Gene Expression Profiles In Liver Research Articles

Light at Night Exposure Effects on Differentiation and Cell Cycle in the Rat Liver With Autonomic Nervous System Denervation.

Introduction: N Exposure to artificial light at night (LAN) affects human health and causes several functional modifications in the body. Obesity, diabetes, and hormonal changes are reported after exposure to LAN in humans. This study aims to highlight the critical features of biological terms that are affected in the liver of rats which received autonomic nervous system denervation. Methods: The liver gene expression profiles of 8 male Wistar rats that received sympathetic plus parasympathetic hepatic denervation and were exposed to LAN from Gene Expression Omnibus (GEO) for 1 hour were compared with 5 controls. The significant differentially-expressed genes (DEGs) were screened by the protein-protein interaction (PPI) network analysis STRING database (an application of Cytoscape software). Also, CuleGO and CleuDedia, the 2 applications of Cytoscape software, were used for more analysis. Results: Among 250 DEGs, 173 characterized genes with fold change more than 2 plus 100 added relevant genes were included in the PPI network. The analysis of the main connected component (MCC) led to introducing 15 hubs and 15 bottlenecks. CCT2, COPS7A, KAT2A, and ERCC1 were determined as hub-bottlenecks. Among hubs and bottlenecks, DHX15, KAT2A, CCT2, HSP90AB1, CCNE1, DHX16, LSM2, WEE1, CWC27, BAZ1B, RAB22A, DNM2, and DHX30 were linked to each other by various kinds of actions. CCT2 and KAT2A, the 2 hub-bottlenecks, were included in the interacted genes in the action map. Four classes of biological terms including negative regulation of non-motile cilium assembly, negative regulation of transforming growth factor beta activation, alpha-tubulin acetylation, and histamine-induced gastric acid secretion were identified as the critical biochemical pathways and biological processes. Conclusion: Several essential functions such as differentiation, cell cycle, ribosome assembly, and splicing are affected by LAN in rat livers with autonomic nervous system denervation.

Gene Expression and Fatty Acid Profiling in Longissimus thoracis Muscle, Subcutaneous Fat, and Liver of Light Lambs in Response to Concentrate or Alfalfa Grazing.

A better understanding of gene expression and metabolic pathways in response to a feeding system is critical for identifying key physiological processes and genes associated with polyunsaturated fatty acid (PUFA) content in lamb meat. The main objective of this study was to investigate transcriptional changes in L. thoracis (LT) muscle, liver, and subcutaneous fat (SF) of lambs that grazed alfalfa (ALF) and concentrate-fed (CON) slaughtered at 23 kg and using the Affymetrix Ovine Gene 1.1 ST whole-genome array. The study also evaluated the relationship between meat traits in LT muscle, including color, pigments and lipid oxidation during 7 days of display, α-tocopherol content, intramuscular fat (IMF) content and the fatty acid (FA) profile. Lambs that grazed on alfalfa had a greater α-tocopherol concentration in plasma than CON lambs (P < 0.05). The treatment did not affect the IMF content, meat color or pigments (P > 0.05). Grazing increased the α-tocopherol content (P < 0.001) and decreased lipid oxidation on day 7 of display (P < 0.05) in LT muscle. The ALF group contained a greater amount of conjugated linoleic acid (CLA), C18:3 n−3, C20:5 n−3, C22:5 n−3, and C22:6 n−3 than did the CON group (P < 0.05). We identified 41, 96 and four genes differentially expressed in LT muscle, liver, and subcutaneous fat, respectively. The most enriched biological processes in LT muscle were skeletal muscle tissue development, being the genes related to catabolic and lipid processes downregulated, except for CPT1B, which was upregulated in the ALF lambs. Animals grazing alfalfa had lower expression of desaturase enzymes in the liver (FADS1 and FADS2), which regulate unsaturation of fatty acids and are directly involved in the metabolism of n−3 PUFA series. The results found in the current study showed that ingesting diets richer in n−3 PUFA might have negative effects on the de novo synthesis of n−3 PUFA by downregulating the FADS1 and FADS2 expression. However, feeding diets poorer in n−3 PUFA can promote fatty acid desaturation, which makes these two genes attractive candidates for altering the content of PUFAs in meat.

