Liver Of Young Rats Research Articles

The Liver of Young and Old Female Rats Exhibits Heightened Susceptibility to Dichlorvos Exposure

Exposure to industrial and agricultural environmental contaminants has been shown to produce deleterious effects on different organs of the human body. Dichlorvos [O, O-dimethyl O-(2,2-dichlorovinyl) phosphate, DDVP] is a major organophosphate pesticide used mostly in developing countries for domestic and agricultural insect control. The toxic effects of DDVP have been reported on many organs. However, its gender and age-dependent effects on the liver are yet to be documented. This study investigated the influence of gender and age on liver damage in male and female rats exposed to DDVP. Animals were divided into control and experimental groups with age and gender classification. Using age, rats were classified into young, middle-aged, and old age groups. Rats in the experimental groups were exposed to DDVP from 8 am to 12 noon for five weeks. Rats were subsequently euthanized and liver tissues were harvested for biochemical assay. Glutamyl transferase (GGT), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), Lactate dehydrogenase (LDH), Albumin, and conjugated bilirubin were assayed using ELISA kits. Statistical analysis was done using two-way ANOVA, followed by Tukey post-Hoc test at significance level of p<0.05. Our study found that DDVP exposure caused liver damage in female rats only with significant elevation in liver enzymes such as ALP, ALT, AST, and LDH. However, the male rats showed more resistance to DDVP exposure. The liver damage observed in female rats was age-dependent, with young and old rats showing higher susceptibility compared to middle-aged female rats. Nutritional and pharmacological strategies are recommended to mitigate the effect of DDVP exposure, particularly in populations at higher risk of exposure.

Differences in the Effect of Beta-Hydroxybutyrate on the Mitochondrial Biogenesis, Oxidative Stress and Inflammation Markers in Tissues from Young and Old Rats.

One of the therapeutic approaches to age-related diseases is modulation of body cell metabolism through certain diets or their pharmacological mimetics. The ketogenic diet significantly affects cell energy metabolism and functioning of mitochondria, which has been actively studied in various age-related pathologies. Here, we investigated the effect of the ketogenic diet mimetic beta-hydroxybutyrate (BHB) on the expression of genes regulating mitochondrial biogenesis (Ppargc1a, Nrf1, Tfam), quality control (Sqstm1), functioning of the antioxidant system (Nfe2l2, Gpx1, Gpx3, Srxn1, Txnrd2, Slc6a9, Slc7a11), and inflammatory response (Il1b, Tnf, Ptgs2, Gfap) in the brain, lungs, heart, liver, kidneys, and muscles of young and old rats. We also analyzed mitochondrial DNA (mtDNA) copy number, accumulation of mtDNA damage, and levels of oxidative stress based on the concentration of reduced glutathione and thiobarbituric acid-reactive substances (TBARS). In some organs, aging disrupted mitochondrial biogenesis and functioning of cell antioxidant system, which was accompanied by the increased oxidative stress and inflammation. Administration of BHB for 2 weeks had different effects on the organs of young and old rats. In particular, BHB upregulated expression of genes coding for proteins associated with the mitochondrial biogenesis and antioxidant system, especially in the liver and muscles of young (but not old) rats. At the same time, BHB contributed to the reduction of TBARS in the kidneys of old rats. Therefore, our study has shown that administration of ketone bodies significantly affected gene expression in organs, especially in young rats, by promoting mitochondrial biogenesis, improving the functioning of the antioxidant defense system, and partially reducing the level of oxidative stress. However, these changes were much less pronounced in old animals.

Detraining after short-term exercise induces hyperphagia and obesity with fatty liver and brown adipose tissue whitening in young male OLETF rats.

