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Special Issue "Transcriptional Regulation in Lipid Metabolism"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 September 2018).

Special Issue Editors

Dr. Yoshimi Nakagawa
E-Mail Website
Guest Editor
International Insutitute for Interative Sleep Medicine (WPI-IIIS), Univerity of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-85875, Japan
Interests: energy homeostasis; lipid metabolism; transcription factor; CREBH; SREBP; hyperlipidemia; diabetes; atherosclerosis
Prof. Hitoshi Shimano
E-Mail Website
Guest Editor
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305–8575, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305–8575, Japan
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Special Issue Information

Dear Colleagues,

In recent years, with the increase in calorie expropriation and lack of exercise, patients with lifestyle diseases have been increasing, and this matter is becoming a social problem all over the world. Lipid metabolism has a crucial role in the pathology of these diseases. The abnormality of lipid metabolism deteriorates to hyperlipidemia, obesity, diabetes, nonalcoholic fatty liver (NAFLD), eventually coronary artery disease, and develops a life crisis. Thus, its elucidation is important for the improvement of lifestyle diseases. Dysregulation in lipid metabolism is caused by the accumulation of abnormalities at long-term gene expression levels. Therefore, an understanding at the transcriptional level is necessary. In this review, we would like to talk about the molecular mechanism of lipid metabolism regulation from crosstalk between transcription factors controlling gene expression involved in lipid metabolism. Among new findings in the regulation of gene expression related to lipid metabolism, we need to think about ways to treat lifestyle diseases in the future.

Dr. Yoshimi Nakagawa
Prof. Dr. Hitoshi Shimano
Guest Editors

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Keywords

  • Lipid metabolism
  • Glucose metabolism
  • Transcription factor interaction
  • Gene expression
  • Fatty liver
  • Atherosclerosis
  • Obesity
  • Diabetes

Published Papers (18 papers)

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Research

Jump to: Review

Article
Distinct Patterns of PPARγ Promoter Usage, Lipid Degradation Activity, and Gene Expression in Subcutaneous Adipose Tissue of Lean and Obese Swine
Int. J. Mol. Sci. 2018, 19(12), 3892; https://doi.org/10.3390/ijms19123892 - 05 Dec 2018
Cited by 3 | Viewed by 1613
Abstract
Subcutaneous adipose tissue is a loose connective tissue specializing in the regulation of energy storage and metabolization. In domesticated pigs (Sus scrofa), the temporal development of subcutaneous adipose tissue is critical for meat production. However, the regulation of adipose tissue development [...] Read more.
Subcutaneous adipose tissue is a loose connective tissue specializing in the regulation of energy storage and metabolization. In domesticated pigs (Sus scrofa), the temporal development of subcutaneous adipose tissue is critical for meat production. However, the regulation of adipose tissue development remains unclear. Here, the subcutaneous adipose tissue development was characterized and compared in lean (Danish-Landrace) and obese (Min) pigs at juvenile and the juvenile-to-adult growth stages. Using RNA sequencing, we profiled the transcriptome of subcutaneous adipose tissue isolated from 4- and 16-week-old pigs and identified 24,718 expressed transcription units. Of them, 6327 genes were differentially expressed between the breeds and/or developmental stages. Compared with obese pigs, upregulated genes in lean pigs showed significant function and pathway enrichment in fatty acid degradation and mitochondrial functions. Further analysis uncovered the distinct usage preferences of the three alternative peroxisome proliferator-activated receptor γ (PPARγ) promoters associated with the development of subcutaneous adipose tissue in both breeds. Transcriptome analysis of subcutaneous adipose tissue in lean and obese pigs suggested that marker-assisted selection of fatty acid degradation and PPARγ signaling pathways could be important directions for future pork quality improvement and modern breeding. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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Article
Differential Metabolic Responses to Adipose Atrophy Associated with Cancer Cachexia and Caloric Restriction in Rats and the Effect of Rikkunshito in Cancer Cachexia
Int. J. Mol. Sci. 2018, 19(12), 3852; https://doi.org/10.3390/ijms19123852 - 03 Dec 2018
Cited by 3 | Viewed by 1517
Abstract
Despite the similar phenotypes, including weight loss, reduction of food intake, and lower adiposity, associated with caloric restriction (CR) and cancer cachexia (CC), CC is a progressive wasting syndrome, while mild CR improves whole body metabolism. In the present study, we compared adipose [...] Read more.