A Multi-Layered Study on Harmonic Oscillations in Mammalian Genomics and Proteomics.

Cellular, organ, and whole animal physiology show temporal variation predominantly featuring 24-h (circadian) periodicity. Time-course mRNA gene expression profiling in mouse liver showed two subsets of genes oscillating at the second (12-h) and third (8-h) harmonic of the prime (24-h) frequency. The aim of our study was to identify specific genomic, proteomic, and functional properties of ultradian and circadian subsets. We found hallmarks of the three oscillating gene subsets, including different (i) functional annotation, (ii) proteomic and electrochemical features, and (iii) transcription factor binding motifs in upstream regions of 8-h and 12-h oscillating genes that seemingly allow the link of the ultradian gene sets to a known circadian network. Our multifaceted bioinformatics analysis of circadian and ultradian genes suggests that the different rhythmicity of gene expression impacts physiological outcomes and may be related to transcriptional, translational and post-translational dynamics, as well as to phylogenetic and evolutionary components.

A Comparative Analysis of Gene Expression Profile in Liver and Esophageal Cancer using Expressed Sequence Tags

A Comparative Analysis of Gene Expression Profile in Liver and Esophageal Cancer using Expressed Sequence Tags

Lack of monoacylglycerol lipase prevents hepatic steatosis by favoring lipid storage in adipose tissue and intestinal malabsorption

Monoacylglycerol lipase (MGL) is the rate-limiting enzyme in the degradation of monoacylglycerols. To examine the role of MGL in hepatic steatosis, WT and MGL KO (MGL-/-) mice were challenged with a Western diet (WD) over 12 weeks. Lipid metabolism, inflammation, and fibrosis were assessed by serum biochemistry, histology, and gene-expression profiling of liver and adipose depots. Intestinal fat absorption was measured by gas chromatography. Primary adipocyte and 3T3-L1 cells were analyzed by flow cytometry and Western blot. Human hepatocytes were treated with MGL inhibitor JZL184. The absence of MGL protected mice from hepatic steatosis by repressing key lipogenic enzymes in liver (Srebp1c, Pparγ2, and diacylglycerol O-acyltransferase 1), while promoting FA oxidation. Liver inflammation was diminished in MGL-/- mice fed a WD, as evidenced by diminished epidermal growth factor-like module-containing mucin-like hormone receptor-like 1 (F4/80) staining and C-C motif chemokine ligand 2 gene expression, whereas fibrosis remained unchanged. Absence of MGL promoted fat storage in gonadal white adipose tissue (gWAT) with increased lipogenesis and unchanged lipolysis, diminished inflammation in gWAT, and subcutaneous AT. Intestinal fat malabsorption prevented ectopic lipid accumulation in livers of MGL-/- mice fed a WD. In vitro experiments demonstrated increased adipocyte size/lipid content driven by PPARγ. In conclusion, our data uncover that MGL deletion improves some aspects of nonalcoholic fatty liver disease by promoting lipid storage in gWAT and fat malabsorption.

1855-P: Effects of Dapagliflozin and/or Insulin Glargine on Hepatic Steatosis in db/db Mice

