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Influence of dietary sucrose and copper content in a rat model of non-alcoholic fatty-liver disease

ABSTRACT: Nutrigenomics analysis was used to investigate the molecular responses to dietary Cu deficiency independently and in combination with 30% (w/w) sucrose in a mature rat model of NAFLD. Low Cu significantly decreased hepatic and serum Cu, and induced NAFLD-like histopathology, mild steatosis, up-regulated transcripts in inflammation and hepatic stellate cell activation, and significantly increased oxidative stress. Rats fed low Cu together with 30% sucrose also developed insulin resistance, increased ATP citrate lyase and FASN expression, and greater oxidative stress. High sucrose with adequate Cu also promoted inflammation and fibrosis, but not steatosis. This study indicates that low dietary Cu and sucrose consumption are singular and synergistic dietary factors in promotion of NAFLD and NASH that act independently of obesity or severe steatosis, likely by promoting oxidative stress and activation of inflammation and fibrosis. Mature (6 months old) male Wistar Rats that had been allowed ad libitum access to Mazuri rodent pellets were used in the study. Twenty-four rats were divided into four groups and fed for 12 weeks with diets based on the Purified AIN76A formulation, modified for target sucrose and Cu content (Custom Animal Diets, Bangor, NJ). Sucrose and copper content in diets were as follows: ‘A’ CuD/30%- Cu deficient (<0.3 mg Cu/kg)/30% sucrose, ‘B’ CuA/30%- Cu adequate (125 mg/kg)/30% sucrose, ‘C’ CuD/10%- <0.3 mg/kg Cu/10% sucrose, and ‘D’ CuA (125 mg/kg Cu)/10% sucrose (control). Starch and dextrin were used to equalize carbohydrates.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Jason Burkhead

PROVIDER: E-GEOD-58875 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Influence of dietary sucrose and copper content in a rat model of non-alcoholic fatty-liver disease

Project description:Nutrigenomics analysis was used to investigate the molecular responses to dietary Cu deficiency independently and in combination with 30% (w/w) sucrose in a mature rat model of NAFLD. Low Cu significantly decreased hepatic and serum Cu, and induced NAFLD-like histopathology, mild steatosis, up-regulated transcripts in inflammation and hepatic stellate cell activation, and significantly increased oxidative stress. Rats fed low Cu together with 30% sucrose also developed insulin resistance, increased ATP citrate lyase and FASN expression, and greater oxidative stress. High sucrose with adequate Cu also promoted inflammation and fibrosis, but not steatosis. This study indicates that low dietary Cu and sucrose consumption are singular and synergistic dietary factors in promotion of NAFLD and NASH that act independently of obesity or severe steatosis, likely by promoting oxidative stress and activation of inflammation and fibrosis.

2015-06-26 | GSE58875 | GEO

Nutritional Strategy to Prevent Fatty Liver and Insulin Resistance Independent of Obesity by Reducing GIP Responses

Project description:High intakes of carbohydrates, particularly sucrose, in Western societies are associated with the development of non-alcoholic fatty liver (NAFL) and diabetes mellitus. It is unclear whether this is related to the carbohydrate quantity or the hormonal responses, particularly Glucose-dependent Insulinotropic Polypeptide (GIP) which is released in the proximal intestine. We, therefore, used the glucose-fructose dimer as proximally resorbed, 1,4-linked sucrose or distally resorbed 1,6-linked palatinose. Palatinose compared to sucrose, indeed, resulted in slower glucose absorption and reduced postprandial insulin and GIP levels. After 22 weeks of isocaloric diets, palatinose feeding prevented hepatic steatosis (48.5%) compared to sucrose and improved glucose tolerance, without differences in body composition and food intake. Ablation of GIP receptor (GIPR) signaling in Gipr-/- mice completely prevented the deleterious metabolic effects of sucrose feeding. Furthermore, our microarray analysis indicated that sucrose increased the hepatic expression of Suppressor of Cytokine Signaling 2 (SOCS2), which is involved in the growth hormone signaling pathway and participates in the development of NAFL. Our results suggest that the site of glucose absorption and the GIP response determine liver fat accumulation and insulin resistance. GIP may play a role in sucrose induced fatty liver by regulating the expression of SOCS2. Expression data from liver tissue of mice fed with isocaloric diets containing either sucrose or palatinose