Despite the similar phenotypes, including weight loss, reduction of food intake, and lower adiposity, associated with caloric restriction (CR) and cancer cachexia (CC), CC is a progressive wasting syndrome, while mild CR improves whole body metabolism. In the present study, we compared adipose metabolic changes in a novel rat model of CC, mild CR (70% of the food intake of control rats, which is similar to the food consumption of CC rats), and severe CR (30% of the food intake of controls). We show that CC and severe CR are associated with much smaller adipocytes with significantly lower mitochondrial DNA content; but, that mild CR is not. CC and both mild and severe CR similarly upregulated proteins involved in lipolysis. CC also downregulated proteins involved in fatty acid biosynthesis, but mild CR upregulated these. These findings suggest that CC might impair de novo fatty acid biosynthesis and reduce mitochondrial biogenesis, similar to severe CR. We also found that rikkunshito, a traditional Japanese herbal medicine, does not ameliorate the enhanced lipolysis and mitochondrial impairment, but rather, rescues de novo fatty acid biosynthesis, suggesting that rikkunshito administration might have partially similar effects to mild CR. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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Article
Identification of Potential Key Genes Associated with Adipogenesis through Integrated Analysis of Five Mouse Transcriptome Datasets
Int. J. Mol. Sci. 2018, 19(11), 3557; https://doi.org/10.3390/ijms19113557 - 12 Nov 2018
Cited by 4 | Viewed by 1503
Abstract
Adipose tissue is the most important energy metabolism and secretion organ, and these functions are conferred during the adipogenesis process. However, the cause and the molecular events underlying adipogenesis are still unclear. In this study, we performed integrated bioinformatics analyses to identify vital [...] Read more.
Adipose tissue is the most important energy metabolism and secretion organ, and these functions are conferred during the adipogenesis process. However, the cause and the molecular events underlying adipogenesis are still unclear. In this study, we performed integrated bioinformatics analyses to identify vital genes involved in adipogenesis and reveal potential molecular mechanisms. Five mouse high-throughput expression profile datasets were downloaded from the Gene Expression Omnibus (GEO) database; these datasets contained 24 samples of 3T3-L1 cells during adipogenesis, including 12 undifferentiated samples and 12 differentiated samples. The five datasets were reanalyzed and integrated to select differentially expressed genes (DEGs) during adipogenesis via the robust rank aggregation (RRA) method. Functional annotation of these DEGs and mining of key genes were then performed. We also verified the expression levels of some potential key genes during adipogenesis. A total of 386 consistent DEGs were identified, with 230 upregulated genes and 156 downregulated genes. Gene Ontology (GO) analysis showed that the biological functions of the DEGs primarily included fat cell differentiation, lipid metabolic processes, and cell adhesion. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that these DEGs were mainly associated with metabolic pathways, the peroxisome proliferator-activated receptor (PPAR) signaling pathway, regulation of lipolysis in adipocytes, the tumor necrosis factor (TNF) signaling pathway, and the FoxO signaling pathway. The 30 most closely related genes among the DEGs were identified from the protein–protein interaction (PPI) network and verified by real-time quantification during 3T3-L1 preadipocyte differentiation. In conclusion, we obtained a list of consistent DEGs during adipogenesis through integrated analysis, which may offer potential targets for the regulation of adipogenesis and treatment of adipose dysfunction. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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Article
Lipid Identification and Transcriptional Analysis of Controlling Enzymes in Bovine Ovarian Follicle
Int. J. Mol. Sci. 2018, 19(10), 3261; https://doi.org/10.3390/ijms19103261 - 20 Oct 2018
Cited by 16 | Viewed by 2099
Abstract
Ovarian follicle provides a favorable environment for enclosed oocytes, which acquire their competence in supporting embryo development in tight communications with somatic follicular cells and follicular fluid (FF). Although steroidogenesis in theca (TH) and granulosa cells (GC) is largely studied, and the molecular [...] Read more.
Ovarian follicle provides a favorable environment for enclosed oocytes, which acquire their competence in supporting embryo development in tight communications with somatic follicular cells and follicular fluid (FF). Although steroidogenesis in theca (TH) and granulosa cells (GC) is largely studied, and the molecular mechanisms of fatty acid (FA) metabolism in cumulus cells (CC) and oocytes are emerging, little data is available regarding lipid metabolism regulation within ovarian follicles. In this study, we investigated lipid composition and the transcriptional regulation of FA metabolism in 3–8 mm ovarian follicles in bovine. Using liquid chromatography and mass spectrometry (MS), 438 and 439 lipids were identified in FF and follicular cells, respectively. From the MALDI-TOF MS lipid fingerprints of FF, TH, GC, CC, and oocytes, and the MS imaging of ovarian sections, we identified 197 peaks and determined more abundant lipids in each compartment. Transcriptomics revealed lipid metabolism-related genes, which were expressed constitutively or more specifically in TH, GC, CC, or oocytes. Coupled with differential lipid composition, these data suggest that the ovarian follicle contains the metabolic machinery that is potentially capable of metabolizing FA from nutrient uptake, degrading and producing lipoproteins, performing de novo lipogenesis, and accumulating lipid reserves, thus assuring oocyte energy supply, membrane synthesis, and lipid-mediated signaling to maintain follicular homeostasis. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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Article
The Peroxisome Proliferator-Activated Receptor α (PPARα) Agonist Pemafibrate Protects against Diet-Induced Obesity in Mice
Int. J. Mol. Sci. 2018, 19(7), 2148; https://doi.org/10.3390/ijms19072148 - 23 Jul 2018
Cited by 23 | Viewed by 3883
Abstract
Peroxisome proliferator-activated receptor α (PPARα) is a therapeutic target for hyperlipidemia. Pemafibrate (K-877) is a new selective PPARα modulator activating PPARα transcriptional activity. To determine the effects of pemafibrate on diet-induced obesity, wild-type mice were fed a high-fat diet (HFD) containing pemafibrate for [...] Read more.
