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AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice.
Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JY, Gao B, Wierzbicki M, Verbeuren TJ, Shaw RJ, Cohen RA, Zang M
(2011) Cell Metab 13: 376-388
MeSH Terms: AMP-Activated Protein Kinases, Animals, Atherosclerosis, Benzopyrans, Dietary Fats, Disease Models, Animal, Fatty Liver, Humans, Insulin Resistance, Lipogenesis, Male, Metformin, Mice, Phosphorylation, Receptors, LDL, Sterol Regulatory Element Binding Protein 1, Sterol Regulatory Element Binding Protein 2, Transcription, Genetic
Show Abstract · Added July 21, 2014
AMPK has emerged as a critical mechanism for salutary effects of polyphenols on lipid metabolic disorders in type 1 and type 2 diabetes. Here we demonstrate that AMPK interacts with and directly phosphorylates sterol regulatory element binding proteins (SREBP-1c and -2). Ser372 phosphorylation of SREBP-1c by AMPK is necessary for inhibition of proteolytic processing and transcriptional activity of SREBP-1c in response to polyphenols and metformin. AMPK stimulates Ser372 phosphorylation, suppresses SREBP-1c cleavage and nuclear translocation, and represses SREBP-1c target gene expression in hepatocytes exposed to high glucose, leading to reduced lipogenesis and lipid accumulation. Hepatic activation of AMPK by the synthetic polyphenol S17834 protects against hepatic steatosis, hyperlipidemia, and accelerated atherosclerosis in diet-induced insulin-resistant LDL receptor-deficient mice in part through phosphorylation of SREBP-1c Ser372 and suppression of SREBP-1c- and -2-dependent lipogenesis. AMPK-dependent phosphorylation of SREBP may offer therapeutic strategies to combat insulin resistance, dyslipidemia, and atherosclerosis.
Copyright © 2011 Elsevier Inc. All rights reserved.
1 Communities
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18 MeSH Terms
Palmitate impairs and eicosapentaenoate restores insulin secretion through regulation of SREBP-1c in pancreatic islets.
Kato T, Shimano H, Yamamoto T, Ishikawa M, Kumadaki S, Matsuzaka T, Nakagawa Y, Yahagi N, Nakakuki M, Hasty AH, Takeuchi Y, Kobayashi K, Takahashi A, Yatoh S, Suzuki H, Sone H, Yamada N
(2008) Diabetes 57: 2382-92
MeSH Terms: Adenoviridae, Animals, Eicosapentaenoic Acid, Gene Expression, Gene Silencing, Insulin, Insulin Receptor Substrate Proteins, Insulin Secretion, Intracellular Signaling Peptides and Proteins, Ion Channels, Islets of Langerhans, Lipogenesis, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Mitochondrial Proteins, Organ Culture Techniques, Palmitates, Phosphoproteins, Proto-Oncogene Proteins c-akt, RNA, Messenger, Signal Transduction, Sterol Regulatory Element Binding Protein 1, Uncoupling Protein 2
Show Abstract · Added March 27, 2013
OBJECTIVE - Chronic exposure to fatty acids causes beta-cell failure, often referred to as lipotoxicity. We investigated its mechanisms, focusing on contribution of SREBP-1c, a key transcription factor for lipogenesis.
RESEARCH DESIGN AND METHODS - We studied in vitro and in vivo effects of saturated and polyunsaturated acids on insulin secretion, insulin signaling, and expression of genes involved in beta-cell functions. Pancreatic islets isolated from C57BL/6 control and SREBP-1-null mice and adenoviral gene delivery or knockdown systems of related genes were used.
RESULTS - Incubation of C57BL/6 islets with palmitate caused inhibition of both glucose- and potassium-stimulated insulin secretion, but addition of eicosapentaenoate (EPA) restored both inhibitions. Concomitantly, palmitate activated and EPA abolished both mRNA and nuclear protein of SREBP-1c, accompanied by reciprocal changes of SREBP-1c target genes such as insulin receptor substrate-2 (IRS-2) and granuphilin. These palmitate-EPA effects on insulin secretion were abolished in SREBP-1-null islets. Suppression of IRS-2/Akt pathway could be a part of the downstream mechanism for the SREBP-1c-mediated insulin secretion defect because adenoviral constitutively active Akt compensated it. Uncoupling protein-2 (UCP-2) also plays a crucial role in the palmitate inhibition of insulin secretion, as confirmed by knockdown experiments, but SREBP-1c contribution to UCP-2 regulation was partial. The palmitate-EPA regulation of insulin secretion was similarly observed in islets from C57BL/6 mice pretreated with dietary manipulations. Furthermore, administration of EPA to diabetic KK-Ay mice ameliorated impairment of insulin secretion in their islets.
