MicroRNA-33 and the SREBP Host Genes Cooperate to Control Cholesterol Homeostasis

The sterol regulatory element binding protein 2 (SREBP-2) and the liver X receptor (LXR) control antagonistic transcriptional programs that stimulate cellular cholesterol uptake and synthesis, and cholesterol efflux, respectively. The clinical importance of SREBP-2 is revealed in patients with hypercholesterolemia treated with statins, which reduce low-density lipoprotein (LDL) cholesterol levels by increasing hepatic expression of SREBP-2 and its target, the LDL receptor. Here we show that miR-33 is encoded within SREBP-2 and that both mRNAs are coexpressed. We also identify sequences in the 3′ UTR of ABCA1 and ABCG1, sterol transporter genes both previously shown to be regulated by LXR, as targets for miR-33-mediated silencing. Our data show that LXR-dependent cholesterol efflux to both ApoAI and serum is ameliorated by miR-33 overexpression and, conversely, stimulated by miR-33 silencing. Finally, we show that ABCA1 mRNA and protein and plasma HDL levels decline after hepatic overexpression of miR-33, whereas they increase after hepatic miR-33 silencing. These results suggest novel ways to manage hypercholesterolemic patients.

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“…While this manuscript was under revision, two independent laboratories reported similar findings (38,39).…”

Section: Methodsmentioning

confidence: 61%

miR-33 links SREBP-2 induction to repression of sterol transporters

Marquart

Allen

Ory

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

495

501

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“…Intronic miRNAs have roles that may complement (18,19) or sometimes actually antagonize those of their host genes (20). We now show that expression of the FGF13 locus, including miR-504, is negatively regulated by p53.…”

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confidence: 65%

Regulatory module involving FGF13, miR-504, and p53 regulates ribosomal biogenesis and supports cancer cell survival

Bublik

Bursać

Sheffer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The microRNA miR-504 targets TP53 mRNA encoding the p53 tumor suppressor. miR-504 resides within the fibroblast growth factor 13 (FGF13) gene, which is overexpressed in various cancers. We report that the FGF13 locus, comprising FGF13 and miR-504, is transcriptionally repressed by p53, defining an additional negative feedback loop in the p53 network. Furthermore, we show that FGF13 1A is a nucleolar protein that represses ribosomal RNA transcription and attenuates protein synthesis. Importantly, in cancer cells expressing high levels of FGF13, the depletion of FGF13 elicits increased proteostasis stress, associated with the accumulation of reactive oxygen species and apoptosis. Notably, stepwise neoplastic transformation is accompanied by a gradual increase in FGF13 expression and increased dependence on FGF13 for survival ("nononcogene addiction"). Moreover, FGF13 overexpression enables cells to cope more effectively with the stress elicited by oncogenic Ras protein. We propose that, in cells in which activated oncogenes drive excessive protein synthesis, FGF13 may favor survival by maintaining translation rates at a level compatible with the protein qualitycontrol capacity of the cell. Thus, FGF13 may serve as an enabler, allowing cancer cells to evade proteostasis stress triggered by oncogene activation.proteostasis | p53 | miR-504 | FGF13 | ribosomal biogenesis

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“…MiR-33, encoded by an intron of the sterol regulatory element binding protein gene, has been shown to collaborate with sterol regulatory element binding protein to regulate intracellular cholesterol levels and lipid homeostasis by targeting the adenosine triphosphatebinding cassette transporter A1, a regulator of cellular cholesterol efflux (15). Other miRNAs have been linked to the regulation of glucose metabolism.…”

mentioning

confidence: 99%

Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*

Carrer

Liu²,

Grueter

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

261

263

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Obesity and metabolic syndrome are associated with mitochondrial dysfunction and deranged regulation of metabolic genes. Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) is a transcriptional coactivator that regulates metabolism and mitochondrial biogenesis through stimulation of nuclear hormone receptors and other transcription factors. We report that the PGC-1β gene encodes two microRNAs (miRNAs), miR-378 and miR-378*, which counterbalance the metabolic actions of PGC-1β. Mice genetically lacking miR-378 and miR-378* are resistant to high-fat diet-induced obesity and exhibit enhanced mitochondrial fatty acid metabolism and elevated oxidative capacity of insulin-target tissues. Among the many targets of these miRNAs, carnitine O-acetyltransferase, a mitochondrial enzyme involved in fatty acid metabolism, and MED13, a component of the Mediator complex that controls nuclear hormone receptor activity, are repressed by miR-378 and miR-378*, respectively, and are elevated in the livers of miR-378/378* KO mice. Consistent with these targets as contributors to the metabolic actions of miR-378 and miR-378*, previous studies have implicated carnitine O-acetyltransferase and MED13 in metabolic syndrome and obesity. Our findings identify miR-378 and miR-378* as integral components of a regulatory circuit that functions under conditions of metabolic stress to control systemic energy homeostasis and the overall oxidative capacity of insulin target tissues. Thus, these miRNAs provide potential targets for pharmacologic intervention in obesity and metabolic syndrome.fatty acid oxidation | adipocytes | mitochondrial CO 2 production

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MicroRNA-33 and the SREBP Host Genes Cooperate to Control Cholesterol Homeostasis

Cited by 851 publications

References 32 publications

miR-33 links SREBP-2 induction to repression of sterol transporters

miR-33 links SREBP-2 induction to repression of sterol transporters

Regulatory module involving FGF13, miR-504, and p53 regulates ribosomal biogenesis and supports cancer cell survival

Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*

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