Rapid proteasomal elimination of 3-hydroxy-3-methylglutaryl-CoA reductase by interferon-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" altimg="si28.gif" overflow="scroll"><mml:mrow><mml:mi>γ</mml:mi></mml:mrow></mml:math> in primary macrophages requires endogenous 25-hydroxycholesterol synthesis

Lu, Hongjin; Talbot, Simon; Robertson, Kevin A.; Watterson, Steven; Forster, Thorsten; Roy, Douglas; Ghazal, Peter

doi:10.1016/j.steroids.2015.02.022

Cited by 30 publications

(19 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Instead, AMPK may be activated as a key upstream regulator for the upregulation of ATF3. More recently, it was reported that ATF3 induction by Toll-like receptors is strictly dependent on IFN-signalling33. In our study, naringenin failed to inhibit the activation of IRF3 or attenuate the production of IFN-β or RANTES.…”

Section: Discussioncontrasting

confidence: 50%

The citrus flavonoid naringenin confers protection in a murine endotoxaemia model through AMPK-ATF3-dependent negative regulation of the TLR4 signalling pathway

Liu

Wang

Fan

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Excessive activation of the TLR4 signalling pathway is critical for inflammation-associated disorders, while negative regulators play key roles in restraining TLR4 from over-activation. Naringenin is a citrus flavonoid with remarkable anti-inflammatory activity, but the mechanisms underlying its inhibition of LPS/TLR4 signalling are less clear. This study investigated the molecular targets and therapeutic effects of naringenin in vitro and in vivo. In LPS-stimulated murine macrophages, naringenin suppressed the expression of TNF-α, IL-6, TLR4, inducible NO synthase (iNOS), cyclo-oxygenase-2 (COX2) and NADPH oxidase-2 (NOX2). Naringenin also inhibited NF-κB and mitogen-activated protein kinase (MAPK) activation. However, it did not affect the IRF3 signalling pathway or interferon production, which upregulate activating transcription factor 3 (ATF3), an inducible negative regulator of TLR4 signalling. Naringenin was demonstrated to directly increase ATF3 expression. Inhibition of AMPK and its upstream calcium-dependent signalling reduced ATF3 expression and dampened the anti-inflammatory activity of naringenin. In murine endotoxaemia models, naringenin ameliorated pro-inflammatory reactions and improved survival. Furthermore, it induced AMPK activation in lung tissues, which was required for ATF3 upregulation and the enhanced anti-inflammatory activity. Overall, this study reveals a novel mechanism of naringenin through AMPK-ATF3-dependent negative regulation of the LPS/TLR4 signalling pathway, which thereby confers protection against murine endotoxaemia.

show abstract

Section: Discussioncontrasting

confidence: 50%

The citrus flavonoid naringenin confers protection in a murine endotoxaemia model through AMPK-ATF3-dependent negative regulation of the TLR4 signalling pathway

Liu

Wang

Fan

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…While JQ1 decreased the number of JQ1-sensitive cells as previously shown, no effects were induced in HepG2-R upon drug administration ( Figure 6B). Importantly, the restoration of cell proliferation observed in HepG2-R cells was completely abolished by 25-hydroxycholesterol (25OHC) treatment, a well-known methodological approach to mediate HMGCR degradation through the activation of a feedback mechanism [40]. Similar results were also obtained by blocking HMGCR activity with simvastatin, a potent inhibitor of cholesterol biosynthesis ( Figure 6C).…”

Section: Bet Inhibition Affects Cell Proliferation In a Cholesterol-dsupporting

confidence: 58%

Inhibition of Bromodomain and Extraterminal Domain (BET) Proteins by JQ1 Unravels a Novel Epigenetic Modulation to Control Lipid Homeostasis