This study examined the effects of exercise and detraining at a young age on fat accumulation in various organs. Four-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF) rats were assigned to either the non-exercise sedentary (OLETF Sed) or exercise groups. The exercise group was subdivided into two groups: exercise between 4 and 12 weeks of age (OLETF Ex) and exercise between 4 and 6 weeks of age followed by non-exercise between 6 and 12 weeks of age (OLETF DT). Body weight was significantly lower in the OLETF Ex group than in the OLETF Sed group at 12 weeks of age. Fat accumulation in the epididymal white adipose tissue, liver, and brown adipose tissue was suppressed in the OLETF Ex group. During the exercise period, body weight and food intake in the OLETF DT group were significantly lower than those in the OLETF Sed group. However, food intake was significantly higher in the OLETF DT group than in the OLETF Sed group after exercise cessation, resulting in extreme obesity with fatty liver and brown adipose tissue whitening. Detraining after early-onset exercise promotes hyperphagia, causing extreme obesity. Overeating should be avoided during detraining periods in cases of exercise cessation at a young age.

AGE-RELATED CHARACTERISTICS OF GLUTATHIONE-DEPENDENT ENZYMES FUNCTIONING IN RATS UNDER CONDITIONS OF TOXIC INJURY BY ACETAMINOPHEN

Aim. The study is dedicated to evaluating the enzymatic activities of the glutathione system in liver cells of rats from different age groups under conditions of toxic injury caused by acetaminophen. In the experiments, rats of two age categories were used: young (138–150 days) and mature age (348–360 days). Mehods. Acute toxic injury from acetaminophen was induced by administering it per os at a dose of 1250 mg/kg of animal body weight during the last two days of the experiment. Results. Under conditions of simulated acute toxic injury by the medicinal xenobiotic acetaminophen in the livers of young and mature rats, a decrease was observed in glutathione-S-transferase, Se-dependent glutathione peroxidase, and glutathione reductase activities. A significant decrease in non-Se-glutathione peroxidase in liver cells is observed only in mature animals that were administered toxic doses of acetaminophen. The influence of the age component can be considered as one of the critically important factors in suppressing the functional activity of the glutathione-dependent enzymatic system, manifested by decreased activity of glutathione-S-transferase, non-Se-glutathione peroxidase, Se-dependent glutathione peroxidase and glutathione reductase under conditions of toxic injury caused by the medicinal xenobiotic acetaminophen. A more pronounced decrease in glutathione-dependent enzymes under conditions of acetaminophen intoxication is observed in animals aged 360 days. Cunclusion. The consequence of the established changes could be the disruption of acetaminophen biotransformation in Phase II involving the glutathione system, which can be considered as one of the risk factors for the development of drug-induced hepatotoxicity in different age groups.

Direct-Acting Antiviral Drug Modulates the Mitochondrial Biogenesis in Different Tissues of Young Female Rats.

(1) Background: Hepatitis C virus (HCV) infection is endemic in Egypt, with the highest prevalence rate worldwide. Sofosbuvir (SOF) is a nucleos(t)ide analog that specifically inhibits HCV replication. This study aimed to explore the possible effects of the therapeutic dose of SOF on the mitochondrial biogenesis and functions of the liver, muscle, and ovarian tissues of young normal female rats. (2) Methods: This study was conducted on 20 female Wistar rats, classified into two groups, the control group and the exposed group; the latter was orally supplemented with 4 mg/kg/day of SOF for 3 months. (3) Results: The exposure to SOF impairs mitochondrial biogenesis via mitochondrial DNA copy number decline and suppressed mitochondrial biogenesis-regulated parameters at mRNA and protein levels. Also, SOF suppresses the DNA polymerase γ (POLG) expression, citrate synthase activity, and mitochondrial NADH dehydrogenase subunit-5 (ND5) content, which impairs mitochondrial functions. SOF increased lipid peroxidation and oxidative DNA damage markers and decreased tissue expression of nuclear factor erythroid 2-related factor 2 (Nfe2l2). (4) Conclusions: The present findings demonstrate the adverse effects of SOF on mitochondrial biogenesis and function in different tissues of young female rats, which mostly appeared in ovarian tissues.

TransOrGAN: An Artificial Intelligence Mapping of Rat Transcriptomic Profiles between Organs, Ages, and Sexes.

