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5-Aminoimidazole-4-carboxamide ribonucleoside stabilizes low density lipoprotein receptor mRNA in hepatocytes via ERK-dependent HuR binding to an AU-rich element

Yashiro, Takuya, Nanmoku, Manami, Shimizu, Makoto, Inoue, Jun, Sato, Ryuichiro·2013·Atherosclerosis
DOI 10.1016/j.atherosclerosis.2012.09.033
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Abstract

Objective 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) has pleiotropic and beneficial effects on metabolic disorders. However, the effects of AICAR on low density lipoprotein (LDL) metabolism are poorly understood. Methods and results AICAR induces increased LDLR mRNA levels and increased LDLR protein production in hepatocytes. The AICAR-dependent LDLR mRNA increase was partially mediated by mRNA stabilization in an extracellular signal-regulated kinase1/2 (ERK1/2)-dependent manner, but not by the AMP-activated protein kinase (AMPK) activation. Reporter assays using a variety of constructs harboring the 3'-untranslated region (UTR) of human LDLR mRNA revealed that the most upstream AU-rich element (ARE) was critical for these AICAR effects. Using UV cross-linking assays, we found increased binding of three cytoplasmic proteins to this ARE region in response to AICAR and identified a 35-kDa protein as Human antigen R (HuR). Blocking ERK signaling pathway activation resulted in attenuated HuR binding. Silencing HuR expression by RNA interference hindered AICAR-induced LDLR mRNA stability, whereas its overexpression stabilized this mRNA. Conclusions AICAR-dependent LDLR mRNA stabilization is mediated, at least in part, by HuR binding to the ARE1 region. Given that AICAR enhanced LDL uptake in hepatocytes, our findings warrant further studies using animal models to develop a novel LDL-cholesterol lowering agent as a possible strategy to treat atherosclerosis-related card…

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  • Some studies suggest that the increase in LDLR mRNA stability may depend on the presence of ARE1, the UCAU sequences, and the RBP HuR.

    “Some studies suggest that this increase may depend on the presence of ARE1, the UCAU sequences, and the RBP HuR [24,40].”

    From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [40]

  • HuR/ELAVL1 binds the same AREs to stabilize LDLR mRNA and increase LDLR proteins in hepatocytes.

    “While these RBPs destabilize their mRNA targets leading to degradation of LDLR, human antigen R (HuR), also known as ELAV-like RNA binding protein 1 (ELAVL1), binds the same AREs to stabilize LDLR mRNA and increase LDLR proteins in hepatocytes65,66.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [66]

  • LDLR 3′UTR associates with the mRNA-stabilizing factor HuR and with decay-promoting factors ZFP36L1, ZFP36L2, KSRP, hnRNP D and hnRNP I.

    “For instance, LDLR 3′UTR has been shown to associate with not only the mRNA-stabilizing factor, human antigen R (HuR), but also with decay-promoting factors, such as ZFP36 ring finger protein-like 1 and –like 2 proteins (ZFP36L1 and ZFP36L2), KH-type splicing regulatory protein (KSRP) as well as the D and I members of the heterogeneous nuclear ribonucleoprotein family (hnRNP D and hnRNP I)16–18.”

    From Triciribine increases LDLR expression and LDL uptake through stabilization of LDLR mRNA (2018) · cites this paper as [16]

  • HuR is a stabilizing factor for LDLR mRNA.

    “A recent new study identified human antigen R (HuR) as a stabilizing factor for LDLR mRNA”

    From A novel posttranscriptional mechanism for dietary cholesterol-mediated suppression of liver LDL receptor expression (2014) · cites this paper as [22]

  • In HepG2 cells, HuR bound to the proximal ARE site of LDLR 3′UTR and led to an increase in LDLR mRNA half-life.

    “It was shown in HepG2 cells that HuR bound to the proximal ARE site of LDLR 3′UTR and led to an increase in LDLR mRNA half-life.”

    From A novel posttranscriptional mechanism for dietary cholesterol-mediated suppression of liver LDL receptor expression (2014) · cites this paper as [22]

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Metadata

Authors
Yashiro, T., Nanmoku, M., Shimizu, M., Inoue, J., & Sato, R.
Venue
Atherosclerosis
Publisher
Elsevier BV
Published
2013-01
Volume
226
Issue
1
Pages
95-101
ISSN
0021-9150
DOI
10.1016/j.atherosclerosis.2012.09.033
Cited by
32
References
2
Language
en
Licence
Funders
Ministry of Education, Culture, Sports, Science and Technology

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