2014-12-05 | E-GEOD-54723 | biostudies-arrayexpress

Role of Farnesoid X Receptor (FXR) in Valproic acid-induced Hepatotoxicity

Project description:Drug-induced steatosis and steatohepatitis manifest clinically as nonalcoholic fatty liver disease (NAFLD). Drugs associated with steatosis include valproic acid (VPA). VPA has been one of the most widely used antiepileptic drugs over the past 40 years. However, clinical follow-up studies have reported that more than 40% of patients who received VPA also developed fatty liver disease. Steatosis is a typical clinical effect of VPA treatment and is characterized by an abnormal accumulation of lipids in liver cells. The aim of this study is to investigate whether activation of the farnesoid X receptor (FXR) by obeticholic acid (OCA), which is an effective agent in the treatment of NAFLD, can also prevent VPA-induced steatosis. OCA is a synthetic bile acid derivative that potently activates FXR and the FXR-regulated pathways that maintain bile acid, lipid and glucose homeostasis. Female C57BL/6 mice were fed a standard chow diet or chow containing OCA (dose 250 mg/kg body weight) for four weeks. Each group was then divided into two sub-groups: one co-treated with VPA (dose 100 mg/kg body weight) and another treated with the same volume of H2O by oral gavage daily for an additional four weeks. Mice liver were isolated and RNA isolated for RNA-Seq.

2020-05-01 | GSE138810 | GEO

High intake of dietary sucrose induces sexually dimorphic metabolic adaptations in liver and adipose tissue

Project description:This data submission reports the effects of 12 weeks supplementaion of 10%w/v sucrose supplied in drinking water on the inguinal white adipose tissue mRNA profiles of male and female mice relative to control groups (littermates that received plain water instead). RNAseq was performed by Novogene and investigators performed all analyses downstream of readcount acquisition. Manuscript abstract: Almost all effective treatments for non-alcoholic fatty liver disease (NAFLD) involve reduction of adiposity, which suggests the metabolic axis between liver and adipose tissue is essential to NAFLD development. Since excessive dietary sugar intake may be an initiating factor for NAFLD, we have characterized the metabolic effects of liquid sucrose intake at concentrations relevant to typical human consumption in mice. We report that sucrose intake induces sexually dimorphic effects in liver, adipose tissue, and the microbiome; differences concordant with steatosis severity. We show that when steatosis is decoupled from impairments in insulin responsiveness, sex is a moderating factor that influences sucrose-driven lipid storage and the contribution of de novo fatty acid synthesis to the overall hepatic triglyceride pool. Our findings provide physiologic insight into how sex influences the regulation of adipose-liver crosstalk and highlight the importance of extrahepatic metabolism in the pathogenesis of diet-induced steatosis and NAFLD.

2021-03-01 | GSE151358 | GEO

Diminazene aceturate (DIZE) stabilizes atherosclerotic plaques and attenuates hepatic steatosis in apolipoprotein E knockout mice by influencing macrophages polarization and taurine biosynthesis

Project description:Atherosclerosis and nonalcoholic fatty liver disease (NAFLD) are leading causes of morbidity and mortality in the Western countries. NAFLD is an important independent risk factor for the development of atherosclerosis. The renin-angiotensin system (RAS) with its two main opposing effectors: angiotensin II (Ang II) and Ang-(1-7) is widely recognized as a major regulator of cardiovascular function and body metabolic processes. Angiotensin-converting enzyme 2 (ACE2) by breaking-down Ang II forms Ang-(1-7) and thus favors Ang-(1-7) actions. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with ACE2 activator – diminazene aceturate (DIZE) on the development of atherosclerotic lesions and hepatic steatosis in apoE-/- mice fed a high-fat diet (HFD). We have shown that DIZE at a dose of 30 mg/kg/day given orally for 16 weeks was able to stabilize atherosclerotic lesions and attenuate hepatic steatosis in apoE-/- mice fed an HFD. Such effects were associated with decreased total macrophages content and increased α-smooth muscle actin levels in atherosclerotic plaques. Moreover, DIZE changed polarization of macrophages towards increased amount of anti-inflammatory M2 macrophages in atherosclerotic lesions. Interestingly, the anti-steatotic action of DIZE in the liver was related to the elevated HDL in the plasma, decreased triglycerides levels and increased biosynthesis and concentration of taurine in liver of apoE-/- mice. However, the exact molecular mechanisms of both the anti-atherosclerotic and anti-steatotic actions of DIZE require further investigations.

2021-09-09 | PXD022829 | Pride

Classifying distinct grades of human non-alcoholic fatty liver disease employing a systems biology approach

Project description:With an estimated prevalence of about 30% in western countries non-alcoholic fatty liver disease (NAFLD) is a major public health issue [PMID: 18956290]. NAFLD is associated with the metabolic syndrome of insulin resistance, obesity, glucose intolerance. Although many studies are pointing to an induction of insulin resistance by NAFLD causality between both phenotypes is not fully clarified. Furthermore, mechanisms leading to strongly differing progression of NAFLD have to be elucidated which range from mild steatosis up to severe steatohepatitis. Steatohepatitis might even result in liver cirrhosis and hepatocellular carcinoma. Additional complexity is introduced into the understanding of the disease by recent studies providing evidence for a direct development of carcinoma from steatosis without the formerly assumed intermediary phase of cirrhosis. Here, we investigate liver samples from patients with varying severities of steatosis in an integrative approach employing transcriptomics, serum biomarker profling, metabolomics data and systems biology models. Total RNA obtained from hepatocytes derived from nine obese patients with distinct grades of steatosis. This dataset is part of the TransQST collection.