CONCLUSIONS - SREBP-1c plays a dominant role in palmitate-mediated insulin secretion defect, and EPA prevents it through SREBP-1c inhibition, implicating a therapeutic potential for treating diabetes related to lipotoxicity.
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25 MeSH Terms
Hepatic glucose sensing: does flux matter?
Shiota M, Magnuson MA
(2008) J Clin Invest 118: 841-4
MeSH Terms: Animals, DNA-Binding Proteins, Gene Expression Regulation, Glucose, Lipogenesis, Liver, Liver X Receptors, Mice, Nuclear Proteins, Orphan Nuclear Receptors, Receptors, Cytoplasmic and Nuclear, Sterol Regulatory Element Binding Protein 1, Transcription Factors
Show Abstract · Added February 23, 2011
In this issue of the JCI, Denechaud et al. report studies investigating the role of the liver X receptors (LXRs) LXRalpha and LXRbeta in carbohydrate sensing by the liver (see the related article beginning on page 956). The results of this study, which utilized LXRalpha/beta double-KO mice, strongly contradict a recent Nature report that proposed that LXRalpha/beta sense glucose independent of metabolic flux. The reported findings further support a key role for the carbohydrate-responsive element-binding protein (ChREBP) in the regulation of lipogenic genes by glucose and dietary carbohydrates.
1 Communities
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13 MeSH Terms
Fatty acid synthase gene regulation in primary hypothalamic neurons.
Kim EK, Kleman AM, Ronnett GV
(2007) Neurosci Lett 423: 200-4
MeSH Terms: Aminoimidazole Carboxamide, Animals, Cells, Cultured, Dose-Response Relationship, Drug, Fatty Acid Synthases, Fetus, Gene Expression Regulation, Glucose, Hypothalamus, Insulin, Neurons, Protein Isoforms, RNA, Messenger, Rats, Rats, Sprague-Dawley, Ribonucleotides, Sterol Regulatory Element Binding Protein 1, Time Factors
Show Abstract · Added August 14, 2014
Understanding the mechanisms that regulate feeding is critical to the development of therapeutic interventions for obesity. Many studies indicate that enzymes within fatty acid metabolic pathways may serve as targets for pharmacological tools to treat this epidemic. We, and others have previously demonstrated that C75, a fatty acid synthase (FAS) inhibitor, induced significant anorexia and weight loss by both central and peripheral mechanisms. Because the hypothalamus is important in the regulation of homeostatic processes for feeding control, we have identified pathways that alter the gene expression of FAS in primary hypothalamic neuronal cultures. Insulin, glucose and AICAR (an activator of AMP-activated protein kinase) affected changes in hypothalamic FAS mRNA, which may be regulated via the SREBP1c dependent or independent pathway.
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18 MeSH Terms
Granuphilin is activated by SREBP-1c and involved in impaired insulin secretion in diabetic mice.
Kato T, Shimano H, Yamamoto T, Yokoo T, Endo Y, Ishikawa M, Matsuzaka T, Nakagawa Y, Kumadaki S, Yahagi N, Takahashi A, Sone H, Suzuki H, Toyoshima H, Hasty AH, Takahashi S, Gomi H, Izumi T, Yamada N
(2006) Cell Metab 4: 143-54
MeSH Terms: Animals, Cells, Cultured, Diabetes Mellitus, Experimental, Insulin, Insulin Secretion, Islets of Langerhans, Maf Transcription Factors, Large, Male, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Transgenic, Palmitates, Potassium, Promoter Regions, Genetic, Signal Transduction, Sterol Regulatory Element Binding Protein 1, Vesicular Transport Proteins
Show Abstract · Added March 27, 2013
Granuphilin is a crucial component of the docking machinery of insulin-containing vesicles to the plasma membrane. Here, we show that the granuphilin promoter is a target of SREBP-1c, a transcription factor that controls fatty acid synthesis, and MafA, a beta cell differentiation factor. Potassium-stimulated insulin secretion (KSIS) was suppressed in islets with adenoviral-mediated overexpression of granuphilin and enhanced in islets with knockdown of granuphilin (in which granuphilin had been knocked down). SREBP-1c and granuphilin were activated in islets from beta cell-specific SREBP-1c transgenic mice, as well as in several diabetic mouse models and normal islets treated with palmitate, accompanied by a corresponding reduction in insulin secretion. Knockdown- or knockout-mediated ablation of granuphilin or SREBP-1c restored KSIS in these islets. Collectively, our data provide evidence that activation of the SREBP-1c/granuphilin pathway is a potential mechanism for impaired insulin secretion in diabetes, contributing to beta cell lipotoxicity.
