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Anders M. Näär - One of the best experts on this subject based on the ideXlab platform.
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srebp1 dependent de novo fatty acid synthesis gene expression is elevated in malignant melanoma and represents a cellular survival trait
Scientific Reports, 2019Co-Authors: Su Wu, Anders M. NäärAbstract:de novo fatty acid biosynthesis (DNFA) is a hallmark adaptation of many cancers that supports survival, proliferation, and metastasis. Here we elucidate previously unexplored aspects of transcription regulation and clinical relevance of DNFA in cancers. We show that elevated expression of DNFA genes is characteristic of many tumor types and correlates with poor prognosis, especially in melanomas. Elevated DNFA gene expression depends on the SREBP1 transcription factor in multiple melanoma cell lines. SREBP1 predominantly binds to the transcription start sites of DNFA genes, regulating their expression by recruiting RNA polymerase II to promoters for productive transcription elongation. We find that SREBP1-regulated DNFA represents a survival trait in melanoma cells, regardless of proliferative state and oncogenic mutation status. Indeed, malignant melanoma cells exhibit elevated DNFA gene expression after the BRAF/MEK signaling pathway is blocked (e.g. by BRAF inhibitors), and DNFA expression remains higher in melanoma cells resistant to vemurafenib treatment than in untreated cells. Accordingly, DNFA pathway inhibition, whether by direct targeting of SREBP1 with antisense oligonucleotides, or through combinatorial effects of multiple DNFA enzyme inhibitors, exerts potent cytotoxic effects on both BRAFi-sensitive and -resistant melanoma cells. Altogether, these results implicate SREBP1 and DNFA enzymes as enticing therapeutic targets in melanomas.
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DNFA gene expression of HT-144 cells increases in ITS medium, and this increase is dependent upon SREBP1.
2019Co-Authors: Anders M. NäärAbstract:(A-F) HT-144 cells were transfected over one day with siRNAs at 50 nM concentrations for non-target control, SREBF1 or SREBF2. Transfected cells were cultured in 10%, 0% FBS or 1% ITS for two more days before RT-qPCR analyses. RT-qPCR results are presented as expression of DNFA genes relative to their expression under scramble siRNA treatment (siNegative) in 10% FBS medium (set as 1 and marked with a dashed line). When a significant interaction between siRNA treatment and medium condition was detected by two-way ANOVA, individual gene expression was compared within groups by post hoc Tukey’s multiple comparison tests. Each data point represents the mean ±SD of triplicate samples. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001.
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DNCS gene expression of HT-144 cells increases in ITS medium, and this increase is dependent upon SREBP2.
2019Co-Authors: Anders M. NäärAbstract:(A-E) HT-144 cells were transfected over one day with siRNAs at 50 nM concentrations for non-target control, SREBF1 or SREBF2. Transfected cells were cultured in 10%, 0% FBS or 1% ITS for two more days before RT-qPCR analyses. RT-qPCR results are presented as expression of genes relative to their expression under scramble siRNA treatment (siNegative) in 10% FBS medium (set as 1 and marked with a dashed line). When a significant interaction between siRNA treatment and medium condition was detected by two-way ANOVA, individual gene expression was compared within groups by post hoc Tukey’s multiple comparison tests. Each data point represents the mean ±SD of triplicate samples. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001.
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Anti-atherosclerosis or No Anti-atherosclerosis: That is the miR-33 question.