Peroxisome proliferator-activated receptor α (PPARα) is a therapeutic target for hyperlipidemia. Pemafibrate (K-877) is a new selective PPARα modulator activating PPARα transcriptional activity. To determine the effects of pemafibrate on diet-induced obesity, wild-type mice were fed a high-fat diet (HFD) containing pemafibrate for 12 weeks. Like fenofibrate, pemafibrate significantly suppressed HFD-induced body weight gain; decreased plasma glucose, insulin and triglyceride (TG) levels; and increased plasma fibroblast growth factor 21 (FGF21). However, compared to the dose of fenofibrate, a relatively low dose of pemafibrate showed these effects. Pemafibrate activated PPARα transcriptional activity in the liver, increasing both hepatic expression and plasma levels of FGF21. Additionally, pemafibrate increased the expression of genes involved in thermogenesis and fatty acid oxidation, including Ucp1, Cidea and Cpt1b in inguinal adipose tissue (iWAT) and the mitochondrial marker Elovl3 in brown adipose tissue (BAT). Therefore, pemafibrate activates thermogenesis in iWAT and BAT by increasing plasma levels of FGF21. Additionally, pemafibrate induced the expression of Atgl and Hsl in epididymal white adipose tissue, leading to the activation of lipolysis. Taken together, pemafibrate suppresses diet-induced obesity in mice and improves their obesity-related metabolic abnormalities. We propose that pemafibrate may be useful for the suppression and improvement of obesity-induced metabolic abnormalities. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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Article
Fatty Acid β-Oxidation Is Essential in Leptin-Mediated Oocytes Maturation of Yellow Catfish Pelteobagrus fulvidraco
Int. J. Mol. Sci. 2018, 19(5), 1457; https://doi.org/10.3390/ijms19051457 - 14 May 2018
Cited by 6 | Viewed by 1736
Abstract
Although several studies have been conducted to study leptin function, information is very scarce on the molecular mechanism of leptin in fatty acid β-oxidation and oocytes maturation in fish. In this study, we investigated the potential role of fatty acid β-oxidation in leptin-mediated [...] Read more.
Although several studies have been conducted to study leptin function, information is very scarce on the molecular mechanism of leptin in fatty acid β-oxidation and oocytes maturation in fish. In this study, we investigated the potential role of fatty acid β-oxidation in leptin-mediated oocytes maturation in Pelteobagrus fulvidraco. Exp. 1 investigated the transcriptomic profiles of ovary and the differential expression of genes involved in β-oxidation and oocytes maturation following rt-hLEP injection; rt-hLEP injection was associated with significant changes in the expression of genes, including twenty-five up-regulated genes (CPT1, Acsl, Acadl, Acadm, Hadhb, Echsl, Hsd17b4, Acca, PPARα, CYP8B1, ACOX1, ACBP, MAPK, RINGO, Cdc2, MEK1, IGF-1R, APC/C, Cdk2, GnRHR, STAG3, SMC1, FSHβ and C-Myc) and ten down-regulated gene (PPARγ, FATCD36, UBC, PDK1, Acads, Raf, Fizzy, C3H-4, Raf and PKC), involved in fatty acid β-oxidation and oocytes maturation. In Exp. 2, rt-hLEP and specific inhibitors AG490 (JAK-STAT inhibitor) were used to explore whether leptin induced oocytes maturation, and found that leptin incubation increased the diameters of oocytes and percentage of germinal vesicle breakdown (GVBD)-MII oocytes, up-regulated mRNA levels of genes involved in oocytes maturation and that leptin-induced oocyte maturation was related to activation of JAK-STAT pathway. In Exp. 3, primary oocytes of P. fulvidraco were treated with (R)-(+)-etomoxir (an inhibitor of β-oxidation) or l-carnitine (an enhancer of β-oxidation) for 48 h under rt-hLEP incubation. Exp. 3 indicated that the inhibition of fatty acid β-oxidation resulted in the down-regulation of gene expression involved in oocytes maturation, and repressed the leptin-induced up-regulation of these gene expression. Activation of fatty acid β-oxidation improved the maturation rate and mean diameter of oocytes, and up-regulated gene expression involved in oocytes maturation. Leptin is one of the main factors that links fatty acid β-oxidation with oocyte maturation; β-oxidation is essential for leptin-mediated oocyte maturation in fish. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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Article
Inactivation of SREBP-1a Phosphorylation Prevents Fatty Liver Disease in Mice: Identification of Related Signaling Pathways by Gene Expression Profiles in Liver and Proteomes of Peroxisomes
Int. J. Mol. Sci. 2018, 19(4), 980; https://doi.org/10.3390/ijms19040980 - 25 Mar 2018
Cited by 10 | Viewed by 2342
Abstract
The key lipid metabolism transcription factor sterol regulatory element-binding protein (SREBP)-1a integrates gene regulatory effects of hormones, cytokines, nutrition and metabolites as lipids, glucose, or cholesterol via phosphorylation by different mitogen activated protein kinase (MAPK) cascades. We have previously reported the impact of [...] Read more.