Animal studies are required for the evaluation of candidate drugs to ensure patient and volunteer safety. Toxicogenomics is often applied in these studies to gain understanding of the underlying mechanisms of toxicity, which is usually focused on critical organs such as the liver or kidney in young male rats. There is a strong ethical reason to reduce, refine and replace animal use (the 3Rs), where the mapping of data between organs, sexes and ages could reduce the cost and time of drug development. Herein, we proposed a generative adversarial network (GAN)-based framework entitled TransOrGAN that allowed the molecular mapping of gene expression profiles in different rodent organ systems and across sex and age groups. We carried out a proof-of-concept study based on rat RNA-seq data from 288 samples in 9 different organs of both sexes and 4 developmental stages. First, we demonstrated that TransOrGAN could infer transcriptomic profiles between any 2 of the 9 organs studied, yielding an average cosine similarity of 0.984 between synthetic transcriptomic profiles and their corresponding real profiles. Second, we found that TransOrGAN could infer transcriptomic profiles observed in females from males, with an average cosine similarity of 0.984. Third, we found that TransOrGAN could infer transcriptomic profiles in juvenile, adult, and aged animals from adolescent animals with an average cosine similarity of 0.981, 0.983, and 0.989, respectively. Altogether, TransOrGAN is an innovative approach to infer transcriptomic profiles between ages, sexes, and organ systems, offering the opportunity to reduce animal usage and to provide an integrated assessment of toxicity in the whole organism irrespective of sex or age.

Depletion and Repletion of Biotinyl Enzymes in Liver of Biotin-Deficient Rats: Evidence of a Biotin Storage System

The quantities of biotinyl proteins in liver of young rats were compared with age-matched controls at intervals during depletion and repletion of biotin. Growth rate and the concentrations of biotinyl proteins previously proposed as mitochondrial storage forms of acetyl CoA carboxylase rapidly decreased in response to biotin deprivation, whereas neither the concentration nor activity of cytosolic acetyl CoA carboxylase was affected. Concentrations of carboxylases active within mitochondria (pyruvate carboxylase, propionyl CoA carboxylase and 3-methyl crotonyl CoA carboxylase) decreased only after d 28. When biotin was injected into biotin-deficient rats, concentrations of the carboxylases active within mitochondria were restored to control levels within 3 h, whereas the concentrations of putative mitochondrial storage forms of acetyl CoA carboxylase reached normal levels only after 9 h, indicating that the injected biotin was preferentially used for the synthesis of the carboxylases active within mitochondria rather than acetyl CoA carboxylase. Mitochondrial acetyl CoA carboxylase may serve as a reservoir to maintain a normal concentration of cytosolic acetyl CoA carboxylase in liver of rats deprived of biotin and provide biotin, indirectly, to maintain essentially normal concentrations of the biotinyl enzymes active within mitochondria for several weeks after rats were fed a biotin-deficient diet.

Short-term fructose feeding alters tissue metabolic pathways by modulating microRNAs expression both in young and adult rats.

Dietary high fructose (HFrD) is known as a metabolic disruptor contributing to the development of obesity, diabetes, and dyslipidemia. Children are more sensitive to sugar than adults due to the distinct metabolic profile, therefore it is especially relevant to study the metabolic alterations induced by HFrD and the mechanisms underlying such changes in animal models of different ages. Emerging research suggests the fundamental role of epigenetic factors such as microRNAs (miRNAs) in metabolic tissue injury. In this perspective, the aim of the present study was to investigate the involvement of miR-122-5p, miR-34a-5p, and miR-125b-5p examining the effects induced by fructose overconsumption and to evaluate whether a differential miRNA regulation exists between young and adult animals. We used young rats (30days) and adult rats (90days) fed on HFrD for a short period (2weeks) as animal models. The results indicate that both young and adult rats fed on HFrD exhibit an increase in systemic oxidative stress, the establishment of an inflammatory state, and metabolic perturbations involving the relevant miRNAs and their axes. In the skeletal muscle of adult rats, HFrD impair insulin sensitivity and triglyceride accumulation affecting the miR-122-5p/PTP1B/P-IRS-1(Tyr612) axis. In liver and skeletal muscle, HFrD acts on miR-34a-5p/SIRT-1: AMPK pathway resulting in a decrease of fat oxidation and an increase in fat synthesis. In addition, liver and skeletal muscle of young and adult rats exhibit an imbalance in antioxidant enzyme. Finally, HFrD modulates miR-125b-5p expression levels in liver and white adipose tissue determining modifications in de novo lipogenesis. Therefore, miRNA modulation displays a specific tissue trend indicative of a regulatory network that contributes in targeting genes of various pathways, subsequently yielding extensive effects on cell metabolism.