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18 MeSH Terms
Physiological relevance of apolipoprotein E recycling: studies in primary mouse hepatocytes.
Zhu MY, Hasty AH, Harris C, Linton MF, Fazio S, Swift LL
(2005) Metabolism 54: 1309-15
MeSH Terms: Animals, Apolipoproteins E, Bone Marrow Transplantation, CCAAT-Enhancer-Binding Proteins, Cells, Cultured, DNA-Binding Proteins, Fatty Acids, Hepatocytes, Lipoproteins, VLDL, Mice, Mice, Inbred C57BL, RNA, Messenger, Sterol Regulatory Element Binding Protein 1, Transcription Factors, Triglycerides
Show Abstract · Added December 10, 2013
Studies in our laboratory have shown that a fraction of apolipoprotein (apo) E internalized by hepatocytes escapes degradation and is resecreted. Although the intracellular routing is not fully understood, our studies suggest that a portion of apoE recycles through the Golgi apparatus. Given the role of the Golgi apparatus in lipoprotein secretion and the fact that apoE modulates the hepatic secretion of very low-density lipoprotein, we hypothesized that recycling apoE has an effect on hepatic very low-density lipoprotein assembly and/or secretion. To test this hypothesis, apoE-/- mice were transplanted with bone marrow from wild-type mice. In this model, extrahepatic (macrophage-derived) apoE is internalized by the hepatocytes in vivo and is resecreted when the hepatocytes are placed in culture. Unexpectedly, our studies demonstrate that recycling apoE has little effect on hepatic lipid content or hepatocyte triglyceride secretion. In addition, recycling apoE has little effect on the expression of enzymes and proteins involved in lipid synthesis as well as plasma lipoprotein apoproteins. We conclude that the physiological relevance of apoE recycling may not be related to cell-specific functions, such as lipoprotein assembly in the liver. Rather, recycling may provide a mechanism for modulating general cellular effects such as intracellular cholesterol transport or cholesterol efflux.
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15 MeSH Terms
The sterol response element binding protein regulates cyclooxygenase-2 gene expression in endothelial cells.
Smith LH, Petrie MS, Morrow JD, Oates JA, Vaughan DE
(2005) J Lipid Res 46: 862-71
MeSH Terms: Animals, Base Sequence, CCAAT-Enhancer-Binding Proteins, Cattle, Cells, Cultured, Cyclooxygenase 2, DNA Primers, DNA-Binding Proteins, Endothelium, Vascular, Epoprostenol, Gene Expression Regulation, Enzymologic, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lovastatin, Membrane Proteins, Promoter Regions, Genetic, Prostaglandin-Endoperoxide Synthases, Reverse Transcriptase Polymerase Chain Reaction, Sterol Regulatory Element Binding Protein 1, Sterol Regulatory Element Binding Protein 2, Transcription Factors
Show Abstract · Added December 10, 2013
We previously demonstrated that cholesterol deprivation increases endothelial cyclooxygenase-2 (COX-2)-dependent prostacyclin [prostaglandin I2 (PGI2)] production in vitro. Cholesterol directly regulates gene transcription through the sterol response element binding protein (SREBP). In this work, we demonstrate that SREBP directly regulates COX-2 expression. Cholesterol reduces human COX-2 promoter-luciferase reporter construct activity in transiently transfected endothelial cells. Conversely, cotransfection with a constitutively active mutant SREBP increases COX-2 promoter activity. SREBP-1a and -2 specifically bind a putative sterol response element (SRE) sequence in the COX-2 promoter. This sequence competes for SREBP binding to a low density lipoprotein receptor consensus sequence in an electromobility-shift assay. These data indicate that endothelial COX-2 is regulated by cholesterol via the SREBP pathway. The present study identifies COX-2 as the first vascular gene without a clear role in lipid metabolism transactivated by SREBP, and suggests that enhanced production of PGI2 through this pathway may be an additional benefit of cholesterol-lowering therapies.