Tonini

Colardo

Colella

et al. 2020

IJMS

View full text Add to dashboard Cite

The homeostatic control of lipid metabolism is essential for many fundamental physiological processes. A deep understanding of its regulatory mechanisms is pivotal to unravel prospective physiopathological factors and to identify novel molecular targets that could be employed to design promising therapies in the management of lipid disorders. Here, we investigated the role of bromodomain and extraterminal domain (BET) proteins in the regulation of lipid metabolism. To reach this aim, we used a loss-of-function approach by treating HepG2 cells with JQ1, a powerful and selective BET inhibitor. The main results demonstrated that BET inhibition by JQ1 efficiently decreases intracellular lipid content, determining a significant modulation of proteins involved in lipid biosynthesis, uptake and intracellular trafficking. Importantly, the capability of BET inhibition to slow down cell proliferation is dependent on the modulation of cholesterol metabolism. Taken together, these data highlight a novel epigenetic mechanism involved in the regulation of lipid homeostasis.

show abstract

“…Our data demonstrate, therefore, an IFN-elicited sequential regulation of the sterol metabolic network in which 25-HC provides an immediate, rapid mechanism for decreasing sterol biosynthesis and mediating antiviral effects. This involves a 25-HC blockade of SREBP2 translocation to the nucleus and the proteolytic degradation of HMGCR [ 18 , 52 ]. The effects of 25-HC are followed by miR-342-5p further promoting a more sustained fine-tuning of sterol metabolism and antiviral effects in the cell by targeting SREBF2 RNA and transcripts encoding select enzymes of the sterol biosynthesis pathway (e.g., IDI1 and SC4MOL ).…”

Section: Discussionmentioning

confidence: 99%

An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway

et al. 2016

Self Cite

View full text Add to dashboard Cite

In invertebrates, small interfering RNAs are at the vanguard of cell-autonomous antiviral immunity. In contrast, antiviral mechanisms initiated by interferon (IFN) signaling predominate in mammals. Whilst mammalian IFN-induced miRNA are known to inhibit specific viruses, it is not known whether host-directed microRNAs, downstream of IFN-signaling, have a role in mediating broad antiviral resistance. By performing an integrative, systematic, global analysis of RNA turnover utilizing 4-thiouridine labeling of newly transcribed RNA and pri/pre-miRNA in IFN-activated macrophages, we identify a new post-transcriptional viral defense mechanism mediated by miR-342-5p. On the basis of ChIP and site-directed promoter mutagenesis experiments, we find the synthesis of miR-342-5p is coupled to the antiviral IFN response via the IFN-induced transcription factor, IRF1. Strikingly, we find miR-342-5p targets mevalonate-sterol biosynthesis using a multihit mechanism suppressing the pathway at different functional levels: transcriptionally via SREBF2, post-transcriptionally via miR-33, and enzymatically via IDI1 and SC4MOL. Mass spectrometry-based lipidomics and enzymatic assays demonstrate the targeting mechanisms reduce intermediate sterol pathway metabolites and total cholesterol in macrophages. These results reveal a previously unrecognized mechanism by which IFN regulates the sterol pathway. The sterol pathway is known to be an integral part of the macrophage IFN antiviral response, and we show that miR-342-5p exerts broad antiviral effects against multiple, unrelated pathogenic viruses such Cytomegalovirus and Influenza A (H1N1). Metabolic rescue experiments confirm the specificity of these effects and demonstrate that unrelated viruses have differential mevalonate and sterol pathway requirements for their replication. This study, therefore, advances the general concept of broad antiviral defense through multihit targeting of a single host pathway.

show abstract

Rapid proteasomal elimination of 3-hydroxy-3-methylglutaryl-CoA reductase by interferon-γ in primary macrophages requires endogenous 25-hydroxycholesterol synthesis

Abstract: HighlightsIFN-γ leads to the proteasomal degradation of HMGCR.IFN-γ and 25-HC can transcriptionally and post-translationally alter levels of HMGCR.The reduction of HMGCR through the action of IFN-γ requires the de novo synthesis of 25-HC by CH25H.

Cited by 30 publications

References 54 publications

The citrus flavonoid naringenin confers protection in a murine endotoxaemia model through AMPK-ATF3-dependent negative regulation of the TLR4 signalling pathway

The citrus flavonoid naringenin confers protection in a murine endotoxaemia model through AMPK-ATF3-dependent negative regulation of the TLR4 signalling pathway

Inhibition of Bromodomain and Extraterminal Domain (BET) Proteins by JQ1 Unravels a Novel Epigenetic Modulation to Control Lipid Homeostasis

An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway

Contact Info

Product

Resources

About