Arteriosclerosis thrombosis and vascular biology, 2013Co-Authors: Anders M. NäärAbstract:Cholesterol/lipid abnormalities, such as high low-density lipoprotein (LDL)/high-density lipoprotein-cholesterol (HDL-C) ratio and elevated circulating triglycerides, are associated with cardiometabolic disorders, including metabolic syndrome, type 2 diabetes mellitus, and atherosclerosis. Cholesterol/lipid homeostasis is controlled by complex gene regulatory circuits involving both transcriptional and posttranscriptional mechanisms. For example, the sterol regulatory element-binding protein (SREBP) 1 and 2 family of transcription factors controls the expression of genes involved in both cholesterol biosynthesis and uptake, as well as fatty acid, phospholipid, and triglyceride production.1 Several groups recently discovered that the human SREBP–encoding genes harbor intronic microRNAs termed miR-33a (present in the SREBF2 gene) and miR-33b (located in the SREBF1 gene).2–6 By contrast with humans and other mammals, rodents lack miR-33b and only have miR-33a in the Srebf2 gene. The miR-33a/b microRNAs, which differ by 2 nucleotides, act in concert with their host gene products to control cholesterol/lipid homeostasis.7 For example, miR-33a/b inhibit the expression of ATP-binding cassette transporter A1 (ABCA1), a cholesterol efflux pump with a key role in reverse cholesterol transport from peripheral tissues such as atherogenic macrophages back to the liver.2–5,8 ABCA1 also promotes the production of nascent lipid-poor HDL-C from the liver and small intestine, and mutation of the ABCA1 gene, as well as aberrant reverse cholesterol transport and low HDL-C levels, has been linked with increased atherosclerosis.9 Intensive efforts have consequently been focused on finding pharmacological tools for increasing circulating HDL-C and promoting reverse cholesterol transport as a novel therapeutic avenue to treat atherosclerosis and cardiovascular …
Xueqing Liu - One of the best experts on this subject based on the ideXlab platform.
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inhibition of mir 33a b in non human primates raises plasma hdl and lowers vldl triglycerides
Nature, 2011Co-Authors: Katey J. Rayner, Christine Esau, Farah N. Hussain, Allison L. Mcdaniel, Stephanie M. Marshall, Janine M. Van Gils, Tathagat Dutta Ray, Frederick J. Sheedy, Leigh Goedeke, Xueqing LiuAbstract:Cardiovascular disease remains the leading cause of mortality in westernized countries, despite optimum medical therapy to reduce the levels of low-density lipoprotein (LDL)-associated cholesterol. The pursuit of novel therapies to target the residual risk has focused on raising the levels of high-density lipoprotein (HDL)-associated cholesterol in order to exploit its atheroprotective effects. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of lipid metabolism and are thus a new class of target for therapeutic intervention. MicroRNA-33a and microRNA-33b (miR-33a/b) are intronic miRNAs whose encoding regions are embedded in the sterol-response-element-binding protein genes SREBF2 and SREBF1 (refs 3-5), respectively. These miRNAs repress expression of the cholesterol transporter ABCA1, which is a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL levels and providing protection against atherosclerosis; however, extrapolating these findings to humans is complicated by the fact that mice lack miR-33b, which is present only in the SREBF1 gene of medium and large mammals. Here we show in African green monkeys that systemic delivery of an anti-miRNA oligonucleotide that targets both miR-33a and miR-33b increased hepatic expression of ABCA1 and induced a sustained increase in plasma HDL levels over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in fatty acid oxidation (CROT, CPT1A, HADHB and PRKAA1) and reduced the expression of genes involved in fatty acid synthesis (SREBF1, FASN, ACLY and ACACA), resulting in a marked suppression of the plasma levels of very-low-density lipoprotein (VLDL)-associated triglycerides, a finding that has not previously been observed in mice. These data establish, in a model that is highly relevant to humans, that pharmacological inhibition of miR-33a and miR-33b is a promising therapeutic strategy to raise plasma HDL and lower VLDL triglyceride levels for the treatment of dyslipidaemias that increase cardiovascular disease risk.
