Genome-wide Localization of SREBP-2 in Hepatic Chromatin Predicts a Role in Autophagy

Seo, Young Kyo; Jeon, Tae Il; Chong, Hansook Kim; Biesinger, Jacob; Xie, Xiaohui; Osborne, Timothy F.

doi:10.1016/j.cmet.2011.03.005

Cited by 151 publications

(151 citation statements)

References 36 publications

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“…Genome-wide binding profi les for SREBP1 versus SREBP2 in hepatic chromatin revealed that only 11.7% of their binding sites overlap and that any genes sharing common binding sites are predominantly associated with lipid metabolism ( 61 ). To determine any possible SREBP subtype specifi city in the low-cholesterol-mediated transcrip- Fig.…”

Section: Cholesterol Regulation Of Hip Expression In 1° Huvecsmentioning

confidence: 99%

Regulation of the human prostacyclin receptor gene by the cholesterol-responsive SREBP1

Turner

Kinsella

2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org G protein-coupled receptor predominantly coupled to Gsmediated activation of adenylyl cyclase ( 1-3 ). The human (h)IP is subject to complex post-translational lipid modifications ( 4,5 ) and to regulation by a range of interacting proteins ( 6-10 ). For example, it undergoes agonist-induced internalization through a Rab5a-dependent mechanism, with subsequent recycling to the plasma membrane involving a direct interaction between the human prostacyclin receptor (hIP) and Rab11a to dynamically regulate the cellular responses to prostacyclin in vivo ( 6,7,9 ). The hIP also directly interacts with the HDL receptor/scavenger receptor class B type 1 adaptor protein "PDZ domaincontaining protein 1 (PDZK1)," and this interaction is essential for prostacyclin-induced endothelial cell migration and in vitro angiogenesis ( 8 ).Consistent with this and with its actions within the vasculature, imbalances in the levels of prostacyclin or of prostacyclin synthase or the IP have been implicated in a range of cardiovascular disorders ( 11-13 ), and, clinically, prostacyclin analogs are used in the treatment of pulmonary arterial hypertension ( 14 ). Prostacyclin also acts as a critical cardio/cytoprotective agent during acute myocardial ischemia ( 15-17 ) and enhances endothelial cell (EC) survival, supporting neovascularization ( 18 ). Several single-nucleotide polymorphisms occur in the hIP gene that correlate with receptor dysfunction, including enhanced platelet activation in deep vein thrombosis and increased intimal hyperplasia ( 19-21 ) and, more recently, with increased occurrence of major obstruction in patients with coronary artery disease ( 19,22,23 )

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Section: Cholesterol Regulation Of Hip Expression In 1° Huvecsmentioning

confidence: 99%

Regulation of the human prostacyclin receptor gene by the cholesterol-responsive SREBP1

Turner

Kinsella

2012

Journal of Lipid Research

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“…An acute cholesterol stimulus such as AcLDL loading in macrophages, 52 or free cholesterol treatment of smooth muscle cells, 83 increased autophagy. Alternatively, cholesterol 84 and sterol 85 depletion have also been reported to increase autophagy. Potentially, autophagy functions to both rid the cell of excessive cholesterol and break down LDstored cholesterol in times of deprivation.…”

Section: Levels Of Autophagy Are Altered By Cellular Lipid Contentmentioning

confidence: 99%

“…Potentially, autophagy functions to both rid the cell of excessive cholesterol and break down LDstored cholesterol in times of deprivation. One mechanism for the effects of cholesterol on autophagy was demonstrated by a genome-wide DNA-binding study of sterol regulatory element-binding protein 2 (SREBP-2), 85 a transcription factor that regulates cholesterol metabolism, 86 which showed that autophagy genes were enriched as SREBP-2 targets. This in silico result was confirmed in cell culture studies, which demonstrated that inhibition of srebp-2 dramatically diminished autophagosome formation during sterol or nutrient depletion, indicating that SREBP-2 can upregulate autophagy under certain circumstances.…”

