SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver

Horton, Jay D.; Goldstein, Joseph L.; Brown, Michael S.

doi:10.1172/jci15593

Cited by 2,534 publications

(2,562 citation statements)

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“…2A–D). SREBPs are key regulators of transcription of many enzymes required for lipid metabolism (Horton et al ., 2002). We hypothesized that SREBPs may be involved in HDGF‐induced transcriptional regulation.…”

Section: Resultsmentioning

confidence: 99%

“…SREBP‐1 mainly activates genes involved in fatty acid and triglyceride synthesis, whereas SREBP‐2 is involved in cholesterol synthesis (Jeon and Osborne, 2012). As the predominant form in cancer cells, SREBP‐1a is a potent activator of all SREBP‐responsive genes, including those that mediate fatty acid, triglyceride, and cholesterol synthesis (Horton et al ., 2002). Increased lipid synthesis is a hallmark of tumor cells and depends primarily on SREBP‐mediated transcription (Menendez and Lupu, 2007; Shao and Espenshade, 2012; Shimano and Sato, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

et al. 2018

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Although identified as a growth factor, the mechanism by which hepatoma‐derived growth factor (HDGF) promotes cancer development remains unclear. We found that nuclear but not cytoplasmic HDGF is closely associated with prognosis of hepatocellular carcinoma (HCC). RNA‐sequencing analysis further demonstrated that the nuclear role of HDGF involved regulation of transcription of lipid metabolism genes. HDGF‐induced expression of lipogenic genes was mainly associated with activation of sterol regulatory element binding protein (SREBP) transcription factor. Coexpression of SREBP‐1 and nuclear HDGF predicts poor prognosis for HCC. In addition, by changing the first amino acid of the PWWP domain from proline to alanine, the type of PWWP domain changed from P‐ to A‐type, resulting in inability to induce SREBP‐1‐mediated gene transcription. The type of PWWP domain affects the recruitment of the C‐terminal binding protein‐1 transcriptional repressor on the promoter of the lipogenic gene. Our data indicate that HDGF acts as a coactivator of SREBP1‐mediated transcription of lipogenic genes. The PWWP domain is crucial for HDGF to promote lipogenesis. Moreover, transcriptional regulation of nuclear HDGF plays important roles in the development of HCC.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

et al. 2018

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“…6 SCAP is the key to the activation of SREBFs, fulfilling two functions: it acts as a sterol sensor and escorts SREBFs from the ER to the Golgi, where a two-step proteolytical process releases the transcriptionally active domain from the membranes to enter the nucleus and activates transcription of more than 30 genes encoding proteins that mediate the uptake and synthesis of cholesterol, unsaturated fatty acids and triglycerides (TGs) biosynthesis. [7][8][9][10] Three SREBFs isoforms have been identified and characterized. SREBF-1a and -1c are derived from a single gene located on chromosome 17p11.2 through the use of alternative forms of exon 1.…”

Section: Introductionmentioning

confidence: 99%

“…SREBF-2 is derived from a second gene located on chromosome 22q13. 10 The SCAP gene has 23 exons and was assigned to chromosome 3p21. 3.…”

Section: Introductionmentioning

confidence: 99%

Determinants of variable response to simvastatin treatment: the role of common variants of SCAP, SREBF-1a and SREBF-2 genes

et al. 2005

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We investigated the effect of single-nucleotide polymorphisms in sterol regulatory element-binding factors-1a and -2 (SREBF-1a and SREBF-2) and SREBF cleavage-activating protein (SCAP) genes on lipid-lowering response to simvastatin. In all, 146 hypercholesterolemic patients of European descent were prospectively treated with simvastatin 20 mg/day for over 6 months. Of these 99 subjects completed the 6-month follow-up. Plasma lipids and lipoproteins were measured before and throughout the study. The mean percentage decrease in plasma total cholesterol (TC) was greater in subject carriers of SCAP 2386G allele compared with those homozygous for 2386A allele (À29.6713.4 vs À22.1713.8%, P ¼ 0.007). About 61% of the 2386G carriers were above-average responders for TC levels (DTC À27.8%), whereas only 29% of 2386A homozygous reached this reduction (P ¼ 0.009). Our data suggest that the SCAP 2386A4G gene polymorphism was a significant predictor of TC and triglyceride responses to simvastatin treatment.

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“…Fatty acid synthesis is performed in the cytosol, and it uses citrate from the TCA cycle and exported from the mitochondria into the cytosol to generate fatty acids ( Figure 2B). As mentioned above, de novo fatty acid synthesis is dependent on key enzymes, such as FASN, that are controlled by either the mTOR signaling pathway 8 , LXR 86, 87 or SREBP-1c 2, 91 . Fatty acids generated by this synthesis can be used to fuel mitochondrial FAO 2 , to activate PPAR nuclear receptors 89 , or can be condensed with glycolysis-derived glycerol to produce triacylglycerol and phospholipids 2 .…”

Section: The Influence Of the Metabolism On Innate Immune Functionmentioning

confidence: 99%

Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

Saas¹,

Varin²,

Perruche³

et al. 2017

F1000Res

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There are more and more data concerning the role of cellular metabolism in innate immune cells, such as macrophages or conventional dendritic cells. However, few data are available currently concerning plasmacytoid dendritic cells (PDC), another type of innate immune cells. These cells are the main type I interferon (IFN) producing cells, but they also secrete other pro-inflammatory cytokines (e.g., tumor necrosis factor or interleukin [IL]-6) or immunomodulatory factors (e.g., IL-10 or transforming growth factor-β). Through these functions, PDC participate in antimicrobial responses or maintenance of immune tolerance, and have been implicated in the pathophysiology of several autoimmune diseases. Recent data support the idea that the glycolytic pathway (or glycolysis), as well as lipid metabolism (including both cholesterol and fatty acid metabolism) may impact some innate immune functions of PDC or may be involved in these functions after Toll-like receptor (TLR) 7/9 triggering. Some differences may be related to the origin of PDC (human versus mouse PDC or blood-sorted versus FLT3 ligand stimulated-bone marrow-sorted PDC). The kinetics of glycolysis may differ between human and murine PDC. In mouse PDC, metabolism changes promoted by TLR7/9 activation may depend on an autocrine/paracrine loop, implicating type I IFN and its receptor IFNAR, explaining a delayed glycolysis. Moreover, PDC functions can be modulated by the metabolism of cholesterol and fatty acids. This may occur via the production of lipid ligands that activate nuclear receptors (e.g., liver X receptor [LXR]) in PDC or through limiting intracellular cholesterol pool size (by statins or LXR agonists) in these cells. Finally, lipid-activated nuclear receptors ( i.e., LXR or peroxisome proliferator activated receptor) may also directly interact with pro-inflammatory transcription factors, such as NF-κB. Here, we discuss how glycolysis and lipid metabolism may modulate PDC functions and how this may be harnessed in pathological situations where PDC play a detrimental role.

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SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver

Cited by 2,534 publications

References 48 publications

Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

Determinants of variable response to simvastatin treatment: the role of common variants of SCAP, SREBF-1a and SREBF-2 genes

Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

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