Chronological Appearance of Endocrine and Metabolic Dysfunctions Induced by an Unhealthy Diet in Rats

Background and Objectives: The work was aimed to determine the chronological sequence of events triggered by a fructose-rich diet (FRD) (10% w/v in the drinking water) in normal rats. Material and Methods: Serum parameters, liver and islet markers of metabolism, inflammation and oxidative stress were determined weekly for 21 days. Results: At the end of the first week, rats fed with a FRD showed an early increase in circulating triglycerides, fat liver deposit, and enzymatic activity of liver glucokinase and glucose-6-phosphate dehydrogenase (G6P-DH). After two weeks of such a diet, liver glucose-6-phosphatase (G6Pase) activity and liver oxidative stress markers were significantly increased. Liver sterol regulatory element-binding protein 1c (SREBP1c) mRNA also increased in the second week while their target genes fatty acid synthase (FAS) and glycerol-3-phosphate dehydrogenase (GPAT) enhanced their expression at the third week. Liver and pancreatic inflammation markers also enhanced their gene expression in the last week of treatment. Whereas both control and FRD rats remained normoglycemic throughout the entire period of treatment, blood insulin levels were significantly higher in FRD animals at the third week, thereby evidencing an insulin-resistant state (higher HOMA-IR, HOMA-B and HIS indexes). Pancreatic islets isolated from rats fed with a FRD for 3 weeks also increased glucose-induced insulin secretion (8.3 and 16.7 mM). Conclusions: FRD induces asynchronous changes involving early hypertriglyceridemia together with intrahepatic lipid deposit and metabolic disturbances from week one, followed by enhanced liver oxidative stress, liver and pancreas inflammation, pancreatic β-cell dysfunction, and peripheral insulin-resistance registered at the third week. Knowledge of time-course adaptation mechanisms involved in our rat model could be helpful in developing appropriate strategies to prevent the progression from prediabetes to Type 2 diabetes (T2D) triggered by unhealthy diets.

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Regulation of the SREBP transcription factors by mTORC1

Biochemical Society Transactions ◽

10.1042/bst0390495 ◽

2011 ◽

Vol 39 (2) ◽

pp. 495-499 ◽

Cited By ~ 42

Author(s):

Caroline A. Lewis ◽

Beatrice Griffiths ◽

Claudio R. Santos ◽

Mario Pende ◽

Almut Schulze

Keyword(s):

Fatty Acid ◽

Fatty Acid Synthase ◽

Target Genes ◽

De Novo ◽

Regulatory Element ◽

Cholesterol Biosynthesis ◽

Mammalian Target Of Rapamycin ◽

Lipid Biosynthesis ◽

De Novo Lipogenesis ◽

Genes Encoding

In recent years several reports have linked mTORC1 (mammalian target of rapamycin complex 1) to lipogenesis via the SREBPs (sterol-regulatory-element-binding proteins). SREBPs regulate the expression of genes encoding enzymes required for fatty acid and cholesterol biosynthesis. Lipid metabolism is perturbed in some diseases and SREBP target genes, such as FASN (fatty acid synthase), have been shown to be up-regulated in some cancers. We have previously shown that mTORC1 plays a role in SREBP activation and Akt/PKB (protein kinase B)-dependent de novo lipogenesis. Our findings suggest that mTORC1 plays a crucial role in the activation of SREBP and that the activation of lipid biosynthesis through the induction of SREBP could be part of a regulatory pathway that co-ordinates protein and lipid biosynthesis during cell growth. In the present paper, we discuss the increasing amount of data supporting the potential mechanisms of mTORC1-dependent activation of SREBP as well as the implications of this signalling pathway in cancer.

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R. verniciflua and E. ulmoides Extract (ILF-RE) Protects against Chronic CCl4-Induced Liver Damage by Enhancing Antioxidation

Nutrients ◽

10.3390/nu11020382 ◽

2019 ◽

Vol 11 (2) ◽

pp. 382 ◽

Cited By ~ 4

Author(s):

Hwa-Young Lee ◽

Geum-Hwa Lee ◽

Young Yoon ◽

Han-Jung Chae

Keyword(s):