Ecotoxicological impacts of industrial effluents on irrigation water quality, animal health and the role of calcium alginate in effluents treatment

The effluents discharged from Mansoura Company for Resins and Chemicals Industry were evaluated for drinking and irrigation purposes. Calcium-alginate beads were used for effluents treatment in this study. Young male rats were also allowed to drink effluents at different concentrations (10%, 50%, 100%) and treated 100% effluents with calcium-alginate for 11 weeks. Results indicated high concentrations of some physicochemical parameters and Cd, Co, Fe, Mn, Ni, Pb, and Zn in effluents that exceeded the permissible limits for drinking and irrigation purposes. Treatment by calcium-alginate alleviate heavy metals concentration but did not affect the physicochemical parameters. Depending on effluents concentration, the liver of young male rats showed high accumulation of Fe, Mn, Zn, Pb, Cd, Co, Cu, Cr, and Ni compared to the control group. Serum levels of liver enzymes, total bilirubin significantly increased while total protein, and albumin contents decreased in effluent groups. Liver concentrations of malondialdehyde and protein carbonyl significantly elevated along with significant decrease in superoxide dismutase, catalase, glutathione-S-transferase activities, and glutathione content. Moreover, growth and thyroid hormones were significantly reduced along with significant elevation in thyroid stimulating hormone. This was accompanied by significant decrease in the body weight, especially with 100% effluents concentration compared to control group. Also, histological investigations of both liver and thyroid gland using hematoxylin and eosin showed distortion in the structure of both organs especially with 50% and 100% effluent groups. However, treatment of effluents by calcium-alginate improved these changes. The study revealed that calcium-alginate are effective biosorbents for heavy metals and consequently decrease animal and human health hazards, but further studies are needed to alleviate physicochemical characteristics.

Sestrins’ Expression in the Liver Is Not Altered by Short-Term Calorie Restriction in Young and Old Rats

Introduction: Short-term calorie restriction (SCR) may have a positive impact on health. We hypothesized that sestrins, a family of stress-inducible proteins (Sesn1, Sesn2, Sesn3) are involved in the response to SCR in the liver. Methods: Young-adult (4-month) and old (24-month) male Wistar rats were either fed ad libitum (control groups) or received 60% of food intake on a daily basis for 30 days (SCR groups). In blood sera, biochemical parameters and fibroblast growth factor 21 (FGF21) concentration were measured (ELISA). Liver samples were collected for analyses of genes’ expression (real-time PCR) and protein levels (Western blotting). Results: SCR caused improvements in blood glucose and lipids and parameters of liver function but did not affect the serum FGF21 concentration. SCR caused changes typically associated with calorie restriction in the gene expression of fatty acid synthase (fasn), ATP-citrate lyase (acly), and sirtuin 1 (sirt1). In the liver of young SCR rats, protein level of Sesn2 tended to increase, while Sesn3 tended to decrease, accompanied by reduced sesn3 expression. In old SCR rats, reduced sesn1 expression was reflected by decreasing trend for Sesn1 content. Activation of AMP-activated protein kinase (phospho-Thr172) and protein content of peroxisome proliferator-activated receptor gamma coactivator 1-alpha were not affected by SCR. Conclusion: Sestrins’ hepatic expression is only minimally affected by SCR in young and old rats. We propose that sestrins may not be a major effector of mild SCR in the liver of young or old rats.

Age-related changes in metabolites in young donor livers and old recipient sera after liver transplantation from young to old rats.