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Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides
Nature, 2011Co-Authors: Katey J. Rayner, Christine Esau, Farah N. Hussain, Allison L. Mcdaniel, Stephanie M. Marshall, Janine M. Van Gils, Tathagat Dutta Ray, Frederick J. Sheedy, Leigh Goedeke, Xueqing LiuAbstract:Cardiovascular disease remains the leading cause of mortality in westernized countries, despite optimum medical therapy to reduce the levels of low-density lipoprotein (LDL)-associated cholesterol. The pursuit of novel therapies to target the residual risk has focused on raising the levels of high-density lipoprotein (HDL)-associated cholesterol in order to exploit its atheroprotective effects. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of lipid metabolism and are thus a new class of target for therapeutic intervention. MicroRNA-33a and microRNA-33b (miR-33a/b) are intronic miRNAs whose encoding regions are embedded in the sterol-response-element-binding protein genes SREBF2 and SREBF1 (refs 3-5), respectively. These miRNAs repress expression of the cholesterol transporter ABCA1, which is a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL levels and providing protection against atherosclerosis; however, extrapolating these findings to humans is complicated by the fact that mice lack miR-33b, which is present only in the SREBF1 gene of medium and large mammals. Here we show in African green monkeys that systemic delivery of an anti-miRNA oligonucleotide that targets both miR-33a and miR-33b increased hepatic expression of ABCA1 and induced a sustained increase in plasma HDL levels over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in fatty acid oxidation (CROT, CPT1A, HADHB and PRKAA1) and reduced the expression of genes involved in fatty acid synthesis (SREBF1, FASN, ACLY and ACACA), resulting in a marked suppression of the plasma levels of very-low-density lipoprotein (VLDL)-associated triglycerides, a finding that has not previously been observed in mice. These data establish, in a model that is highly relevant to humans, that pharmacological inhibition of miR-33a and miR-33b is a promising therapeutic strategy to raise plasma HDL and lower VLDL triglyceride levels for the treatment of dyslipidaemias that increase cardiovascular disease risk.
Jing Qing - One of the best experts on this subject based on the ideXlab platform.
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FGFR3 Stimulates Stearoyl CoA Desaturase 1 Activity to Promote Bladder Tumor Growth
Cancer Research, 2012Co-Authors: Xiangnan Du, Qian-rena Wang, Mark Merchant, Avi Ashkenazi, Dorothy French, Emily Chan, Jing QingAbstract:Fibroblast growth factor receptor 3 (FGFR3) belongs to a family of receptor tyrosine kinases that control cell proliferation, differentiation, and survival. Aberrant activation of FGFR3 via overexpression or mutation is a frequent feature of bladder cancer; however, its molecular and cellular consequences and functional relevance to carcinogenesis are not well understood. Through transcriptional profiling of bladder carcinoma cells subjected to short hairpin RNA knockdown of FGFR3, we identified a gene-signature linking FGFR3 signaling with de novo sterol and lipid biosynthesis and metabolism. We found that FGFR3 signaling promotes the cleavage and activation of the master transcriptional regulator of lipogenesis, sterol regulatory element-binding protein 1(SREBP1 /SREBF1), in a PI3K-mTORC1-dependent fashion. In turn, SREBP1 regulates the expression of key lipogenic enzymes, including stearoyl CoA desaturase 1 (SCD1/SCD). SCD1 is the rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids and is crucial for lipid homeostasis. In human bladder cancer cell lines expressing constitutively active FGFR3, knockdown of SCD1 by small interfering RNA markedly attenuated cell cycle progression, reduced proliferation and induced apoptosis. Furthermore, inducible knockdown of SCD1 in a bladder cancer xenograft model substantially inhibited tumor progression. Pharmacological inhibition of SCD1 blocked fatty acid desaturation and also exerted anti-tumor activity in vitro and in vivo. Together, these findings reveal a previously unrecognized role of FGFR3 in regulating lipid metabolism to maintain tumor growth and survival, and also identify SCD1 as a potential therapeutic target for FGFR3-driven bladder cancer.
Katey J. Rayner - One of the best experts on this subject based on the ideXlab platform.