Oxidative Stress ◽

Er Stress ◽

Liver Damage ◽

Lipid Accumulation ◽

Fatty Acid Synthase ◽

Regulatory Element ◽

Protective Effects ◽

Gamma Glutamyl Transpeptidase ◽

Hepatic Lipid Accumulation ◽

Lipogenic Genes

This study aimed to characterize the protective effects of R. verniciflua extract (ILF-R) and E. ulmoides extract (ILF-E), the combination called ILF-RE, against chronic CCl4-induced liver oxidative injury in rats, as well as to investigate the mechanism underlying hepatoprotection by ILF-RE against CCl4-induced hepatic dysfunction. Chronic hepatic stress was induced via intraperitoneal (IP) administration of a mixture of CCl4 (0.2 mL/100 g body weight) and olive oil [1:1(v/v)] twice a week for 4 weeks to rats. ILF-RE was administered orally at 40, 80, and 120 mg/kg to rats for 4 weeks. Alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transpeptidase (GGT), and lipid peroxidation assays were performed, and total triglyceride, cholesterol, and LDL-cholesterol levels were quantified. Furthermore, ER stress and lipogenesis-related gene expression including sterol regulatory element-binding transcription factor 1 (SREBP-1), fatty acid synthase (FAS), and P-AMPK were assessed. ILF-RE markedly protected against liver damage by inhibiting oxidative stress and increasing antioxidant enzyme activity including glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase. Furthermore, hepatic dyslipidemia was regulated after ILF-RE administration. Moreover, hepatic lipid accumulation and its associated lipogenic genes, including those encoding SREBP-1 and FAS, were regulated after ILF-RE administration. This was accompanied by regulation of ER stress response signaling, suggesting a mechanism underlying ILF-RE-mediated hepatoprotection against lipid accumulation. The present results indicate that ILF-RE exerts hepatoprotective effects against chronic CCl4-induced dysfunction by suppressing hepatic oxidative stress and lipogenesis, suggesting that ILF-RE is a potential preventive/therapeutic natural product in treating hepatoxicity and associated dysfunction.

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Dietary chia seed induced changes in hepatic transcription factors and their target lipogenic and oxidative enzyme activities in dyslipidaemic insulin-resistant rats

British Journal Of Nutrition ◽

10.1017/s0007114512003558 ◽

2012 ◽

Vol 109 (9) ◽

pp. 1617-1627 ◽

Cited By ~ 26

Author(s):

Andrea S. Rossi ◽

Maria E. Oliva ◽

Maria R. Ferreira ◽

Adriana Chicco ◽

Yolanda B. Lombardo

Keyword(s):

Fatty Acid ◽

Enzyme Activities ◽

Fatty Acid Synthase ◽

Regulatory Element ◽

Liver Steatosis ◽

Control Group ◽

Acid Oxidase ◽

Insulin Resistant ◽

Protein Levels ◽

Chia Seed

The present study analyses the effect of dietary chia seed rich in n-3 α-linolenic acid on the mechanisms underlying dyslipidaemia and liver steatosis developed in rats fed a sucrose-rich diet (SRD) for either 3 weeks or 5 months. The key hepatic enzyme activities such as fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), glucose-6-phosphate dehydrogenase (G-6-PDH), carnitine palmitoyltransferase-1 (CPT-1) and fatty acid oxidase (FAO) involved in lipid metabolism and the protein mass levels of sterol regulatory element-binding protein-1 (SREBP-1) and PPARα were studied. (1) For 3 weeks, Wistar rats were fed either a SRD with 11 % of maize oil (MO) as dietary fat or a SRD in which chia seed replaced MO (SRD+Chia). (2) A second group of rats were fed a SRD for 3 months. Afterwards, half the rats continued with the SRD while for the other half, MO was replaced by chia for 2 months (SRD+Chia). In a control group, maize starch replaced sucrose. Liver TAG and the aforementioned parameters were analysed in all groups. The replacement of MO by chia in the SRD prevented (3 weeks) or improved/normalised (5 months) increases in dyslipidaemia, liver TAG, FAS, ACC and G-6-PDH activities, and increased FAO and CPT-1 activities. Protein levels of PPARα increased, and the increased mature form of SREBP-1 protein levels in the SRD was normalised by chia in both protocols (1 and 2). The present study provides new data regarding some key mechanisms related to the fate of hepatic fatty acid metabolism that seem to be involved in the effect of dietary chia seed in preventing and normalising/improving dyslipidaemia and liver steatosis in an insulin-resistant rat model.