The key lipid metabolism transcription factor sterol regulatory element-binding protein (SREBP)-1a integrates gene regulatory effects of hormones, cytokines, nutrition and metabolites as lipids, glucose, or cholesterol via phosphorylation by different mitogen activated protein kinase (MAPK) cascades. We have previously reported the impact of SREBP-1a phosphorylation on the phenotype in transgenic mouse models with liver-specific overexpression of the N-terminal transcriptional active domain of SREBP-1a (alb-SREBP-1a) or a MAPK phosphorylation site-deficient variant (alb-SREBP-1a∆P; (S63A, S117A, T426V)), respectively. In this report, we investigated the molecular basis of the systemic observations by holistic analyses of gene expression in liver and of proteome patterns in lipid-degrading organelles involved in the pathogenesis of metabolic syndrome, i.e., peroxisomes, using 2D-DIGE and mass spectrometry. The differences in hepatic gene expression and peroxisomal protein patterns were surprisingly small between the control and alb-SREBP-1a mice, although the latter develop a severe phenotype with visceral obesity and fatty liver. In contrast, phosphorylation site-deficient alb-SREBP-1a∆P mice, which are protected from fatty liver disease, showed marked differences in hepatic gene expression and peroxisomal proteome patterns. Further knowledge-based analyses revealed that disruption of SREBP-1a phosphorylation resulted in massive alteration of cellular processes, including signs for loss of targeting lipid pathways. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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Article
In Vitro Cocktail Effects of PCB-DL (PCB118) and Bulky PCB (PCB153) with BaP on Adipogenesis and on Expression of Genes Involved in the Establishment of a Pro-Inflammatory State
Int. J. Mol. Sci. 2018, 19(3), 841; https://doi.org/10.3390/ijms19030841 - 13 Mar 2018
Cited by 3 | Viewed by 1871
Abstract
(1) Objective: Highlight the in vitro effects of 3T3-L1 cell exposure to polychlorinated biphenyls (PCB118 and 153) or benzo(a)pyrene (BaP) alone or as a cocktail on adipogenesis (ADG) by focusing on changes in lipid metabolism and inflammatory-related genes expression (INFG) and ADG-related genes [...] Read more.
(1) Objective: Highlight the in vitro effects of 3T3-L1 cell exposure to polychlorinated biphenyls (PCB118 and 153) or benzo(a)pyrene (BaP) alone or as a cocktail on adipogenesis (ADG) by focusing on changes in lipid metabolism and inflammatory-related genes expression (INFG) and ADG-related genes expression (ADGG); (2) Results: Treatment from the early stage of cell differentiation by BaP alone or in combination with PCBs decreased the expression of some of the ADGG (PPARγ Glut-4, FAS, Lipin-1a, Leptin, and Adiponectin). BaP enhanced the INFG, especially MCP-1 and TNFα. Co-exposure to BaP and PCB153 showed a synergistic effect on TNFα and IL6 expression. Treatment with BaP and PCBs during only the maturation period up-regulated the INFG (IL6, TNFα, CXCL-10 & MCP-1). PCB118 alone also enhanced TNFα, CXCL-10, and PAI-1 expression. The change in MCP-1 protein expression was in agreement with that of the gene. Finally, the BaP-induced up-regulation of the xenobiotic responsive element (XRE)-controlled luciferase activity was impaired by PCB153 but not by PCB118; (3) Conclusion: BaP and PCBs down-regulate a part of ADGG and enhance INFG. The direct regulatory effect of PCBs on both ADGG and INFG is usually rather lower than that of BaP and synergistic or antagonistic cocktail effects are clearly observed. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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Article
Metabolic Effects of FecB Gene on Follicular Fluid and Ovarian Vein Serum in Sheep (Ovis aries)
Int. J. Mol. Sci. 2018, 19(2), 539; https://doi.org/10.3390/ijms19020539 - 11 Feb 2018
Cited by 15 | Viewed by 2022
Abstract
The FecB gene has been discovered as an important gene in sheep for its high relationship with the ovulation rate, but its regulatory mechanism remains unknown. In the present study, liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) techniques were adopted to [...] Read more.