Background: Although several studies have shown that SGLT2 inhibitors exert ameliorating effects on hepatic steatosis, the mechanism remains unknown. Therefore, we compare the glucose-lowering effects of the SGLT2 inhibitor, dapagliflozin on hepatic steatosis with those of insulin glargine. Methods: Six-week-old db/db mice were assigned to one of four groups: untreated (Placebo), treated with dapagliflozin (Dapa), treated with insulin glargine (Gla), and treated with both dapagliflozin and insulin glargine (Dapa+Gla). After 8 weeks of treatment, blood glucose levels, liver triglyceride (TG) content and liver gene expression profiles were examined. Results: Fed blood glucose levels were significantly lower in the three treatment groups compared with the Placebo group (Placebo 904.2 ± 35.6, Dapa 425.0 ± 26.7, Gla 406.1 ± 25.8, Dapa+Gla 347.3 ± 24.0 mg/dL). HE staining and oil red O staining of the liver revealed that there was high fat and lipid droplets accumulation in the Gla group compared with that in the other three groups. The liver TG content was significantly increased in the Gla group compared with the others (Placebo 24.1 ± 5.7, Dapa 30.6 ± 6.4, Gla 128 ± 25, and Dapa+Gla 54.4 ± 7.1 mg per gram liver). Microarray analysis revealed that Cidea, Cidec and Mogat1 were upregulated in the Gla group compared with the Placebo group. Real-time quantitative PCR revealed that expression levels associated in fatty acid synthesis, such as Fas, Elovl6, Scd1 and Mogat1 significantly upregulated in the Gla group compared with the Placebo group. As for the expression levels of genes related to fatty acid uptake and storage, Cidea and Cidec, elevated in the Gla group compared with the Placebo group. Pparg2, which is associated with Fas, Elovl6, Scd1, Mogat1 and Cidec significantly increased in the Gla group compared with the Placebo group. Conclusion: Hepatic steatosis was prevented in db/db mice, after 8 weeks of treatment with dapagliflozin and/or insulin glargine, but not with insulin glargine alone. Disclosure K. Omori: None. A. Nakamura: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Ono Pharmaceutical Co., Ltd. H. Miyoshi: Research Support; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceutical Europe Co. Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceutical Europe Co. Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. H. Nomoto: None. H. Kameda: None. K. Cho: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi &amp; Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi &amp; Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. T. Atsumi: Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Takeda Pharmaceutical Company Limited, UCB, Inc. Funding AstraZeneca

Effect of Ephedrae Herba methanol extract on high-fat diet-induced hyperlipidaemic mice

Context: Ephedrae Herba (EH), the dried stems and leaves of Ephedra sinica Stapf., E. intermedia Schrenk et C. A. Mey., or E. equisetina Bge. (Ephedraceae [Ephedra]) is used to treat respiratory diseases. Recently, especially in the Republic of Korea, EH has also been used for weight reduction.Objective: We evaluated the effects and molecular targets of methanol EH extract (EHM) on high-fat diet (HFD)-induced hyperlipidemic ICR mice.Materials and methods: EHM was orally administered (100 mg/kg body weight/day) for 3 weeks. We observed changes in body weight (BW), total cholesterol (TC), high-density lipoprotein–cholesterol, and triglycerides to evaluate the physiological changes induced by HFD or EHM administration. To evaluate lipid peroxidation and liver toxicity, malondialdehyde and blood alanine aminotransferase levels were measured. In addition to analyzing liver gene expression profiles, EHM target proteins were identified using a protein interaction database.Results: EHM administration for 3 weeks significantly (p < 0.05) decreased TC and triglyceride levels without altering BW in mice, and gene expression levels in the livers of EHM-treated mice were restored at 34.0% and 48.4% of those up- or down-regulated by hyperlipidaemia, respectively. Proteins related to DNA repair and energy metabolism were identified via protein interaction network analysis as molecular targets of EHM that play key roles in ameliorating hyperlipidaemia.Discussion and conclusions: EHM regulated hyperlipidaemia by decreasing total blood lipid and triglyceride levels in hyperlipidaemic mice. EHM showed preventive effects against hyperlipidaemia in mice, possibly via the regulation of DNA repair and the expression of energy metabolism-related genes and proteins.

Defective Autophagy in T Cells Impairs the Development of Diet-Induced Hepatic Steatosis and Atherosclerosis.