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Aqueous Extract of Pepino (Solanum muriactum Ait) Leaves Ameliorate Lipid Accumulation and Oxidative Stress in Alcoholic Fatty Liver Disease

Nutrients ◽

10.3390/nu10070931 ◽

2018 ◽

Vol 10 (7) ◽

pp. 931 ◽

Cited By ~ 9

Author(s):

Jen-Ying Hsu ◽

Hui-Hsuan Lin ◽

Cheng-Chin Hsu ◽

Bing-Chen Chen ◽

Jing-Hsien Chen

Keyword(s):

Oxidative Stress ◽

Fatty Liver ◽

Aqueous Extract ◽

Lipid Accumulation ◽

Fatty Acid Synthase ◽

Regulatory Element ◽

Adenosine Monophosphate ◽

Peroxisome Proliferator ◽

Alcoholic Fatty Liver ◽

Anti Inflammatory

Chronic alcohol intake leads to alcoholic fatty liver. The pathogenesis of alcoholic fatty liver is related to abnormal lipid accumulation, oxidative stress, endotoxins, and cytokines. Solanum muricatum Ait. (Pepino) is a plant food commonly cultivated in the Penghu island, Taiwan. Previous studies indicated that the aqueous extract of pepino was able to attenuate diabetic progression via its antioxidative and anti-inflammatory effects. However, the mechanisms of the antioxidative and anti-inflammatory effects of pepino leaf in preventing alcoholic fatty liver remain unknown. In this study, Lieber–DeCarli ethanol-containing liquid diet was used to induce alcoholic hepatic injury in C57BL/6 mice. The hepatoprotective effects and the related mechanisms of aqueous extract of pepino leaf (AEPL) were examined. Our results showed that 2% AEPL treatments protected the liver from ethanol-induced injury through reducing serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC) and triglyceride (TG) (all p < 0.05). AEPL had the effects in improving the ethanol-induced lipid accumulation in mice under histological examination. Molecular data indicated that the anti-lipid accumulation effect of AEPL might be mediated via inducing hepatic levels of phospho-adenosine monophosphate-activated kinase (p-AMPK) and peroxisome proliferator-activated receptor (PPAR)-α, and reducing the expressions of hepatic lipogenic enzymes, including sterol regulatory element-binding protein (SREBP)-1c, acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) (all p < 0.05). AEPL also decreased hepatic levels of thiobarbituric acid relative substances (TBARS), tumor necrosis factor (TNF)-α, and interleukin (IL)-6, as well as the expression of nuclear factor kappa B (NF-κB) (all p < 0.05). Moreover, AEPL significantly elevated the activities of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx), and glutathione (GSH) content compared to the ethanol-fed group (all p < 0.05). Our present study suggests that AEPL could protect the liver against ethanol-induced oxidative injury and lipid accumulation.

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Treatment with SRT1720, a SIRT1 activator, ameliorates fatty liver with reduced expression of lipogenic enzymes in MSG mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90997.2008 ◽

2009 ◽

Vol 297 (5) ◽

pp. E1179-E1186 ◽

Cited By ~ 95

Author(s):

Yu Yamazaki ◽

Isao Usui ◽

Yukiko Kanatani ◽

Yuji Matsuya ◽

Koichi Tsuneyama ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Fatty Liver ◽

Fatty Acid Synthase ◽

Regulatory Element ◽

Liver Lipid ◽

Monosodium Glutamate ◽

Marker Genes ◽

Lipogenic Genes ◽

Sirt1 Activator

Nonalcoholic fatty liver disease (NAFLD) is an abnormal liver metabolism often observed with insulin resistance and metabolic syndrome. Calorie restriction is a useful treatment for NAFLD and reportedly prolongs the life spans of several species in which sirtuin plays an important role. In this study, we examined whether the activation of SIRT1, a mammalian ortholog of sirtuin, may ameliorate the development of NAFLD. Monosodium glutamate (MSG) mice, which exhibited obesity and insulin resistance, were treated with SRT1720, a specific SIRT1 activator from the age of 6–16 wk. Sixteen-week-old MSG mice exhibited increased liver triglyceride content and elevated levels of aminotransferase. SRT1720 treatment significantly reduced these levels without affecting body weight or food intake. These results suggested that the administration of SRT1720 ameliorated the development of NAFLD in MSG mice. The expressions of lipogenic genes, such as sterol regulatory element-binding protein-1c, acetyl-CoA carboxylase, and fatty acid synthase, and the serum lipid profiles, including free fatty acids, were elevated in MSG mice and were reduced by SRT1720 treatment. SRT1720 treatment also reduced the expressions of lipogenic genes in cultured HepG2 cells. Furthermore, SRT1720 treatment decreased the expressions of marker genes for oxidative stress and inflammatory cytokines in the liver of MSG mice. Taken together, SRT1720 treatment may reduce liver lipid accumulation, at least in part, by directly reducing the expressions of lipogenic genes. The reduction of oxidative stress and inflammation may also be involved in the amelioration of NAFLD.