Liver ageing not only damages liver function but also harms systemic metabolism. To better understand the mechanisms underlying liver ageing, we transplanted the livers of young rats to young and old rats and performed untargeted metabolomics to detect changes in the metabolites in the liver tissues and sera. A total of 153 metabolites in the livers and 83 metabolites in the sera were different between the old and young rats that did not undergo liver transplantation; among these metabolites, 7 different metabolites were observed in both the livers and sera. Five weeks after liver transplantation, the levels of 25 metabolites in the young donor livers were similar to those in the old rats, and this result probably occurred due to the effect of the whole‐body environment of the older recipients on the young livers. The 25 altered metabolites included organic acids and derivatives, lipids and lipid‐like molecules, etc. In the sera, the differences in 78 metabolites, which were significant between the young and old rats, were insignificant in the old recipient rats and made the metabolic profile of the old recipients more similar to that of the young recipients. Finally, combining the above metabolomic data with the transcriptomic data from the GEO, we found that the altered metabolites and genes in the liver were enriched in 9 metabolic pathways, including glycerophospholipid, arachidonic acid, histidine and linoleate. Thus, this study revealed important age‐related metabolites and potential pathways as well as the interaction between the liver and the whole‐body environment.

Sleep deprivation induces oxidative stress in the liver and pancreas in young and aging rats

The aging process is characterized by a gradual impairment generally caused by oxidative stress and, more specifically, sleep deprivation, which induces oxidative stress in the brain. The objective of this study was to assess the effect of three types of paradoxical sleep deprivation (PSD): 96 h of PSD (96PSD group); 192 h of PSD (192PSD group); 192 h of PSD followed by a recovery period of 20 days (192PSD + Recovery group) on an oral glucose tolerance test (OGTT), lipid peroxidation (LPO), and superoxide dismutase (SOD) and catalase (CAT) activities in the liver and pancreas of young (3-month-old) and adult (14-month-old) rats. The 96PSD and 192PSD groups of young rats showed lower glucose levels on the OGTT than the control group. In the adult rats, only the 96PSD group had lower glucose levels than the control group. However, the areas under the curve for the young and adult 192 and 192PSD + Recovery groups showed significant differences. Both LPO and SOD increased in the 192PSD and 192PSD + Recovery groups, but CAT decreased in the liver of young rats in the 192PSD group. Regarding the pancreas, LPO and SOD levels increased after 96 h of PSD. In adult animals, CAT decreased in the liver after 96 and 192 h of PSD, while LPO and SOD increased in the pancreas of the 192PSD and PSD + Recovery groups. Differences in the SOD and CAT activities in the liver and SOD activities in the pancreas were also observed between the young and adult rats and maintained across all the PSD groups. In conclusion, PSD induced differential responses that appeared to depend on the duration of the induced condition, the animals’ age, and the tissue analyzed. It was found that adult rats were more susceptible to the effects of PSD than young rats.

Effects of Multiple Doses of Dichloroacetate on GSTZ1 Expression and Activity in Liver and Extrahepatic Tissues of Young and Adult Rats.

Glutathione transferase zeta 1 (GSTZ1), expressed in liver and several extrahepatic tissues, catalyzes dechlorination of dichloroacetate (DCA) to glyoxylate. DCA inactivates GSTZ1, leading to autoinhibition of its metabolism. DCA is an investigational drug for treating several congenital and acquired disorders of mitochondrial energy metabolism, including cancer. The main adverse effect of DCA, reversible peripheral neuropathy, is more common in adults treated long-term than in children, who metabolize DCA more quickly after multiple doses. One dose of DCA to Sprague Dawley rats reduced GSTZ1 expression and activity more in liver than in extrahepatic tissues; however, the effects of multiple doses of DCA that mimic its therapeutic use have not been studied. Here, we examined the expression and activity of GSTZ1 in cytosol and mitochondria of liver, kidney, heart, and brain 24 hours after completion of 8-day oral dosing of 100 mg/kg per day sodium DCA to juvenile and adult Sprague Dawley rats. Activity was measured with DCA and with 1,2-epoxy-3-(4-nitrophenoxy)propane (EPNPP), reported to be a GSTZ1-selective substrate. In DCA-treated rats, liver retained higher expression and activity of GSTZ1 with DCA than other tissues, irrespective of rodent age. DCA-treated juvenile rats retained more GSTZ1 activity with DCA than adults. Consistent with this finding, there was less measurable DCA in tissues of juvenile than adult rats. DCA-treated rats retained activity with EPNPP, despite losing over 98% of GSTZ1 protein. These data provide insight into the differences between children and adults in DCA elimination under a therapeutic regimen and confirm that the liver contributes more to DCA metabolism than other tissues. SIGNIFICANCE STATEMENT: Dichloroacetate (DCA) is one of few drugs exhibiting higher clearance from children than adults, after repeated doses, for reasons that are unclear. We hypothesized that juveniles retain more glutathione transferase zeta 1 (GSTZ1) than adults in tissues after multiple DCA doses and found this was the case for liver and kidney, with rat as a model to assess GSTZ1 protein expression and activity with DCA. Although 1,2-epoxy-3-(4-nitrophenoxy)propane was reported to be a selective GSTZ1 substrate, its activity was not reduced in concert with GSTZ1 protein.

