Article

Expanding roles for SREBP in metabolism

Department of Cell Biology, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA.
Cell Metabolism (Impact Factor: 17.57). 10/2012; 16(4):414-419. DOI: 10.1016/j.cmet.2012.09.002.

ABSTRACT

Sterol regulatory element-binding protein (SREBP) transcription factors regulate cellular lipogenesis and lipid homeostasis. Recent studies reveal expanding roles for SREBPs with the description of new regulatory mechanisms, the identification of unexpected transcriptional targets, and the discovery of functions for SREBPs in type II diabetes, cancer, immunity, neuroprotection, and autophagy.

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    • "Subsequently, decreasing cholesterol levels will induce the maturation of the transcription factor sterol regulatory element-binding protein (SREBP) and its nuclear translocation (Kallin et al., 2007; Shao and Espenshade, 2012). Although the transcription activity of SREBP up-regulates expression of multiple genes involved in fatty acid and cholesterol metabolism (Kim and Spiegelman, 1996; Shao and Espenshade, 2012; Shimano et al., 1999), SREBP is also able alter the regulation of expression of neuronal markers (Kallin et al., 2007; Suzuki et al., 2010). For example, ectopic overexpression of SREBP-1 induced a clear mRNA increase of the synaptic vesicles glycoprotein 2A (SV2A) up to 40 folds which correlates to the increase induced with statin treatment in non-neuronal cells (Kallin et al., 2007). "
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    ABSTRACT: The identification of an effective disease-modifying treatment for the neurodegenerative progression in Parkinson's disease (PD) remains a major challenge. Epidemiological studies have reported that intake of statins, cholesterol lowering drugs, could be associated to a reduced risk of developing PD. In-vivo studies suggest that statins may reduce the severity of dopaminergic neurodegeneration. We have investigated the trophic potential of statins and their impact on the expression of dopaminergic synaptic markers and dopamine (DA) transport function in SH-SY5Y cells. Our findings show that statin treatment induces neurite outgrowth involving a specific effect on the complexity of the neurite branching pattern. Statins increased the levels of presynaptic dopaminergic biomarkers such as vesicular monoamine transporter 2 (VMAT2), synaptic vesicle glycoproteins 2A and 2C (SV2C) and synaptogyrin-3 (SYNGR3). Gene expression analysis confirmed a rapid statin-induced up-regulation of VMAT2-, SV2C- and SYNGR3-mRNA levels. Assessment of [(3) H]DA transport in statin-treated cells showed a reduction in DA uptake concomitant to a modification of VMAT2 pharmacological properties. We also observed a nuclear translocation of the sterol regulatory element-binding protein 1 (SREBP-1). Our results suggest that statins induce phenotypic changes in dopaminergic cells characterized by an increase of growth, complexity of structural synaptic elements and expression of key presynaptic proteins with functional impact on the DA transport capacity. Statin-induced changes are likely the result of a downstream modulation of SREBP-1 pathway. Overall, these mechanisms may contribute to the neuroprotective or neurorestorative effects observed in the dopaminergic system and strengthen the therapeutic potential of statins for PD. This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2015 · Synapse
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    • "The sterol regulatory element-binding proteins (SreBPs), a family of membrane-bound, basic helix-loop-helix leucine zipper (bHlH-lZ) transcription factors, play a critical role in controlling cholesterol and lipid metabolism and are involved in several biological processes and disease states (Bengoechea-Alonso and ericsson 2007; Shao and espenshade 2012). Three major SreBP proteins (SreBP1a, SreBP1c, and SreBP2) are encoded by the Srebf1 and Srebf2 genes, and most data suggest that the regulatory functions of the two SreBP1 isoforms are primarily in fatty acid metabolism and SreBP2 is mainly in cholesterol metabolism (Jeon and Osborne 2012; Shao and espenshade 2012). Tissue distribution of the three mammalian SreBPs differs, with SreBP1c the predominant isoform in most adult nondividing metabolic tissues such as liver and adipose (Jeon and Osborne 2012; raghow et al. 2008). "
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    ABSTRACT: Perfluoroalkyl acids are widely used in numerous industrial and commercial applications due to their unique physical and chemical characteristics. Although perfluorooctanoic acid (PFOA) is associated with hepatomegaly through peroxisome proliferator-activated receptor α (PPARα) activation, liver fat accumulation and changes in gene expression related to fatty acid metabolism could still be found in PPARα-null mice exposed to PFOA. To explore the potential effects of PFOA on sterol regulatory element-binding proteins (SREBPs) activity, male mice were dosed with either Milli-Q water or PFOA at doses of 0.08, 0.31, 1.25, 5, and 20 mg/kg/day by gavage for 28 days. Liver total cholesterol concentrations and PFOA contents showed a dose-dependent decrease and increase, respectively. Transcriptional activity of PPARα and SREBPs was significantly enhanced in livers. Protein expression analyzed by Western blotting showed that PFOA exposure stimulated SREBP maturation. Furthermore, proteins blocked SREBP precursor transport, insulin-induced gene 1 (INSIG1) and INSIG2 proteins, as well as a protein-mediated nuclear SREBP proteolysis, F-box and WD-40 domain protein 7, decreased in mouse liver exposed to PFOA. The expression levels of the miR-183-96-182 cluster, which is possibly involved in a regulatory loop intermediated by SREBPs maturation, were also increased in the mouse liver after PFOA exposure. We also observed that PFOA induced lipid content and PPARα in Hepa 1-6 cells after exposure to PFOA for 72 h but SREBPs were not activated in vitro. These results demonstrated that SREBPs were maturated by activating the miR-183-96-182 cluster-SREBP regulatory loop in PFOA-exposed mouse liver.
    Full-text · Article · Sep 2015 · Archives of Toxicology
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    • "In the Golgi, SREBP is cleaved by site-1 and site-2 proteases to generate active SREBP. Active SREBP is then translocated into the nucleus and promotes transcription of genes involved in lipid metabolism (Shao and Espenshade, 2012). Although SREBP expressed in the gut responds to levels of circulating lipids and cholesterol, the blood-brain-barrier prevents lipids from entering the brain in mammals and de novo lipogenesis is critical for nervous system function (Camargo et al., 2009). "
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    ABSTRACT: Reactive oxygen species (ROS) and mitochondrial defects in neurons are implicated in neurodegenerative disease. Here, we find that a key consequence of ROS and neuronal mitochondrial dysfunction is the accumulation of lipid droplets (LD) in glia. In Drosophila, ROS triggers c-Jun-N-terminal Kinase (JNK) and Sterol Regulatory Element Binding Protein (SREBP) activity in neurons leading to LD accumulation in glia prior to or at the onset of neurodegeneration. The accumulated lipids are peroxidated in the presence of ROS. Reducing LD accumulation in glia and lipid peroxidation via targeted lipase overexpression and/or lowering ROS significantly delays the onset of neurodegeneration. Furthermore, a similar pathway leads to glial LD accumulation in Ndufs4 mutant mice with neuronal mitochondrial defects, suggesting that LD accumulation following mitochondrial dysfunction is an evolutionarily conserved phenomenon, and represents an early, transient indicator and promoter of neurodegenerative disease. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Jan 2015 · Cell
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