Macroautophagy (or autophagy) is a conserved cellular process in which cytoplasmic cargo is targeted for lysosomal degradation. Autophagy is crucial for the functional integrity of different subsets of T cells in various developmental stages. Since atherosclerosis is an inflammatory disease of the vessel wall which is partly characterized by T cell mediated autoimmunity, we investigated how advanced atherosclerotic lesions develop in mice with T cells that lack autophagy-related protein 7 (Atg7), a protein required for functional autophagy. Mice with a T cell-specific knock-out of Atg7 (Lck-Cre Atg7f/f) had a diminished naïve CD4+ and CD8+ T cell compartment in the spleen and mediastinal lymph node as compared to littermate controls (Atg7f/f). Lck-Cre Atg7f/f and Atg7f/f mice were injected intravenously with rAAV2/8-D377Y-mPCSK9 and fed a Western-type diet to induce atherosclerosis. While Lck-Cre Atg7f/f mice had equal serum Proprotein Convertase Subtilisin/Kexin type 9 levels as compared to Atg7f/f mice, serum cholesterol levels were significantly diminished in Lck-Cre Atg7f/f mice. Histological analysis of the liver revealed less steatosis, and liver gene expression profiling showed decreased expression of genes associated with hepatic steatosis in Lck-Cre Atg7f/f mice as compared to Atg7f/f mice. The level of hepatic CD4+ and CD8+ T cells was greatly diminished but both CD4+ and CD8+ T cells showed a relative increase in their IFNγ and IL-17 production upon Atg7 deficiency. Atg7 deficiency furthermore reduced the hepatic NKT cell population which was decreased to < 0.1% of the lymphocyte population. Interestingly, T cell-specific knock-out of Atg7 decreased the mean atherosclerotic lesion size in the tri-valve area by over 50%. Taken together, T cell-specific deficiency of Atg7 resulted in a decrease in hepatic steatosis and limited inflammatory potency in the (naïve) T cell compartment in peripheral lymphoid tissues, which was associated with a strong reduction in experimental atherosclerosis.

Maternal High-Protein and Low-Protein Diets Perturb Hypothalamus and Liver Transcriptome and Metabolic Homeostasis in Adult Mouse Offspring.

Early life nutritional imbalances are risk factors for metabolic dysfunctions in adulthood, but the long term effects of perinatal exposure to high versus low protein diets are not completely understood. We exposed C57BL/6J offspring to a high protein/low carbohydrate (HP/LC) or low protein/high carbohydrate (LP/HC) diet during gestation and lactation, and measured metabolic phenotypes between birth and 10 months of age in male offspring. Perinatal HP/LC and LP/HC exposures resulted in a decreased ability to clear glucose in the offspring, with reduced baseline insulin and glucose concentrations in the LP/HC group and a reduced insulin response post-glucose challenge in the HP/LC group. The LP/HC diet group also showed reduced birth and weanling weights, whereas the HP/LC offspring displayed increased weanling weight with increased adiposity beyond 5 months of age. Gene expression profiling of hypothalamus and liver revealed alterations in diverse molecular pathways by both diets. Specifically, hypothalamic transcriptome and pathway analyses demonstrated perturbations of MAPK and hedgehog signaling, processes associated with neural restructuring and transmission, and phosphate metabolism by perinatal protein imbalances. Liver transcriptomics revealed changes in purine and phosphate metabolism, hedgehog signaling, and circadian rhythm pathways. Our results indicate maternal protein imbalances perturbing molecular pathways in central and peripheral metabolic tissues, thereby predisposing the male offspring to metabolic dysfunctions.

Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD

ObjectiveBile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are...

In Vivo Analysis of miR-34a Regulated Glucose Metabolism Related Genes in Megalobrama amblycephala.

The Megalobrama amblycephala (M. amblycephala) is one of the most important economic freshwater fish in China. The molecular mechanism under the glucose intolerance responses which affects the growth performance and feed utilization is still confused. miR-34a was reported as a key regulator in the glucose metabolism, but how did the miR-34a exert its function in the metabolism of glucose/insulin in M. amblycephala was still unclear. In this study, we intraperitoneally injected the miR-34a inhibitor (80 nmol/100 g body weight) into M. amblycephala (fed with high starch diet, 45% starch) for 12 h, and then analyzed the gene expression profiling in livers by RNA-seq. The results showed that miR-34a expression in M. amblycephala livers was inhibited by injection of miR-34a inhibitor, and a total of 2212 differentially expressed genes (DEGs) were dysregulated (including 1183 up- and 1029 downregulated DEGs). Function enrichment analysis of DEGs showed that most of them were enriched in the peroxisome proliferator-activated receptor (PPAR), insulin, AMP-activated protein kinase (AMPK) and janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways, which were all associated with the glucose/lipid metabolic and biosynthetic processes. In addition, we examined and verified the differential expression levels of some genes involved in AMPK signaling pathway by qRT-PCR. These results demonstrated that the inhibition of miR-34a might regulate glucose metabolism in M. amblycephala through downstream target genes.

