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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    ABSTRACT: Human cytomegalovirus (HCMV) infection rewires host-cell metabolism, upregulating flux from glucose into acetyl-CoA to feed fatty acid metabolism, with saturated very-long-chain fatty acids (VLFCAs) required for production of infectious virion progeny. The human genome encodes seven elongase enzymes (ELOVL) that extend long-chain fatty acids into VLCFA. Here, we identify ELOVL7 as pivotal for HCMV infection. HCMV induces ELOVL7 by more than 150-fold. This induction is dependent on mTOR and SREBP-1. ELOVL7 knockdown or mTOR inhibition impairs HCMV-induced fatty acid elongation, HCMV particle release, and infectivity per particle. ELOVL7 overexpression enhances HCMV replication. During HCMV infection, mTOR activity is maintained by the viral protein pUL38. Expression of pUL38 is sufficient to induce ELOVL7, and pUL38-deficient virus is partially defective in ELOVL7 induction and fatty acid elongation. Thus, through its ability to modulate mTOR and SREBP-1, HCMV induces ELOVL7 to synthesize the saturated VLCFA required for efficient virus replication. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Mar 2015 · Cell Reports
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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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    ABSTRACT: Although best known as a risk factor for cardiovascular disease, cholesterol is a vital component of all mammalian cells. In addition to key structural roles, cholesterol is a vital biochemical precursor for numerous biologically important compounds including oxysterols and bile acids, as well as acting as an activator of critical morphogenic systems (e.g., the Hedgehog system). A variety of sophisticated regulatory mechanisms interact to coordinate the overall level of cholesterol in cells, tissues and the entire organism. Accumulating evidence indicates that in additional to the more "traditional" regulatory schemes, cholesterol homeostasis is also under the control of epigenetic mechanisms such as histone acetylation and DNA methylation. The available evidence supporting a role for these mechanisms in the control of cholesterol synthesis, elimination, transport and storage are the focus of this review.
    Full-text · Article · Sep 2014 · Frontiers in Genetics
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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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    ABSTRACT: Increased lipogenesis is a hallmark of a wide variety of cancers and is under intense investigation as potential antineoplastic target. Although brisk lipogenesis is observed in the presence of exogenous lipids, evidence is mounting that these lipids may adversely affect the efficacy of inhibitors of lipogenic pathways. Therefore, to fully exploit the therapeutic potential of lipid synthesis inhibitors, a better understanding of the interrelationship between de novo lipid synthesis and exogenous lipids and their respective role in cancer cell proliferation and therapeutic response to lipogenesis inhibitors is of critical importance. Here, we show that the proliferation of various cancer cell lines (PC3M, HepG2, HOP62 and T24) is attenuated when cultured in lipid-reduced conditions in a cell line-dependent manner, with PC3M being the least affected. Interestingly, all cell lines - lipogenic (PC3M, HepG2, HOP62) as well as non-lipogenic (T24) - raised their lipogenic activity in these conditions, albeit to a different degree. Cells that attained the highest lipogenic activity under these conditions were best able to cope with lipid reduction in term of proliferative capacity. Supplementation of the medium with very low density lipoproteins, free fatty acids and cholesterol reversed this activation, indicating that the mere lack of lipids is sufficient to activate de novo lipogenesis in cancer cells. Consequently, cancer cells grown in lipid-reduced conditions became more dependent on de novo lipid synthesis pathways and were more sensitive to inhibitors of lipogenic pathways, like Soraphen A and Simvastatin. Collectively, these data indicate that limitation of access to exogenous lipids, as may occur in intact tumors, activates de novo lipogenesis is cancer cells, helps them to thrive under these conditions and makes them more vulnerable to lipogenesis inhibitors. These observations have important implications for the design of new antineoplastic strategies targeting the cancer cell's lipid metabolism.
    Full-text · Article · Sep 2014 · PLoS ONE
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