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micrornas regulating lipid metabolism in atherogenesis
Thrombosis and Haemostasis, 2012Co-Authors: Katey J. Rayner, Carlos Fernandezhernando, Kathryn J MooreAbstract:MicroRNAs have emerged as important post-transcriptional regulators of lipid metabolism, and represent a new class of targets for therapeutic intervention. Recently, microRNA-33a and b (miR-33a/b) were discovered as key regulators of metabolic programs including cholesterol and fatty acid homeostasis. These intronic microRNAs are embedded in the sterol response element binding protein genes, SREBF2 and SREBF1, which code for transcription factors that coordinate cholesterol and fatty acid synthesis. By repressing a variety of genes involved in cholesterol export and fatty acid oxidation, including ABCA1, CROT, CPT1, HADHB and PRKAA1, miR-33a/b act in concert with their host genes to boost cellular sterol levels. Recent work in animal models has shown that inhibition of these small non-coding RNAs has potent effects on lipoprotein metabolism, including increasing plasma high-density lipoprotein (HDL) and reducing very low density lipoprotein (VLDL) triglycerides. Furthermore, other microRNAs are being discovered that also target the ABCA1 pathway, including miR-758, suggesting that miRNAs may work cooperatively to regulate this pathway. These exciting findings support the development of microRNA antagonists as potential therapeutics for the treatment of dyslipidaemia, atherosclerosis and related metabolic diseases.
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inhibition of mir 33a b in non human primates raises plasma hdl and lowers vldl triglycerides
Nature, 2011Co-Authors: Katey J. Rayner, Christine Esau, Farah N. Hussain, Allison L. Mcdaniel, Stephanie M. Marshall, Janine M. Van Gils, Tathagat Dutta Ray, Frederick J. Sheedy, Leigh Goedeke, Xueqing LiuAbstract:Cardiovascular disease remains the leading cause of mortality in westernized countries, despite optimum medical therapy to reduce the levels of low-density lipoprotein (LDL)-associated cholesterol. The pursuit of novel therapies to target the residual risk has focused on raising the levels of high-density lipoprotein (HDL)-associated cholesterol in order to exploit its atheroprotective effects. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of lipid metabolism and are thus a new class of target for therapeutic intervention. MicroRNA-33a and microRNA-33b (miR-33a/b) are intronic miRNAs whose encoding regions are embedded in the sterol-response-element-binding protein genes SREBF2 and SREBF1 (refs 3-5), respectively. These miRNAs repress expression of the cholesterol transporter ABCA1, which is a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL levels and providing protection against atherosclerosis; however, extrapolating these findings to humans is complicated by the fact that mice lack miR-33b, which is present only in the SREBF1 gene of medium and large mammals. Here we show in African green monkeys that systemic delivery of an anti-miRNA oligonucleotide that targets both miR-33a and miR-33b increased hepatic expression of ABCA1 and induced a sustained increase in plasma HDL levels over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in fatty acid oxidation (CROT, CPT1A, HADHB and PRKAA1) and reduced the expression of genes involved in fatty acid synthesis (SREBF1, FASN, ACLY and ACACA), resulting in a marked suppression of the plasma levels of very-low-density lipoprotein (VLDL)-associated triglycerides, a finding that has not previously been observed in mice. These data establish, in a model that is highly relevant to humans, that pharmacological inhibition of miR-33a and miR-33b is a promising therapeutic strategy to raise plasma HDL and lower VLDL triglyceride levels for the treatment of dyslipidaemias that increase cardiovascular disease risk.