Expression of Genes Encoding for Xenobiotic Metabolism After Exposure to Dialkylnitrosamines in the Chicken Egg Genotoxicity Alternative Model.

The Chicken Egg Genotoxicity Assay (CEGA) demonstrated responsiveness to various DNA-reactive chemicals requiring metabolic activation, which implies broad bioactivation capability. To assess potential metabolic competence, expression profiles of metabolic genes in the embryo-chicken fetal liver were determined using microarray technology. Fertilized chicken eggs were injected under the CEGA protocol with vehicle (deionized water [DW]), the activation-dependent carcinogens, diethylnitrosamine (DEN), and N-nitrosodiethanolamine (NDELA) at doses producing no effect on survival. Previously in CEGA, DEN produced DNA damage, whereas NDELA did not. Expressions of 463 genes known to encode for phase I and II of endo- and xenobiotic metabolism were detected on the array. DW did not affect the expression of the selected genes, deregulating less than 1% of them. In contrast, DEN at 2 mg/egg and NDELA at 4 mg/egg produced significant transcriptomic alterations, up-regulating up to 41% and down-regulating over 31% of studied genes. Both nitrosamines modulated the majority of the genes in a similar manner, sharing 64 up-regulated and 93 down-regulated genes with respect to control group, indicating similarity in the regulation of their metabolism by avian liver. Differences in gene expression between DEN and NDELA were documented for several phase I CYP 450 genes that are responsible for nitrosamine biotransformation, as well as for phase II genes that regulate detoxication reactions. These findings could underlie the difference in genotoxicity of DEN and NDELA in CEGA. In conclusion, the analysis of gene expression profiles in embryo-chicken fetal liver dosed with dialkylnitrosamines demonstrated that avian species possess a complex array of inducible genes coding for biotransformation.

Skeletal muscle and liver gene expression profiles in finishing steers supplemented with Amaize.

Our main objective was to evaluate the effects of feeding α-amylase (Amaize, Alltech Inc., Nicholasville, KY, USA) for 140days on skeletal muscle and liver gene transcription in beef steers. Steers fed Amaize had lower average daily gain (p=.03) and gain:feed ratio (p=.05). No differences (p>.10) in serum metabolites or carcass traits were detected between the two groups but Amaize steers tended (p<.15) to have increased 12th rib fat depth. Microarray analysis of skeletal muscle revealed 21 differentially expressed genes (DEG), where 14 were up-regulated and seven were down-regulated in Amaize-fed steers. The bioinformatics analysis indicated that metabolic pathways involved in fat formation and deposition, stress response, and muscle function were activated, while myogenesis was inhibited in Amaize-fed steers. The quantitative PCR results for liver revealed a decrease (p<.01) in expression of fatty acid binding protein 1 (FABP1) and 3-hydroxybutyrate dehydrogenase 1 (BDH1) with Amaize. Because these genes are key for intracellular fatty acid transport, oxidation and ketone body production, data suggest a reduction in hepatic lipid catabolism. Future work to investigate potential positive effects of Amaize on cellular stress response, muscle function, and liver function in beef cattle appears warranted.

