Regulation of Cholesterol and Fatty Acid Synthesis

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Cold Spring Harbor perspectives in biology (Impact Factor: 8.68). 04/2011; 3(7). DOI: 10.1101/cshperspect.a004754
Source: PubMed


In mammals, intracellular levels of cholesterol and fatty acids are controlled through a feedback regulatory system mediated by a family of transcription factors called sterol regulatory element-binding proteins (SREBPs). SREBPs are synthesized as inactive precursors bound to membranes of the endoplasmic reticulum. When cells are deprived of cholesterol and fatty acids, NH(2)-terminal fragments of SREBPs become proteolytically released from membranes and migrate to the nucleus to activate transcription of genes required for lipid synthesis and uptake. Conversely, lipid repletion inhibits proteolytic processing of SREBPs and thereby suppresses lipid accumulation. We review here studies in cultured cells that reveal the mechanism for regulation of SREBP proteolytic activation, and those in animal models in which SREBP proteolysis has been either activated or inhibited to show the essential role of SREBPs in regulating hepatic lipid homeostasis.

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    • "The level of each transcription factor was reduced by approximately 80% compared to non-targeting shRNA control cells (Figure 5F). RNA for ELOVL7 was reduced by 2-fold in cells with reduced SREBP1; this reduction was similar to the RNA level of a known gene regulated by SREBP1, FAS (Ye and DeBose-Boyd, 2011). In contrast, only a 20% reduction in ELOVL7 RNA level was observed with knockdown of SREBP2—compared to a 2-fold decrease in the RNA level of a SREBP2-regulated gene, HMG-CoA reductase—demonstrating that SREBPs, particularly SREBP1, regulates the level of ELOVL7 in HCMV-infected cells. "
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    Cell Reports 03/2015; 10(8-8):1375-1385. DOI:10.1016/j.celrep.2015.02.003 · 8.36 Impact Factor
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    • "Regulation of cholesterol biosynthesis is achieved via an elegant system of feedback inhibition which senses intracellular levels of cholesterol and subsequently modulates the expression of the key proteins involved in cholesterol homeostasis (Ye and DeBose-Boyd, 2011). The master regulators of this process are the sterol response element binding proteins (SREBF1 and SREBF2, also known as SREBP1 and SREBP2), which are hairpin-shaped membrane-anchored transcription factors localized to the endoplasmic reticulum (ER). "
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    Frontiers in Genetics 09/2014; 5:311. DOI:10.3389/fgene.2014.00311
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    • "In contrast with fatty acid addition, supplementation of the lipid-reduced growth medium with cholesterol did not lead to decreased mRNA levels of SREBP1a, SREBP1c or SREBP2 (Supplementary Figure S5c), yet still affected the mRNA levels of the downstream lipogenic genes, FASN, ACLY, ACSS2 and HMGCR (Figure 6c). This is in accordance with previous reports showing cholesterol to regulate SREBP activity at the post-translational level, rather than at the translational level [34]. The cholesterol-induced decrease in the expression of lipogenic enzymes was accompanied by a decreased activity of the lipogenic pathway (Figure 6f), indicating that also exogenous cholesterol influences the activity of the lipogenesis pathway in cancer cells. "
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    PLoS ONE 09/2014; 9(9):e106913. DOI:10.1371/journal.pone.0106913 · 3.23 Impact Factor
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