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Time course of adipose tissue dysfunction associated with antioxidant defense, inflammatory cytokines and oxidative stress in dyslipemic insulin resistant rats

Food & Function ◽

10.1039/c4fo00903g ◽

2015 ◽

Vol 6 (4) ◽

pp. 1299-1309 ◽

Cited By ~ 19

Author(s):

María Eugenia D'Alessandro ◽

Dante Selenscig ◽

Paola Illesca ◽

Adriana Chicco ◽

Yolanda B. Lombardo

Keyword(s):

Oxidative Stress ◽

Adipose Tissue ◽

Inflammatory Cytokines ◽

Time Course ◽

Antioxidant Defense ◽

Insulin Resistant ◽

Adipose Tissue Dysfunction ◽

And Oxidative Stress

Time course of adipose tissue dysfunction in dyslipemic insulin resistant rats.

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Influence of virgin coconut oil-enriched diet on the transcriptional regulation of fatty acid synthesis and oxidation in rats – a comparative study

British Journal Of Nutrition ◽

10.1017/s000711451400004x ◽

2014 ◽

Vol 111 (10) ◽

pp. 1782-1790 ◽

Cited By ~ 26

Author(s):

Sakunthala Arunima ◽

Thankappan Rajamohan

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Mrna Expression ◽

Fatty Acid Synthase ◽

Target Genes ◽

De Novo ◽

Regulatory Element ◽

Coconut Oil ◽

Acid Oxidation ◽

Virgin Coconut Oil

The present study was carried out to evaluate the effects of virgin coconut oil (VCO) compared with copra oil, olive oil and sunflower-seed oil on the synthesis and oxidation of fatty acids and the molecular regulation of fatty acid metabolism in normal rats. Male Sprague–Dawley rats were fed the test oils at 8 % for 45 d along with a synthetic diet. Dietary supplementation of VCO decreased tissue lipid levels and reduced the activity of the enzymes involved in lipogenesis, namely acyl CoA carboxylase and fatty acid synthase (FAS) (P< 0·05). Moreover, VCO significantly (P< 0·05) reduced thede novosynthesis of fatty acids by down-regulating the mRNA expression of FAS and its transcription factor, sterol regulatory element-binding protein-1c, compared with the other oils. VCO significantly (P< 0·05) increased the mitochondrial and peroxisomal β-oxidation of fatty acids, which was evident from the increased activities of carnitine palmitoyl transferase I, acyl CoA oxidase and the enzymes involved in mitochondrial β-oxidation; this was accomplished by up-regulating the mRNA expression of PPARα and its target genes involved in fatty acid oxidation. In conclusion, the present results confirmed that supplementation of VCO has beneficial effects on lipid parameters by reducing lipogenesis and enhancing the rate of fatty acid catabolism; this effect was mediated at least in part via PPARα-dependent pathways. Thus, dietary VCO reduces the risk for CHD by beneficially modulating the synthesis and degradation of fatty acids.

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Use of Oxidative Stress Responses to Determine the Efficacy of Inactivation Treatments on Cryptosporidium Oocysts

Microorganisms ◽

10.3390/microorganisms9071463 ◽

2021 ◽

Vol 9 (7) ◽

pp. 1463

Author(s):

Tamirat Tefera Temesgen ◽

Kristoffer Relling Tysnes ◽

Lucy Jane Robertson

Keyword(s):