The FecB gene has been discovered as an important gene in sheep for its high relationship with the ovulation rate, but its regulatory mechanism remains unknown. In the present study, liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) techniques were adopted to detect the metabolic effects of FecB gene in follicular fluid (FF) and ovarian vein serum (OVS) in Small Tail Han (STH) sheep. ANOVA and random forest statistical methods were employed for the identification of important metabolic pathways and biomarkers. Changes in amino acid metabolism, redox environment, and energy metabolism were observed in FF from the three FecB genotype STH ewes. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) showed that metabolic effects of FecB gene are more pronounced in FF than in OVS. Therefore, the difference of the metabolic profile in FF is also affected by the FecB genotypes. In Spearman correlation analysis, key metabolites (e.g., glucose 6-phosphate, glucose 1-phosphate, aspartate, asparagine, glutathione oxidized (GSSG), cysteine-glutathione disulfide, γ-glutamylglutamine, and 2-hydrosybutyrate) in ovine FF samples showed a significant correlation with the ovulation rate. Our findings will help to explain the metabolic mechanism of high prolificacy ewes and benefit fertility identification. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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Article
Different Lipid Regulation in Ovarian Cancer: Inhibition of the Immune System
Int. J. Mol. Sci. 2018, 19(1), 273; https://doi.org/10.3390/ijms19010273 - 17 Jan 2018
Cited by 12 | Viewed by 2143
Abstract
Lipid metabolism is altered in several cancer settings leading to different ratios of intermediates. Ovarian cancer is the most lethal gynecological malignancy. Cancer cells disperse in the abdominal space and ascites occurs. T cells obtained from ascites are unable to proliferate after an [...] Read more.
Lipid metabolism is altered in several cancer settings leading to different ratios of intermediates. Ovarian cancer is the most lethal gynecological malignancy. Cancer cells disperse in the abdominal space and ascites occurs. T cells obtained from ascites are unable to proliferate after an antigenic stimulus. The proliferation of ascites-derived T cells can be restored after culturing the cells for ten days in normal culture medium. No pathway aberrancies were detected. The acellular fraction of ascites can inhibit the proliferation of autologous as well as allogeneic peripheral blood lymphocytes, indicating the presence of soluble factors that interfere with T cell functionality. Therefore, we analyzed 109 lipid mediators and found differentially regulated lipids in suppressive ascitic fluid compared to normal abdominal fluid. Our study indicates the presence of lipid intermediates in ascites of ovarian cancer patients, which coincidences with T cell dysfunctionality. Since the immune system in the abdominal cavity is compromised, this may explain the high seeding efficiency of disseminated tumor cells. Further research is needed to fully understand the correlation between the various lipids and T cell proliferation, which could lead to new treatment options. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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Article
Modulatory Effects of Breed, Feeding Status, and Diet on Adipogenic, Lipogenic, and Lipolytic Gene Expression in Growing Iberian and Duroc Pigs
Int. J. Mol. Sci. 2018, 19(1), 22; https://doi.org/10.3390/ijms19010022 - 22 Dec 2017
Cited by 17 | Viewed by 1629
Abstract
Meat quality depends on tissue composition which is in turn influenced by different factors, such as diet, genotype, age, or sex. We evaluated the effects of breed, 24 h fasting, and dietary energy source (HO: oleic acid versus CH: carbohydrates) on the expression [...] Read more.