Sirtuin-1 expression and activity is diminished in aged liver grafts

The cellular mechanisms underlying impaired function of aged liver grafts have not been fully elucidated, but mitochondrial dysfunction appears to be contributory. Sirtuin1 has been identified as a key mediator of mitochondrial recovery following ischemia–reperfusion injury. The purpose of this study was to determine whether differences exist in sirtuin-1 expression/activity in old vs. young liver grafts and to determine correlations with mitochondrial function, graft metabolic function, and graft injury. Old and young rat liver grafts (N = 7 per group) were exposed to 12 h of static cold storage (SCS), followed by a 2 h period of graft reperfusion ex vivo. Sirtuin1 expression and activity, mitochondrial function, graft metabolic function, and graft injury were compared. Sirtuin1 expression is upregulated in young, but not old, liver grafts in response to cold storage and reperfusion. This is associated with diminished tissue ATP, antioxidant defense, and graft metabolic function in old liver grafts. There was no evidence of increased inflammation or histologic injury in old grafts. Sirtuin1 expression is diminished in old liver grafts and correlates with mitochondrial and metabolic function. The sirtuin pathway may represent a target for intervention to enhance the function of aged liver grafts.

Submicroscopic changes in the liver of young rats with hyperhomocysteinemia

To date, it has been established that hyperhomocysteinemia plays a significant role in the development and progression of many diseases. The accumulation of homocysteine occurs due to a violation of the relationship between its production and excretion from the body. The liver plays an important role in the metabolism of homocysteine, because it undergoes most of the reactions of its transmethylation, and, therefore, it is the first to be adversely affected. The aim of the study is to identify the features of electron microscopic changes in the liver structure of young rats with hyperhomocysteinemia. The experimental study was performed on 22 white nonlinear young (1-2 months) male rats, which were divided into a control group and an experimental group. A model of persistent hyperhomocysteinemia was created by administering to rats the experimental group of thiolactone homocysteine at a dose of 200 mg/kg body weight intragastrically for 60 days. The study of ultrastructural changes in the liver of rats was performed using an electron microscope PEM-125K. It was found that the introduction of thiolactone homocysteine at a dose of 200 mg/kg in rats led to the development of degenerative changes in hepatocytes. Changes in the structure of liver cells manifested themselves in the form of edema of the cytoplasm and mitochondria, destruction of mitochondrial cristae, dilation of the tubules of the granular endoplasmic reticulum and tanks of the Golgi complex. The activity of fat-accumulating liver cells and stellate macrophages is characteristically. In the lumens of the sinusoidal capillaries found sweeter shaped blood elements, the cytoplasm of endothelial cells had signs of edema. Thus, in experimental hyperhomocysteinemia revealed changes at the ultrastructural level in all structural components of the liver of young rats. The identified changes are compensatory-adaptive in nature and are reversible.

Etiology of disrupted cholesterol metabolism in the liver of young rats submitted to obesogenic diets