Section: Levels Of Autophagy Are Altered By Cellular Lipid Contentmentioning

confidence: 99%

Regulation of lipid stores and metabolism by lipophagy

2012

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Intracellular lipids are stored in lipid droplets (LDs) and metabolized by cytoplasmic neutral hydrolases to supply lipids for cell use. Recently, an alternative pathway of lipid metabolism through the lysosomal degradative pathway of autophagy has been described and termed lipophagy. In this form of lipid metabolism, LD triglycerides (TGs) and cholesterol are taken up by autophagosomes and delivered to lysosomes for degradation by acidic hydrolases. Free fatty acids generated by lipophagy from the breakdown of TGs fuel cellular rates of mitochondrial b-oxidation. Lipophagy therefore functions to regulate intracellular lipid stores, cellular levels of free lipids such as fatty acids and energy homeostasis. The amount of lipid metabolized by lipophagy varies in response to the extracellular supply of nutrients. The ability of the cell to alter the amount of lipid targeted for autophagic degradation depending on nutritional status demonstrates that this process is selective. Intracellular lipids themselves regulate levels of autophagy by unclear mechanisms. Impaired lipophagy can lead to excessive tissue lipid accumulation such as hepatic steatosis, alter hypothalamic neuropeptide release to affect body mass, block cellular transdifferentiation and sensitize cells to death stimuli. Future studies will likely identify additional mechanisms by which lipophagy regulates cellular physiology, making this pathway a potential therapeutic target in a variety of diseases. Open QuestionsHow does the autophagic machinery selectively target stored lipids for degradation in response to changes in nutrient levels? What are the relative contributions of cytosolic lipolysis and lipophagy to lipid metabolism in different cell types, and is there cross-talk between the two pathways? What are the mechanisms by which intracellular lipids and other factors regulate levels of lipophagy? Do defects in lipophagy underlie human disease and can lipophagy be a therapeutic target? Intracellular lipids are essential to cells as an energy source, structural components for membranes, synthetic building blocks for other molecules, such as hormones, and as mediators of cell signaling. The ability to safely store adequate, but not excessive, amounts of lipids and to metabolize them when needed is critical for cell function and survival. The recent finding that lipids can be selectively degraded by the lysosomal pathway of macroautophagy through a process termed lipophagy 1 has opened up a new understanding of how lipid metabolism regulates cellular physiology and pathophysiology. Many new functions for autophagic lipid metabolism have now been defined in diverse cellular processes ranging from transdifferentiation to resistance to death. Intracellular Lipids are Degraded by LipophagyTGs and cholesterol are safely stored as neutral lipids in specialized cellular organelles called LDs. 2,3 Until recently, the breakdown of LD-stored TG and cholesterol was attributed exclusively to the actions of cytosolic hydrolytic enzymes or lipases. The role of l...

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“…However, no clear evidence in support of such a hypothesis has been presented so far, and recent analysis of SREBP ChIP-seq in the human HAS2 locus did not highlight specific peaks within the gene promoter (56). Other pathways involved in regulation of cholesterol homeostasis may be responsible for HAS2 activation, one possibility being the oxysterol receptor LXR (57).…”

Section: Discussionmentioning

confidence: 96%

Oxidized Low Density Lipoprotein (LDL) Affects Hyaluronan Synthesis in Human Aortic Smooth Muscle Cells

Viola

Bartolini

Vigetti

et al. 2013

Journal of Biological Chemistry

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Background: OxLDL and the high level of hyaluronan are major triggering factors of atherosclerosis. Results: The oxLDL load of the aortic human smooth muscle cells (SMC) via the scavenger receptor LOX-1 causes ER stress, overexpression of HAS2, and hyaluronan deposition. Conclusion: the oxidized sterols driven into the SMC by oxLDL have a role in hyaluronan metabolism. Significance: oxLDL influences extracellular matrix hyaluronan.

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Genome-wide Localization of SREBP-2 in Hepatic Chromatin Predicts a Role in Autophagy

Cited by 151 publications

References 36 publications

Regulation of the human prostacyclin receptor gene by the cholesterol-responsive SREBP1

Regulation of the human prostacyclin receptor gene by the cholesterol-responsive SREBP1

Regulation of lipid stores and metabolism by lipophagy

Oxidized Low Density Lipoprotein (LDL) Affects Hyaluronan Synthesis in Human Aortic Smooth Muscle Cells

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