Oxidative Stress ◽

Stress Responses ◽

Target Genes ◽

Cryptosporidium Oocyst ◽

Drinking Water Treatment ◽

Proof Of Concept ◽

Environmental Matrices ◽

Oocyst Wall ◽

Novel Approach ◽

Cryptosporidium Oocysts

Cryptosporidium oocysts are known for being very robust, and their prolonged survival in the environment has resulted in outbreaks of cryptosporidiosis associated with the consumption of contaminated water or food. Although inactivation methods used for drinking water treatment, such as UV irradiation, can inactivate Cryptosporidium oocysts, they are not necessarily suitable for use with other environmental matrices, such as food. In order to identify alternative ways to inactivate Cryptosporidium oocysts, improved methods for viability assessment are needed. Here we describe a proof of concept for a novel approach for determining how effective inactivation treatments are at killing pathogens, such as the parasite Cryptosporidium. RNA sequencing was used to identify potential up-regulated target genes induced by oxidative stress, and a reverse transcription quantitative PCR (RT-qPCR) protocol was developed to assess their up-regulation following exposure to different induction treatments. Accordingly, RT-qPCR protocols targeting thioredoxin and Cryptosporidium oocyst wall protein 7 (COWP7) genes were evaluated on mixtures of viable and inactivated oocysts, and on oocysts subjected to various potential inactivation treatments such as freezing and chlorination. The results from the present proof-of-concept experiments indicate that this could be a useful tool in efforts towards assessing potential technologies for inactivating Cryptosporidium in different environmental matrices. Furthermore, this approach could also be used for similar investigations with other pathogens.

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Time Course of Redox Biomarkers in COVID-19 Pneumonia: Relation with Inflammatory, Multiorgan Impairment Biomarkers and CT Findings

Antioxidants ◽

10.3390/antiox10071126 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1126

Author(s):

Tijana Kosanovic ◽

Dragan Sagic ◽

Vladimir Djukic ◽

Marija Pljesa-Ercegovac ◽

Ana Savic-Radojevic ◽

...

Keyword(s):

Oxidative Stress ◽

Time Course ◽

Redox Homeostasis ◽

Original Data ◽

Advanced Oxidation Protein Products ◽

Oxidative Stress Parameters ◽

Systemic Oxidative Stress ◽

Dependent Relation ◽

Organ Tissue ◽

Insight Into

Although the original data on systemic oxidative stress in COVID-19 patients have recently started to emerge, we are still far from a complete profile of changes in patients’ redox homeostasis. We aimed to assess the extent of oxidative damage of proteins, lipids and DNA during the course of acute disease, as well as their association with CT pulmonary patterns. In order to obtain more insight into the origin of the systemic oxidative stress, the observed parameters were correlated with inflammatory biomarkers and biomarkers of multiorgan impairment. In this prospective study, we included 58 patients admitted between July and October 2020 with COVID-19 pneumonia. Significant changes in malondialdehyde, 8-hydroxy-2’-deoxyguanosine and advanced oxidation protein products levels exist during the course of COVID-19. Special emphasis should be placed on the fact that the pattern of changes differs between non-hospitalized and hospitalized individuals. Our results point to the time-dependent relation of oxidative stress parameters with inflammatory and multiorgan impairment biomarkers, as well as pulmonary patterns in COVID-19 pneumonia patients. Correlation between redox biomarkers and immunological or multiorgan impairment biomarkers, as well as pulmonary CT pattern, confirms the suggested involvement of neutrophils networks, IL-6 production, along with different organ/tissue involvement in systemic oxidative stress in COVID-19.

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Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00296.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. G419-G427 ◽

Cited By ~ 3

Author(s):

Tatsuhide Nabeshima ◽

Shin Hamada ◽

Keiko Taguchi ◽

Yu Tanaka ◽

Ryotaro Matsumoto ◽

...

Keyword(s):

Oxidative Stress ◽

Cancer Progression ◽

Stress Responses ◽

Target Genes ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Related Factor ◽

Loss Of Function ◽

P53 Expression ◽

Nrf2 Activation

The activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) pathway contributes to cancer progression in addition to oxidative stress responses. Loss-of-function Keap1 mutations were reported to activate Nrf2, leading to cancer progression. We examined the effects of Keap1 deletion in a cholangiocarcinoma mouse model using a mutant K-ras/ p53 mouse. Introduction of the Keap1 deletion into liver-specific mutant K-ras/ p53 expression resulted in the formation of invasive cholangiocarcinoma. Comprehensive analyses of the gene expression profiles identified broad upregulation of Nrf2-target genes such as Nqo1 and Gstm1 in the Keap1-deleted mutant K-ras/ p53 expressing livers, accompanied by upregulation of cholangiocyte-related genes. Among these genes, the transcriptional factor Sox9 was highly expressed in the dysplastic bile duct. The Keap-Nrf2-Sox9 axis might serve as a novel therapeutic target for cholangiocarcinoma. NEW & NOTEWORTHY The Keap1-Nrf2 system has a wide variety of effects in addition to the oxidative stress response in cancer cells. Addition of the liver-specific Keap1 deletion to mice harboring mutant K-ras and p53 accelerated cholangiocarcinoma formation, together with the hallmarks of Nrf2 activation. This process involved the expansion of Sox9-positive cells, indicating increased differentiation toward the cholangiocyte phenotype.

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