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Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides
Nature, 2011Co-Authors: Katey J. Rayner, Christine Esau, Farah N. Hussain, Allison L. Mcdaniel, Stephanie M. Marshall, Janine M. Van Gils, Tathagat Dutta Ray, Frederick J. Sheedy, Leigh Goedeke, Xueqing LiuAbstract:Cardiovascular disease remains the leading cause of mortality in westernized countries, despite optimum medical therapy to reduce the levels of low-density lipoprotein (LDL)-associated cholesterol. The pursuit of novel therapies to target the residual risk has focused on raising the levels of high-density lipoprotein (HDL)-associated cholesterol in order to exploit its atheroprotective effects. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of lipid metabolism and are thus a new class of target for therapeutic intervention. MicroRNA-33a and microRNA-33b (miR-33a/b) are intronic miRNAs whose encoding regions are embedded in the sterol-response-element-binding protein genes SREBF2 and SREBF1 (refs 3-5), respectively. These miRNAs repress expression of the cholesterol transporter ABCA1, which is a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL levels and providing protection against atherosclerosis; however, extrapolating these findings to humans is complicated by the fact that mice lack miR-33b, which is present only in the SREBF1 gene of medium and large mammals. Here we show in African green monkeys that systemic delivery of an anti-miRNA oligonucleotide that targets both miR-33a and miR-33b increased hepatic expression of ABCA1 and induced a sustained increase in plasma HDL levels over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in fatty acid oxidation (CROT, CPT1A, HADHB and PRKAA1) and reduced the expression of genes involved in fatty acid synthesis (SREBF1, FASN, ACLY and ACACA), resulting in a marked suppression of the plasma levels of very-low-density lipoprotein (VLDL)-associated triglycerides, a finding that has not previously been observed in mice. These data establish, in a model that is highly relevant to humans, that pharmacological inhibition of miR-33a and miR-33b is a promising therapeutic strategy to raise plasma HDL and lower VLDL triglyceride levels for the treatment of dyslipidaemias that increase cardiovascular disease risk.
Haim Y Cohen - One of the best experts on this subject based on the ideXlab platform.
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multiple regulatory layers of srebp1 2 by sirt6
Cell Reports, 2013Co-Authors: Sivan Elhanati, Yariv Kanfi, Shaul Barth, Asael Roichman, Alexander Varvak, Ilana Carmelgross, Gilad Gibor, Haim Y CohenAbstract:Summary The NAD + -dependent protein deacetylase SIRT6 regulates genome stability, cancer, and lifespan. Mice overexpressing SIRT6 (MOSES) have lower low-density lipoprotein cholesterol levels and are protected against the physiological damage of obesity. Here, we examined the role of SIRT6 in cholesterol regulation via the lipogenic transcription factors SREBP1 and SREBP2, and AMP-activated protein kinase (AMPK). We show that SIRT6 represses SREBP1 and SREBP2 by at least three mechanisms. First, SIRT6 represses the transcription levels of SREBP1/SREBP2 and that of their target genes. Second, SIRT6 inhibits the cleavage of SREBP1/SREBP2 into their active forms. Third, SIRT6 activates AMPK by increasing the AMP/ATP ratio, which promotes phosphorylation and inhibition of SREBP1 by AMPK. Reciprocally, the expression of miR33a and miR33b from the introns of SREBP2 and SREBP1, respectively, represses SIRT6 levels. Together, these findings explain the mechanism underlying the improved cholesterol homeostasis in MOSES mice, revealing a relationship between fat metabolism and longevity.
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Multiple Regulatory Layers of SREBP1/2 by SIRT6
Cell Reports, 2013Co-Authors: Sivan Elhanati, Yariv Kanfi, Shaul Barth, Asael Roichman, Alexander Varvak, Gilad Gibor, Ilana Carmel-gross, Haim Y CohenAbstract:Summary The NAD + -dependent protein deacetylase SIRT6 regulates genome stability, cancer, and lifespan. Mice overexpressing SIRT6 (MOSES) have lower low-density lipoprotein cholesterol levels and are protected against the physiological damage of obesity. Here, we examined the role of SIRT6 in cholesterol regulation via the lipogenic transcription factors SREBP1 and SREBP2, and AMP-activated protein kinase (AMPK). We show that SIRT6 represses SREBP1 and SREBP2 by at least three mechanisms. First, SIRT6 represses the transcription levels of SREBP1/SREBP2 and that of their target genes. Second, SIRT6 inhibits the cleavage of SREBP1/SREBP2 into their active forms. Third, SIRT6 activates AMPK by increasing the AMP/ATP ratio, which promotes phosphorylation and inhibition of SREBP1 by AMPK. Reciprocally, the expression of miR33a and miR33b from the introns of SREBP2 and SREBP1, respectively, represses SIRT6 levels. Together, these findings explain the mechanism underlying the improved cholesterol homeostasis in MOSES mice, revealing a relationship between fat metabolism and longevity.