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.


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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Available from: Wei Shao, Oct 04, 2015
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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.
    Archives of Toxicology 09/2015; 89(9):1569-78. DOI:10.1007/s00204-014-1322-7 · 5.98 Impact Factor
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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.
    Cell 01/2015; 160(1-2):177-90. DOI:10.1016/j.cell.2014.12.019 · 32.24 Impact Factor
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    • "The sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate expression of the majority of enzymes necessary for fatty acid and cholesterol synthesis, with SREBP1c mainly regulating enzymes of the fatty acid synthesis pathway and SREBP2 primarily cholesterol synthesis enzymes (Shao and Espenshade, 2012). SREBPs are synthesized as inactive full-length precursors bound to SCAP (SREBP cleavage-activating protein) and INSIG (insulin-induced gene) in the endoplasmic reticulum (ER) (Shao and Espenshade, 2012). In a sterol-dependent fashion, the SREBPs are transported to the Golgi for proteolytic processing. "
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    ABSTRACT: Myelin formation during peripheral nervous system (PNS) development, and reformation after injury and in disease, requires multiple intrinsic and extrinsic signals. Akt/mTOR signaling has emerged as a major player involved, but the molecular mechanisms and downstream effectors are virtually unknown. Here, we have used Schwann-cell-specific conditional gene ablation of raptor and rictor, which encode essential components of the mTOR complexes 1 (mTORC1) and 2 (mTORC2), respectively, to demonstrate that mTORC1 controls PNS myelination during development. In this process, mTORC1 regulates lipid biosynthesis via sterol regulatory element-binding proteins (SREBPs). This course of action is mediated by the nuclear receptor RXRγ, which transcriptionally regulates SREBP1c downstream of mTORC1. Absence of mTORC1 causes delayed myelination initiation as well as hypomyelination, together with abnormal lipid composition and decreased nerve conduction velocity. Thus, we have identified the mTORC1-RXRγ-SREBP axis controlling lipid biosynthesis as a major contributor to proper peripheral nerve function.
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