The purpose of the study was to test the hypothesis that a short period (2 weeks) of a high fat (HFD) and a western (WD) diet leading to an increase in liver fat accumulation will disrupt key markers of liver cholesterol metabolism mainly targeting the LDL‐receptor (LDL‐R) pathway. Rats were submitted to either a standard (SD), HFD (60%) or a WD (40% fat + 35% sucrose) diet for 2 and 6 weeks. Body weight gain and body fat values were higher (p < 0.01) in rats fed the HFD and WD for 6 weeks although food intakes in kcal/d were not different for all groups throughout the experimental period. Liver fat accumulation was significantly (P < 0.01) higher in HFD and WD rats as compared to the SD diet for both feeding durations. On the other hand, liver fat accumulation was higher in WD rats (P < 0.05) than HFD animals after two weeks of treatment. In addition, WD animals displayed the highest plasma cholesterol levels. After 2 and 6 weeks of treatment, hepatic gene expression of LDL‐R, Pcsk9 and SREBP‐2 was lower (p < 0.01) in WD animals than in HFD and SD rats. In addition, mRNA levels of Lrp1 and Acat2 were lower (p < 0.01) in WD rats as compared to those fed with SD. Gene expression of HMGCoA‐r, the main enzyme involved in the regulation of cholesterol synthesis, was lower in HFD (2 weeks) and even more so in rats fed the WD diet (2 and 6 weeks). The WD was associated with a higher (p < 0.01) gene expression of markers involved in the mediation of de novo lipogenesis (ACC and ChREBP). It is concluded that a short‐term WD promptly increased fat accumulation while disrupting cholesterol metabolism in the liver. The present results provide new insights on the mechanisms through which westernized diets rapidly promote increases in plasma cholesterol levels.Support or Funding InformationNSERC, FRQS, CFI

Systemic Metabolomics and Mitochondrial Energetics in High- Compared to Low-Running Capacity Rats as a Function of Age

Exercise capacity during aging is strongly linked to life quality, morbidity and mortality. In a selectively-bred rat model of intrinsic aerobic phenotypes, low-capacity (LCR) compared to high-capacity running (HCR) rats exhibit increased rates of metabolic syndrome, adiposity, dyslipidemia, endothelial dysfunction, and insulin resistance. Previously, we showed that with aging HCR rats present greater mitochondrial turnover underlying higher cardiomyocyte energetic performance, sustained by preferential selection of lipids oxidation with improved control of acetyl-CoA (AcCoA) concentration. All these positive indexes decline with aging, but they are better preserved in HCR vs. LCR, parallel with healthier aging and extended longevity. To investigate systemic metabolism in main organs supplying substrates (fatty acids, glucose, ketone bodies) to the heart, untargeted metabolomics was performed in liver and serum of young and middle age female HCR and LCR rats. Multivariate statistics indicated a metabolome pattern in liver comprised by higher abundance of fatty acids (e.g., palmitic, palmitoleic, oleic) at similar levels of intermediates from glucose metabolism in HCR vs. LCR. As a function of age, the serum of HCR rats exhibited an enrichment in fatty acids (e.g., linoleic, palmitic, arachidic) consistent with the changes observed in liver's metabolome. Higher liver AMP levels in HCR vs. LCR suggest activation of AMPK signaling, in agreement with the enhanced autophagy/mitophagy observed in HCR. Importantly, the higher relative LCR/HCR fold-changes of acetylated intermediates, in both liver and serum, agrees with the idea of widespread increased acetylation, compatible with the higher concentration of AcCoA measured in cardiomyocytes from LCR vs. HCR. Metabolomics reveal systemic, organ-concerted (liver-serum-heart), metabolic remodeling compatible with higher energetic performance, better preserved mitochondrial turnover, preferential lipid oxidation, and improved control of acetylation in HCR leading to extended longevity and better functional capacity.

PO-230 Treadmill Running Ameliorates Alcohol-Induced Malfunctioning of Intra- and Extra-Mitochondrial Enzymes in Liver of Aged Rats