Toxicity and Transcriptome Sequencing (RNA-seq) Analyses of Adult Zebrafish in Response to Exposure Carboxymethyl Cellulose Stabilized Iron Sulfide Nanoparticles

Increasing utilization of stabilized iron sulfides (FeS) nanoparticles implies an elevated release of the materials into the environment. To understand potential impacts and underlying mechanisms of nanoparticle-induced stress, we used the transcriptome sequencing (RNA-seq) technique to characterize the transcriptomes from adult zebrafish exposed to 10 mg/L carboxymethyl cellulose (CMC) stabilized FeS nanoparticles for 96 h, demonstrating striking differences in the gene expression profiles in liver. The exposure caused significant expression alterations in genes related to immune and inflammatory responses, detoxification, oxidative stress and DNA damage/repair. The complement and coagulation cascades Kyoto encyclopedia of genes and genomes (KEGG) pathway was found significantly up-regulated under nanoparticle exposure. The quantitative real-time polymerase chain reaction using twelve genes confirmed the RNA-seq results. We identified several candidate genes commonly regulated in liver, which may serve as gene indicators when exposed to the nanoparticles. Hepatic inflammation was further confirmed by histological observation of pyknotic nuclei, and vacuole formation upon exposure. Tissue accumulation tests showed a 2.2 times higher iron concentration in the fish tissue upon exposure. This study provides preliminary mechanistic insights into potential toxic effects of organic matter stabilized FeS nanoparticles, which will improve our understanding of the genotoxicity caused by stabilized nanoparticles.

A novel nutrient blend mimics calorie restriction transcriptomics in multiple tissues of mice and increases vitality and lifespan in C. elegans

Identification of caloric restriction mimetics (CRMs), compounds that mimic the beneficial effects of caloric restriction (CR) without limiting energy intake would be a scientific advancement. This study investigated transcriptomics elicited by a putative CRM nutrient blend compared to CR in diverse tissues following long-term feeding in 4 groups of B6C3F1 mice: Young Controls (YC; 5 months) and 3 groups treated from 14–30 months: Old Controls (OC), Old CR (OCR; 25% CR) and Old Supplemented (OS). Gene expression profiling in cerebral cortex (CC), skeletal muscle (SKL), heart (HRT), white adipose (WAT)and liver (LVR) was performed with Affymetrix Mouse 2.0ST arrays. This was followed by a dose-response study in C. elegans investigating longevity and mobility. Principal component analysis revealed that gene expression profiles of YC and OC were distinct from one another in all tissues except WAT at 30 months. The OS mimicked OCR transcriptomics most dramatically in tissues most relevant to aging and age-associated diseases, CCT, HRT and SKL. In C. elegans, the blend mimicked the known benefits of CR, increasing lifespan and vitality in a dose-dependent manner. These CRM effects may have positive implications for healthy human aging or ‘youthspan’ and warrant further investigation.

Gene expression profiling of rat livers after continuous whole-body exposure to low-dose rate of gamma rays

Purpose: To study gene expression modulation in response to continuous whole-body exposure to low-dose-rate gamma radiation and improve our understanding of the mechanism of this impact at the molecular basis.Materials and methods: cDNA microarray method with complete pooling of samples was used to study expression changes in the transcriptome profile of livers from rats treated with prolonged low-dose-rate ionizing radiation (IR) relative to that of sham-irradiated rats.Results: Of the 209 genes that were two-fold-up or down-regulated, 143 were known genes of which 27 were found in previous literatures to be modulated by IR. Remarkably, there were a significant number of differentially expressed genes involved in hepatic lipid metabolism.Conclusion: This study showed changes in transcriptome profile of livers from low-dose irradiated rats when compared with that of sham-irradiated ones. This study will be useful for studying the metabolic changes of human exposed for long term to cosmic ray such as in space and in polar regions.

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

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.