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21 MeSH Terms
Hepatic glucokinase is required for the synergistic action of ChREBP and SREBP-1c on glycolytic and lipogenic gene expression.
Dentin R, Pégorier JP, Benhamed F, Foufelle F, Ferré P, Fauveau V, Magnuson MA, Girard J, Postic C
(2004) J Biol Chem 279: 20314-26
MeSH Terms: Acetyl-CoA Carboxylase, Adenoviridae, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Blotting, Northern, CCAAT-Enhancer-Binding Proteins, Carbohydrate Metabolism, Cell Nucleus, Cells, Cultured, DNA-Binding Proteins, Fatty Acid Synthases, Gene Expression Regulation, Glucokinase, Glucose, Glucose-6-Phosphate, Glycogen, Hepatocytes, Immunoblotting, Kinetics, Lipid Metabolism, Liver, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Microscopy, Fluorescence, Nuclear Proteins, Pentosephosphates, Proteins, Pyruvate Kinase, RNA, RNA, Messenger, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Sterol Regulatory Element Binding Protein 1, Time Factors, Transcription Factors, Transcription, Genetic
Show Abstract · Added February 23, 2011
Hepatic glucokinase (GK) catalyzes the phosphorylation of glucose to glucose 6-phosphate (G6P), a step which is essential for glucose metabolism in liver as well as for the induction of glycolytic and lipogenic genes. The sterol regulatory element-binding protein-1c (SREBP-1c) has emerged as a major mediator of insulin action on hepatic gene expression, but the extent to which its transcriptional effect is caused by an increased glucose metabolism remains unclear. Through the use of hepatic GK knockout mice (hGK-KO) we have shown that the acute stimulation by glucose of l-pyruvate kinase (l-PK), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and Spot 14 genes requires GK expression. To determine whether the effect of SREBP-1c requires GK expression and subsequent glucose metabolism, a transcriptionally active form of SREBP-1c was overexpressed both in vivo and in primary cultures of control and hGK-KO hepatocytes. Our results demonstrate that the synergistic action of SREBP-1c and glucose metabolism via GK is necessary for the maximal induction of l-PK, ACC, FAS, and Spot 14 gene expression. Indeed, in hGK-KO hepatocytes overexpressing SREBP-1c, the effect of glucose on glycolytic and lipogenic genes is lost because of the impaired ability of these hepatocytes to efficiently metabolize glucose, despite a marked increase in low K(m) hexokinase activity. Our studies also reveal that the loss of glucose effect observed in hGK-KO hepatocytes is associated with a decreased in the carbohydrate responsive element-binding protein (ChREBP) gene expression, a transcription factor suggested to mediate glucose signaling in liver. Decreased ChREBP gene expression, achieved using small interfering RNA, results in a loss of glucose effect on endogenous glycolytic (l-PK) and lipogenic (FAS, ACC) gene expression, thereby demonstrating the direct implication of ChREBP in glucose action. Together these results support a model whereby both SREBP-1c and glucose metabolism, acting via ChREBP, are necessary for the dietary induction of glycolytic and lipogenic gene expression in liver.
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39 MeSH Terms
Lanosterol metabolism and sterol regulatory element binding protein (SREBP) expression in male germ cell maturation.