Objective Alcohol consumption particularly at old age can cause severe liver damage through malfunctioning of vital organelles, including mitochondria. Exercise is known to improve the cellular functions against alcohol-induced adverse effects and oxidative stress. Nevertheless, whether exercise can promote mitochondrial function in old alcohol-fed rats remains unclear. In this study, we investigated the effect of exercise training on intra- and extra-mitochondrial enzyme activities in alcohol/ethanol treated rats.
 Methods Young (3-month, n=24) and old (18-month, n=24) Wistar albino rats were equally divided into control, exercise, ethanol and combination of exercise plus ethanol treated groups. Following treadmill exercise (23 m/min, 30 min/day 5-day/wk) and ethanol (2 g/kg b.w.) treatment for 2 months, cytosol and mitochondrial enzyme activities, triglycerides and phospholipids were estimated in the liver of young and old rats.
 Results We found ethanol intoxication significantly decreased (P<0.01) the hepatic intra- and extra-mitochondrial enzyme activities, including glucose-6-phosphate dehydrogenase (G6PD), succinate dehydrogenase (SDH), malate dehydrogenase (MDH) and glutamate dehydrogenase (GDH) in both young and old rats. However, exercise training considerably reversed the loss of these enzyme activities, and further maintained above control levels in respective age groups. Restoration of mitochondrial marker enzymes (SDH and GDH) with exercise against ethanol-loss was prominent in young compared to old rats, which indicates old rats are prone to alcohol-induced adverse effects. Alcohol-induced elevated LDH levels in both ages were slightly decreased by exercise plus ethanol treatment. We further noticed that amplified triglycerides and phospholipids were substantially decreased following treadmill exercise in both age groups. Decreased triglycerides level with exercise was prominent in young alcohol-fed rats than that of old.
 Conclusions Our results imply that 2-month treadmill exercise training effectively ameliorated the ruined cytosol and mitochondrial enzyme activities in young and old ethanol-fed rats. Improved mitochondrial enzymes and decreased triglycerides with exercise training may protect the alcohol-induced liver damage.

Circadian Rhythms of Antioxidant Enzyme’s Activity in Young and Adult Rats under Light Deprivation Conditions

We studied the age-related features of circadian rhythms of superoxide dismutase (SOD) and catalase activity in the liver of rats under light deprivation. In standard light conditions (LD), significant daily fluctuations in SOD activity with a maximum at 07:00 am was detected only in young animals (1,5 months) but catalase activity was observed in young (1,5 months) and in adults (7,5 months) with peak at 04:00 am. The daily dynamics of total and specific activity of SOD and catalase in the liver in young and adult rats differed depending on the period of ontogeny in which the impact of light deprivation began. When the females and offspring were moved to darkness after birth (group LD/DD), the circadian rhythms of SOD and catalase activitys were observed in young and were absent in adult rats. However, circadian rhythms of the antioxidant enzymes (AOE) activities were inherent only adult rats when light deprivation impacted on pregnant females (group DD/DD). Changes in circadian rhythms under light deprivation were characterized either by a phase shift of the enzymes activity (in the LD/DD group) or by a violation of their develpoment in ontogeny (in the DD/DD group). During aging significant decreasing of catalase activity was compensated by an increase in the amplitude of circadian rhythms of activity of this enzyme in animals of all groups. A distinctive feature of daily fluctuations in AOЕ activity in young rats in LD and LD/DD groups can be considered the presence of an ultradian rhythm in the general circadian cycle, which had a second peak with a smaller amplitude and shorter period.

Oxidative stress response to air particle pollution in a rat nutritional growth retardation model

ABSTRACTAir pollution consisting of gases and particulate matter-(PM) represents a health problem in cities worldwide. However, air pollution does not impact equally all individuals, as children appear to be more vulnerable subpopulations. Air pollution and malnutrition are two distinct factors that have been associated with oxidative damage. Therefore, the interaction between environmental exposure and nutritional status in populations at risk needs to be explored. The aim of this study was to examine oxidative metabolism in lung, heart and liver in malnourished young rats exposed to residual oil fly ash (ROFA). A Nutritional Growth Retardation (NGR) model was developed in weanling male rats placed on a 20% restricted balanced diet for 4 weeks. Then, NGR and control rats were intranasally instilled with either ROFA (1mg/kg BW) or phosphate buffered saline (PBS). Twenty-four hr post-exposure lung, heart and liver were excised, and serum collected. ROFA induced lung and liver inflammation in control and NGR animals as evidenced by lung polymorphonuclear neutrophil (PMN) recruitment and alveolar space reduction accompanied by liver lymphocyte and binucleated hepatocyte level increase. In lung and liver, antioxidant defense mechanisms reduced lipoperoxidation. In contrast, only in NGR animals did ROFA exposure alter heart oxidative metabolism leading to lipid peroxidation. Although histological and biochemical tissue alterations were detected, no marked changes in serum liver and heart systemic biomarkers were observed. In conclusion, NGR animals responded differently to PM exposure than controls suggesting that nutritional status plays a key role in responsiveness to ambient air contaminants.