Meat quality depends on tissue composition which is in turn influenced by different factors, such as diet, genotype, age, or sex. We evaluated the effects of breed, 24 h fasting, and dietary energy source (HO: oleic acid versus CH: carbohydrates) on the expression of candidate genes involved in adipogenesis, lipogenesis, and lipolysis in the adipose tissue from Iberian and Duroc growing pigs. The Iberian pigs showed greater feed intake, backfat thickness, and saturated fatty acids (SFA) content in the subcutaneous fat, whereas the Duroc pigs had greater ham weight and polyunsaturated fatty acids (PUFA) content. In both breeds, the diet induced changes in the fatty acid (FA) composition of subcutaneous fat samples. The HO group had higher monounsaturated fatty acids (MUFA) and oleic acid, and lower SFA than the CH group. Regarding gene expression, breed and feeding status (fasting versus postprandial) had significant effects on gene expression, with quantitative interactions between them, while diet showed negligible effects. In general, adipogenic and lipogenic genes were upregulated in the Iberian pigs and in postprandial samples. In contrast, the expression of lipolytic genes showed complex interaction effects. Our results agree with the phenotypic differences between the Iberian and Duroc breeds and with the inhibition of lipogenesis by fasting. Quantitative interactions between breed and feeding status effects were observed, which indicates a different response to fasting of the two breeds, with the obese Iberian breed showing a more stable expression of lipogenic genes. These results highlight the complexity of lipid metabolism regulation, especially in relation to lipolysis processes. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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Review

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Review
Transcriptional Regulation of Acyl-CoA:Glycerol-sn-3-Phosphate Acyltransferases
Int. J. Mol. Sci. 2019, 20(4), 964; https://doi.org/10.3390/ijms20040964 - 22 Feb 2019
Cited by 8 | Viewed by 2153
Abstract
Acyl-CoA:glycerol-sn-3-phosphate acyltransferase (GPAT) is an enzyme responsible for the rate-limiting step in the synthesis of glycerophospholipids and triacylglycerol (TAG). The enzymes of mammalian species are classified into four isoforms; GPAT1 and GPAT2 are localized in the mitochondrial outer membrane, whereas GPAT3 [...] Read more.
Acyl-CoA:glycerol-sn-3-phosphate acyltransferase (GPAT) is an enzyme responsible for the rate-limiting step in the synthesis of glycerophospholipids and triacylglycerol (TAG). The enzymes of mammalian species are classified into four isoforms; GPAT1 and GPAT2 are localized in the mitochondrial outer membrane, whereas GPAT3 and GPAT4 are localized in the endoplasmic reticulum membrane. The activity of each enzyme expressed is associated with physiological and pathological functions. The transcriptional regulation is well known, particularly in GPAT1. GPAT1 mRNA expression is mainly regulated by the binding of the transcriptional factor SREBP-1c to the specific element (the sterol regulatory element) flanking the GPAT1 promoter. The TAG level is controlled by the insulin-induced transcriptional expression of GPAT1, which occupies most of the GPAT activity in the liver. The transcriptional regulation of the other three GPAT isoforms remains undetermined in detail. It is predicted that retinoic acid serves as a transcription factor in the GPAT2 promoter. PPARγ (peroxisome proliferator-activated receptor γ) increases the mRNA expression of GPAT3, which is associated with TAG synthesis in adipose tissues. Although GPAT has been considered to be a key enzyme in the production of TAG, unexpected functions have recently been reported, particularly in GPAT2. It is likely that GPAT2 is associated with tumorigenesis and normal spermatogenesis. In this review, the physiological and pathophysiological roles of the four GPAT isoforms are described, alongside the transcriptional regulation of these enzymes. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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Review
Effective Food Ingredients for Fatty Liver: Soy Protein β-Conglycinin and Fish Oil
Int. J. Mol. Sci. 2018, 19(12), 4107; https://doi.org/10.3390/ijms19124107 - 18 Dec 2018
Cited by 6 | Viewed by 2924
Abstract
Obesity is prevalent in modern society because of a lifestyle consisting of high dietary fat and sucrose consumption combined with little exercise. Among the consequences of obesity are the emerging epidemics of hepatic steatosis and nonalcoholic fatty liver disease (NAFLD). Sterol regulatory element-binding [...] Read more.
