple-nucleotides (CUG) repeats. Myoblast in DM1 displayed many defects, including defective myoblast differentiation, ribonuclear foci, and aberrant alternative splicing. Despite many were revealed to function in DM1, microRNAs that regulated DM1 via directly targeting the expanded CUG repeats were rarely reported. Here we discovered that miR-322/-503 rescued myoblast defects in DM1 cell model by targeting the expanded CUG repeats. First, we studied the function of miR-322/-503 in normal C2C12 myoblast cells. Downregulation of miR-322/-503 significantly hindered the myoblast differentiation, while miR-322/-503 overexpression promoted the process. Next, we examined the role of miR-322/-503 in the DM1 C2C12 cell model. miR-322/-503 was downregulated in the differentiation of DM1 C2C12 cells. When we introduced ectopic miR-322/-503 expression into DM1 C2C12 cells, myoblast defects were almost fully rescued, marked by significant improvements of myoblast differentiation and repressions of ribonuclear foci formation and aberrant alternative splicing. Then we investigated the downstream mechanism of miR-322/-503 in DM1. Agreeing with our previous work, Celf1 was proven to be miR-322/-503′s target. Celf1 knockdown partially reproduced miR-322/-503′s function in rescuing DM1 C2C12 differentiation but was unable to repress ribonuclear foci, suggesting other targets of miR-322/-503 existed in the DM1 C2C12 cells. As the seed regions of miR-322 and miR-503 were complementary to the CUG repeats, we hypothesized that the CUG repeats were the target of miR-322/-503. Through expression tests, reporter assays, and colocalization staining, miR-322/-503 was proved to directly and specifically target the expanded CUG repeats in the DM1 cell model rather than the shorter ones in normal cells. Those results implied a potential therapeutic function of miR-322/-503 on DM1, which needed further investigations in the future.

show abstract

Saturated fatty acids-induced miR-424–5p aggravates insulin resistance via targeting insulin receptor in hepatocytes

Cited by 33 publications

References 23 publications

NR6A1 regulates lipid metabolism through mammalian target of rapamycin complex 1 in HepG2 cells

NR6A1 regulates lipid metabolism through mammalian target of rapamycin complex 1 in HepG2 cells

MicroRNAs as Regulators of Insulin Signaling: Research Updates and Potential Therapeutic Perspectives in Type 2 Diabetes

miR-322/-503 rescues myoblast defects in myotonic dystrophy type 1 cell model by targeting CUG repeats

Contact Info

Product

Resources

About