Serum biochemistry, histology and transcriptomic profile analysis reflect liver inflammation and damage following dietary histamine supplementation in yellow catfish (Pelteobagrus fulvidraco)

Previous studies suggested that diets containing high levels of histamine influenced digestive system of aquatic animals. In addition, the exogenous histamine was first detoxified by diamine oxidase in the intestine, while the rest of histamine was further detoxified in the liver. Thus, based on the evidence from the previous studies, we hypothesized that high levels of histamine may lead to damage on liver of the aquatic animals. Here, in current attempt, we sought to investigate the toxic effect of histamine on yellow catfish (Pelteobagrus fulvidraco) liver physiology and pathogenesis. In the present study, yellow catfish were fed for 56 days on diets supplemented with 1000 mg kg−1 histamine (His) or a basal diet as the control group (Con). A significant change on the morphology of the intestine and liver was observed, followed with an induction of serum activity of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Furthermore, the transcriptomic analysis was performed to gain an overview of the gene expression profile in liver between control and histamine supplemented groups. Through the bioinformatics analysis, 431 differentially expressed genes were identified. Among these genes, Gene Ontology enrichment analysis (GO) suggests that immune-related genes are significantly dysregulated. In addition, TNF signaling pathway is enriched in Kyoto Encyclopedia of Genes and Genomes analysis (KEGG), and is also the dominant pathway in immune system, suggesting that the inflammatory response and apoptosis of hepatocytes are induced by exogenous histamine.

Dietary grape seed proanthocyanidin extract regulates metabolic disturbance in rat liver exposed to lead associated with PPARα signaling pathway

Lead, a pervasive environmental hazard worldwide, causes a wide range of physiological and biochemical destruction, including metabolic dysfunction. Grape seed proanthocyanidin extract (GSPE) is a natural production with potential metabolic regulation in liver. This study was performed to investigate the protective role of GSPE against lead-induced metabolic dysfunction in liver and elucidate the potential molecular mechanism of this event. Wistar rats received GSPE (200 mg/kg) daily with or without lead acetate (PbA, 0.5 g/L) exposure for 56 d. According to biochemical and histopathologic analysis, GSPE attenuated lead-induced metabolic dysfunction, oxidative stress, and liver dysfunction. Liver gene expression profiling was assessed by RNA sequencing and validated by qRT-PCR. Expression of some genes in peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway was significantly suppressed in PbA group and revived in PbA + GSPE group, which was manifested by Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis and validated by western blot analysis. This study supports that dietary GSPE ameliorates lead-induced fatty acids metabolic disturbance in rat liver associated with PPARα signaling pathway, and suggests that dietary GSPE may be a protector against lead-induced metabolic dysfunction and liver injury, providing a novel therapy to protect liver against lead exposure.

Oryzanol Modifies High Fat Diet-Induced Obesity, Liver Gene Expression Profile, and Inflammation Response in Mice.

In Western countries and China, the dietary habit of high calories usually results in hyperlipidemia, which is closely associated with cardiovascular diseases. In the study, we investigated the antihyperlipidemic effect of oryzanol and its molecular mechanism in the high fat diet (HFD) mouse model. In total, 60 ICR mice were randomly divided into control group, HFD group, and HFD+Ory group. The mice from the HFD+Ory group were additionally fed with 100 mg/kg of oryzanol by intragastric administration. Our data indicated that oryzanol treatment for 10 weeks significantly reduced bodyweight, liver weight, and adipose tissues weight of the mice; lowered the contents of total cholesterol (TC), triglycerides (TG), and low density lipoprotein-cholesterol (LDL-C); and elevated high density lipoprotein-cholesterol (HDL-C) in the plasma of HFD mice. Compared with the HFD group, H&E staining showed that oryzanol treatment decreased the size of fat droplets of liver tissues and the size of adipocytes. Gene chip data found that oryzanol administration caused 32 genes to increase expressions while 60 genes had reduced expressions in the liver tissues of HFD mice. IPA software was used to analyze the protein interaction network and found that transcript factor NF-κB located in the central role of network, meaning NF-κB may have important function in the lipid-lowering effect of oryzanol. Western blotting and RT-qPCR confirmed that lipid metabolism-related gene expressions were obviously regulated by oryzanol administration. Oryzanol also inhibited expressions of inflammatory factor in the liver tissues of HDF mice. Taken together, our data indicate that oryzanol treatment can regulate lipid metabolism-related gene expressions and inhibit HDF-caused obesity in mice.