Fon Tacer K, Kalanj-Bognar S, Waterman MR, Rozman D
(2003) J Steroid Biochem Mol Biol 85: 429-38
MeSH Terms: Animals, CCAAT-Enhancer-Binding Proteins, DNA-Binding Proteins, Gene Expression Regulation, Lanosterol, Liver, Male, Mice, Mice, Inbred CBA, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Sexual Maturation, Spermatogenesis, Sterol Regulatory Element Binding Protein 1, Sterol Regulatory Element Binding Protein 2, Testis, Transcription Factors
Show Abstract · Added February 12, 2015
Expression of genes involved in cholesterol biosynthesis in male germ cells is insensitive to the negative cholesterol feedback regulation, in contrast to cholesterol level-sensitive/sterol regulatory element binding protein (SREBP)-dependent gene regulation in somatic cells. The role of sterol regulatory element binding proteins in spermatogenic cells was an enigma until recently, when a soluble, 55kDa cholesterol-insensitive form of SREBP2 (SREBP2gc) was discovered [Mol. Cell. Endocrinol. 22 (2002) 8478], being translated from a germ cell-specific SREBP2 mRNA. Our RT-PCR results also show that SREBP2 as well as SREBP1c mRNAs are detectable in prepubertal and postpubertal male germ cells while SREBP1a is not detected. Surprisingly, three SREBP2 immunoreactive proteins (72, 63 and 55kDa), that are not present in mouse liver nuclei, reside in testis nuclei of prepubertal and adult mice. The 55kDa protein is likely SREBP2gc, the other two isoforms are novel. HPLC measurements in liver and testes of fasted prepubertal and postpubertal mice showed no significant difference in cholesterol level. However, FF-MAS and lanosterol/testis-meiosis activating sterol (T-MAS) intermediates that are detectable mainly in testes, increase in fasted postpubertal mice which coincides well with the elevated level of 68kDa SREBP2. Similar to SREBP2gc, the two novel SREBP2 immunoreactive proteins seem to be insensitive to the level of cholesterol.
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17 MeSH Terms
Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-1c promoter through inhibition of LXR signaling.
Yoshikawa T, Ide T, Shimano H, Yahagi N, Amemiya-Kudo M, Matsuzaka T, Yatoh S, Kitamine T, Okazaki H, Tamura Y, Sekiya M, Takahashi A, Hasty AH, Sato R, Sone H, Osuga J, Ishibashi S, Yamada N
(2003) Mol Endocrinol 17: 1240-54
MeSH Terms: Animals, Anticholesteremic Agents, CCAAT-Enhancer-Binding Proteins, Cells, Cultured, DNA-Binding Proteins, Fatty Acids, Gene Expression Regulation, Hepatocytes, Humans, Hydrocarbons, Fluorinated, Liver, Liver X Receptors, Male, Mice, Mice, Inbred C57BL, Nutritional Physiological Phenomena, Orphan Nuclear Receptors, Promoter Regions, Genetic, Pyrimidines, Rats, Rats, Sprague-Dawley, Receptors, Cytoplasmic and Nuclear, Receptors, Retinoic Acid, Response Elements, Retinoid X Receptors, Signal Transduction, Sterol Regulatory Element Binding Protein 1, Sulfonamides, Transcription Factors
Show Abstract · Added March 27, 2013
Liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) are members of nuclear receptors that form obligate heterodimers with retinoid X receptors (RXRs). These nuclear receptors play crucial roles in the regulation of fatty acid metabolism: LXRs activate expression of sterol regulatory element-binding protein 1c (SREBP-1c), a dominant lipogenic gene regulator, whereas PPARalpha promotes fatty acid beta-oxidation genes. In the current study, effects of PPARs on the LXR-SREBP-1c pathway were investigated. Luciferase assays in human embryonic kidney 293 cells showed that overexpression of PPARalpha and gamma dose-dependently inhibited SREBP-1c promoter activity induced by LXR. Deletion and mutation studies demonstrated that the two LXR response elements (LXREs) in the SREBP-1c promoter region are responsible for this inhibitory effect of PPARs. Gel shift assays indicated that PPARs reduce binding of LXR/RXR to LXRE. PPARalpha-selective agonist enhanced these inhibitory effects. Supplementation with RXR attenuated these inhibitions by PPARs in luciferase and gel shift assays, implicating receptor interaction among LXR, PPAR, and RXR as a plausible mechanism. Competition of PPARalpha ligand with LXR ligand was observed in LXR/RXR binding to LXRE in gel shift assay, in LXR/RXR formation in nuclear extracts by coimmunoprecipitation, and in gene expression of SREBP-1c by Northern blot analysis of rat primary hepatocytes and mouse liver RNA. These data suggest that PPARalpha activation can suppress LXR-SREBP-1c pathway through reduction of LXR/RXR formation, proposing a novel transcription factor cross-talk between LXR and PPARalpha in hepatic lipid homeostasis.
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29 MeSH Terms