Obesity is prevalent in modern society because of a lifestyle consisting of high dietary fat and sucrose consumption combined with little exercise. Among the consequences of obesity are the emerging epidemics of hepatic steatosis and nonalcoholic fatty liver disease (NAFLD). Sterol regulatory element-binding protein-1c (SREBP-1c) is a transcription factor that stimulates gene expression related to de novo lipogenesis in the liver. In response to a high-fat diet, the expression of peroxisome proliferator-activated receptor (PPAR) γ2, another nuclear receptor, is increased, which leads to the development of NAFLD. β-Conglycinin, a soy protein, prevents NAFLD induced by diets high in sucrose/fructose or fat by decreasing the expression and function of these nuclear receptors. β-Conglycinin also improves NAFLD via the same mechanism as for prevention. Fish oil contains n-3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid. Fish oil is more effective at preventing NAFLD induced by sucrose/fructose because SREBP-1c activity is inhibited. However, the effect of fish oil on NAFLD induced by fat is controversial because fish oil further increases PPARγ2 expression, depending upon the experimental conditions. Alcohol intake also causes an alcoholic fatty liver, which is induced by increased SREBP-1c and PPARγ2 expression and decreased PPARα expression. β-Conglycinin and fish oil are effective at preventing alcoholic fatty liver because β-conglycinin decreases the function of SREBP-1c and PPARγ2, and fish oil decreases the function of SREBP-1c and increases that of PPARα. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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Review
Genomic and Transcriptomic Analysis of Hypercholesterolemic Rabbits: Progress and Perspectives
Int. J. Mol. Sci. 2018, 19(11), 3512; https://doi.org/10.3390/ijms19113512 - 08 Nov 2018
Cited by 6 | Viewed by 1628
Abstract
Rabbits (Oryctolagus cuniculus) are one of the most widely used animal models for the study of human lipid metabolism and atherosclerosis because they are more sensitive to a cholesterol diet than other experimental animals such as rodents. Currently, two hypercholesterolemic rabbit models are [...] Read more.
Rabbits (Oryctolagus cuniculus) are one of the most widely used animal models for the study of human lipid metabolism and atherosclerosis because they are more sensitive to a cholesterol diet than other experimental animals such as rodents. Currently, two hypercholesterolemic rabbit models are frequently used for atherosclerosis studies. One is a cholesterol-fed wild-type rabbit and the other is the Watanabe heritable hyperlipidemic (WHHL) rabbit, which is genetically deficient in low density lipoprotein (LDL) receptor function. Wild-type rabbits can be easily induced to develop severe hypercholesterolemia with a cholesterol-rich diet due to the marked increase in hepatically and intestinally derived remnant lipoproteins, called β-very low density lipoproteins (VLDL), which are rich in cholesteryl esters. WHHL rabbits are characterized by elevated plasma LDL levels on a standard chow diet, which resembles human familial hypercholesterolemia. Therefore, both rabbit models develop aortic and coronary atherosclerosis, but the elevated plasma cholesterol levels are caused by completely different mechanisms. In addition, cholesterol-fed rabbits but not WHHL rabbits exhibit different degrees of hepatosteatosis. Recently, we along with others have shown that there are many differentially expressed genes in the atherosclerotic lesions and livers of cholesterol-fed rabbits that are either significantly up- or down-regulated, compared with those in normal rabbits, including genes involved in the regulation of inflammation and lipid metabolism. Therefore, dietary cholesterol plays an important role not only in hypercholesterolemia and atherosclerosis but also in hepatosteatosis. In this review, we make an overview of the recent progress in genomic and transcriptomic analyses of hypercholesterolemic rabbits. These transcriptomic profiling data should provide novel insight into the relationship between hypercholesterolemia and atherosclerosis or hepatic dysfunction caused by dietary cholesterol. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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Review
SREBP-1c-Dependent Metabolic Remodeling of White Adipose Tissue by Caloric Restriction
Int. J. Mol. Sci. 2018, 19(11), 3335; https://doi.org/10.3390/ijms19113335 - 26 Oct 2018
Cited by 8 | Viewed by 2350
Abstract
Caloric restriction (CR) delays the onset of many age-related pathophysiological changes and extends lifespan. White adipose tissue (WAT) is not only a major tissue for energy storage, but also an endocrine tissue that secretes various adipokines. Recent reports have demonstrated that alterations in [...] Read more.
Caloric restriction (CR) delays the onset of many age-related pathophysiological changes and extends lifespan. White adipose tissue (WAT) is not only a major tissue for energy storage, but also an endocrine tissue that secretes various adipokines. Recent reports have demonstrated that alterations in the characteristics of WAT can impact whole-body metabolism and lifespan. Hence, we hypothesized that functional alterations in WAT may play important roles in the beneficial effects of CR. Previously, using microarray analysis of WAT from CR rats, we found that CR enhances fatty acid (FA) biosynthesis, and identified sterol regulatory element-binding protein 1c (SREBP-1c), a master regulator of FA synthesis, as a mediator of CR. These findings were validated by showing that CR failed to upregulate factors involved in FA biosynthesis and to extend longevity in SREBP-1c knockout mice. Furthermore, we revealed that SREBP-1c is implicated in CR-associated mitochondrial activation through the upregulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis. Notably, these CR-associated phenotypes were observed only in WAT. We conclude that CR induces SREBP-1c-dependent metabolic remodeling, including the enhancement of FA biosynthesis and mitochondrial activation, via PGC-1α in WAT, resulting in beneficial effects. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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Review
Epigenomic Control of Thermogenic Adipocyte Differentiation and Function
Int. J. Mol. Sci. 2018, 19(6), 1793; https://doi.org/10.3390/ijms19061793 - 17 Jun 2018
Cited by 11 | Viewed by 2121
Abstract
Obesity and its associated metabolic disorders are spreading at a fast pace throughout the world; thus, effective therapeutic approaches are necessary to combat this epidemic. Obesity develops when there is a greater caloric intake than energy expenditure. Promoting energy expenditure has recently attracted [...] Read more.