2015-11-01 | E-GEOD-46300 | biostudies-arrayexpress

A cytoplasmic chemoreceptor and Reactive Oxygen Species mediate bacterial chemotaxis to copper

Project description:Chemotaxis is a widespread strategy used by unicellular and multicellular living organisms to maintain their fitness in stressful environments. We previously showed that bacteria can trigger a negative chemotactic response to a copper (Cu)-rich environment. Cu ions toxicity on bacterial cell physiology has been mainly linked to mismetallation events and ROS production, although the precise role of Cu-generated ROS remains largely debated. Here, we found that the cytoplasmic Cu ions content mirrors variations of the extracellular Cu ions concentration and triggers a dose-dependent oxidative stress, which can be abrogated by superoxide dismutase and catalase overexpression. The inhibition of ROS production in the cytoplasm not only improves bacterial growth but also impedes Cu-chemotaxis, indicating that ROS derived from cytoplasmic Cu ions mediate the control of bacterial chemotaxis to Cu. We also identified the Cu chemoreceptor McpR, which binds Cu ions with low affinity, suggesting a labile interaction. In addition, we demonstrate that the cysteine 75 and histidine 99 within the McpR sensor domain are key residues in Cu chemotaxis and Cu coordination. Finally, we discovered that in vitro both Cu(I) and Cu(II) ions modulate McpR conformation in a distinct manner. Overall,our study provides mechanistic insights on a redox-based control of Cu chemotaxis, indicating that the cellular redox status can play a key role in bacterial chemotaxis.

2023-09-05 | PXD044512 | Pride

Transcription profiling of copper-stressed Pseudomonas aeruginosa

Project description:Anthropogenic pollution has increased the levels of heavy metals in the environment. Bacterial populations continue to thrive in highly polluted environments and bacteria must have mechanisms to counter heavy metal stress. We chose to examine the response of the environmentally-relevant organism Pseudomonas aeruginosa to two different copper treatments. A short, 45 min exposure to copper was done in the Cu shock treatment to examine the immediate transcriptional profile to Cu stress. The Cu adapted treatment was designed to view the transcriptional profile of cells that were actively growing in the presence of Cu. Experiment Overall Design: We analyzed 2 biological replicates of Pseudomonas aeruginosa exposed to a 45 min Cu shock as compared to a control that was exposed to HCl to bring the pH to similar levels. We analyzed 2 biological replicates of Pseudomonas aeruginosa that were grown in the presence of Cu for approx. 6h (Cu adapted) as compared to an untreated control.

2007-10-24 | E-GEOD-4152 | biostudies-arrayexpress

Transcription profiling of Danio rerio livers following exposure to combinations of copper, sodium and calcium

Project description:Zebrafish (n=420; 70/treatment) were weighed and placed in 8L aerated tanks, served with flow-through soft-water at 25ml/min. A combination of Mariotte bottles were used to dose tanks with Cu (concentrated Cu solution made from CuSO4 dissolved in 0.05% HNO3), Na (concentrated NaCl solution), and Ca (concentrated CaCl2 solution) to 6 treatment regimes of either control (Ctrl), Cu only (Cu), high Ca only (Ca), Ca + Cu (CaCu), high Na only (Na), and Na + Cu (NaCu; See Table 1 for ion concentrations). Nitric acid had no measurable impact on water pH. Fish were fed 2% body weight of commercial tropical fish food, once per day. Tanks were monitored daily for mortality and cleaned of any food or waste that had accumulated. Water samples (10 ml) were taken from each tank, filtered though a 0.45?m filtration disc (Pall Corporation, East Hills, NY), added to a plastic tube containing 100?l HNO3 and kept at 4oC for analysis of ion content and Cu concentration. Throughout the experiment, there were no mortalities in any of the tanks. At the end of the exposure period, fish were quickly euthanized by overdose of buffered aesthetic (MS-222, Sigma) and sampled for gill, liver, and gut, which were immediately frozen in liquid N2 for further analysis of Cu burden, gene expression, and enzyme activity.

2009-09-01 | E-MEXP-2288 | biostudies-arrayexpress

Contrasting Effects of Acclimated Copper Limitation on the Photosynthetic Apparatus in Two Strains of the open ocean diatom Thalassiosira oceanica

Project description:The physiological adaptations of diatoms to cope with Cu limitation are largely unknown. In the present study we investigated the response to Cu limitation in two strains of the model open ocean diatom T. oceanica (CCMP 1003 and CCMP 1005), focusing on physiological and proteomic changes in the photosynthetic apparatus. Our results show remarkable differences between the adaptations of TO05 and TO03 to low Cu, highlighting significant intra specific variations.

2017-08-15 | PXD006237 | Pride

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