Obesity and its associated metabolic disorders are spreading at a fast pace throughout the world; thus, effective therapeutic approaches are necessary to combat this epidemic. Obesity develops when there is a greater caloric intake than energy expenditure. Promoting energy expenditure has recently attracted much attention as a promising approach for the management of body weight. Thermogenic adipocytes are capable of burning fat to dissipate chemical energy into heat, thereby enhancing energy expenditure. After the recent re-discovery of thermogenic adipocytes in adult humans, much effort has focused on understanding the molecular mechanisms, especially the epigenetic mechanisms, which regulate thermogenic adipocyte development and function. A number of chromatin signatures, such as histone modifications, DNA methylation, chromatin accessibilities, and interactions, have been profiled at the genome level and analyzed in various murine and human thermogenic fat cell systems. Moreover, writers and erasers, as well as readers of the epigenome are also investigated using genomic tools in thermogenic adipocytes. In this review, we summarize and discuss the recent advance in these studies and highlight the insights gained into the epigenomic regulation of thermogenic program as well as the pathogenesis of human metabolic diseases. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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Review
CREBH Regulates Systemic Glucose and Lipid Metabolism
Int. J. Mol. Sci. 2018, 19(5), 1396; https://doi.org/10.3390/ijms19051396 - 08 May 2018
Cited by 23 | Viewed by 3510
Abstract
The cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CREBH, encoded by CREB3L3) is a membrane-bound transcriptional factor that primarily localizes in the liver and small intestine. CREBH governs triglyceride metabolism in the liver, which mediates the changes in gene expression governing fatty acid [...] Read more.
The cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CREBH, encoded by CREB3L3) is a membrane-bound transcriptional factor that primarily localizes in the liver and small intestine. CREBH governs triglyceride metabolism in the liver, which mediates the changes in gene expression governing fatty acid oxidation, ketogenesis, and apolipoproteins related to lipoprotein lipase (LPL) activation. CREBH in the small intestine reduces cholesterol transporter gene Npc1l1 and suppresses cholesterol absorption from diet. A deficiency of CREBH in mice leads to severe hypertriglyceridemia, fatty liver, and atherosclerosis. CREBH, in synergy with peroxisome proliferator-activated receptor α (PPARα), has a crucial role in upregulating Fgf21 expression, which is implicated in metabolic homeostasis including glucose and lipid metabolism. CREBH binds to and functions as a co-activator for both PPARα and liver X receptor alpha (LXRα) in regulating gene expression of lipid metabolism. Therefore, CREBH has a crucial role in glucose and lipid metabolism in the liver and small intestine. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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Review
Genetic and Epigenetic Regulation in Nonalcoholic Fatty Liver Disease (NAFLD)
Int. J. Mol. Sci. 2018, 19(3), 911; https://doi.org/10.3390/ijms19030911 - 19 Mar 2018
Cited by 47 | Viewed by 3442
Abstract
Genetics and epigenetics play a key role in the development of several diseases, including nonalcoholic fatty liver disease (NAFLD). Family studies demonstrate that first degree relatives of patients with NAFLD are at a much higher risk of the disease than the general population. [...] Read more.
Genetics and epigenetics play a key role in the development of several diseases, including nonalcoholic fatty liver disease (NAFLD). Family studies demonstrate that first degree relatives of patients with NAFLD are at a much higher risk of the disease than the general population. The development of the Genome Wide Association Study (GWAS) technology has allowed the identification of numerous genetic polymorphisms involved in the evolution of diseases (e.g., PNPLA3, MBOAT7). On the other hand, epigenetic changes interact with inherited risk factors to determine an individual’s susceptibility to NAFLD. Modifications of the histones amino-terminal ends are key factors in the maintenance of chromatin structure and gene expression (cAMP-responsive element binding protein H (CREBH) or SIRT1). Activation of SIRT1 showed potential against the physiological mechanisms related to NAFLD. Abnormal DNA methylation represents a starting point for cancer development in NAFLD patients. Besides, the evaluation of circulating miRNA profiles represents a promising approach to assess and non-invasively monitor liver disease severity. To date, there is no approved pharmacologic therapy for NAFLD and the current treatment remains weight loss with lifestyle modification and exercise. In this review, the status of research into relevant genetic and epigenetic modifiers of NAFLD progression will be discussed. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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