LIVER LIPIDS OF CHOLINE-DEFICIENT RATS.
Ontology highlight
ABSTRACT:
SUBMITTER: TINOCO J
PROVIDER: S-EPMC1206611 | biostudies-other | 1965 Mar
REPOSITORIES: biostudies-other
Similar Datasets
Project description:BACKGROUND:Proliferation of oval cells, the bipotent precursor cells of the liver, requires impeded proliferation and loss of hepatocytes as well as a specific micro-environment, provided by adjacent sinusoidal cells of liver. Despite their immense importance for triggering the oval cell response, cells of hepatic sinusoids are rarely investigated. To elucidate the response of sinusoidal liver cells we have employed a choline-deficient, ethionine-supplemented (CDE) diet, a common method for inducing an oval cell response in rodent liver. We have utilised selected expression markers commonly used in the past for phenotypic discrimination of oval cells and sinusoidal cells: cytokeratin, E-cadherin and M2-pyruvate kinase for oval cells; and glial fibrillary acidic protein (GFAP) was used for hepatic stellate cells (HSCs). RESULTS:CDE diet leads to an activation of all cells of the hepatic sinusoid in the mouse liver. Beside oval cells, also HSCs and Kupffer cells proliferate. The entire fraction of proliferating cells in mouse liver as well as endothelial cells and cholangiocytes express M2-pyruvate kinase. Concomitantly, GFAP, long considered a unique marker of quiescent HSCs was upregulated in activated HSCs and expressed also in cholangiocytes and oval cells. CONCLUSIONS:Our results point to an important role of all types of sinusoidal cells in regeneration from CDE induced liver damage and call for utmost caution in using traditional marker for identifying specific cell types. Thus, M2-pyruvate kinase should no longer be used for estimating the oval cell response in mouse liver. CDE diet leads to activation of GFAP positive HSCs in the pericentral zone of liver lobulus. In the periportal zone the detection of GFAP in biliary cells and oval cells, calls other cell types as progenitors of hepatocytes into question under CDE diet conditions.
| S-EPMC2964607 | biostudies-literature
Project description:Stress signaling, both within and outside the endoplasmic reticulum, has been linked to metabolic dysregulation and hepatic steatosis. Methionine-choline-deficient (MCD) diets cause severe fatty liver disease and have the potential to cause many types of cellular stress. The purpose of this study was to characterize hepatic stress in MCD-fed mice and explore the relationship between MCD-mediated stress and liver injury.Stress signaling was examined in mice fed MCD formulas for 4-21 days. Signaling also was evaluated in mice fed MCD formulas supplemented with clofibrate, which inhibits hepatic triglyceride accumulation. The role of the pro-apoptotic stress protein C/EBP homologous protein (CHOP) in MCD-mediated liver injury was assessed by comparing the responses of wild-type and CHOP-deficient mice to an MCD diet.MCD feeding caused steatohepatitis coincident with the activation of cJun N-terminal kinase and caspase-12. In contrast, MCD feeding did not activate inositol-requiring protein-1 and actually suppressed the expression of X-box protein-1s. MCD feeding caused weak stimulation of double-stranded RNA-activated protein kinase-like endoplasmic reticulum-resident kinase, but robust activation of general control nonderepressible-2, followed by the phosphorylation of eukaryotic initiating factor-2? and induction of CHOP. Clofibrate eliminated MCD-mediated hepatic steatosis but did not inhibit diet-induced stress. CHOP deficiency did not alleviate, and in fact worsened, MCD-mediated liver disease.MCD feeding causes an integrated stress response in the liver rather than a classic unfolded protein response. This stress response does not by itself lead to liver injury. CHOP, despite its identity as a mediator of stress-related cell death, does not play a central role in the pathogenesis of MCD-mediated liver disease.
| S-EPMC2967598 | biostudies-literature
Project description:Choline and methionine/choline deficient diets are widely used to generate severe rodent hepatic steatosis and steatohepatitis in an attempt to reflect stages of human non-alcoholic fatty liver disease (NAFLD). The underlying mechanism of hepatic injury in these models, and how this reflects human disease remains incompletely understood. We used detailed transcriptional analysis to interrogate the molecular mechanisms of this intervention and its similarity to human disease. Adult C57Bl/6J mice were maintained on control, choline deficient (CDD) or methionine/choline deficient (MCDD) diets for 4 weeks. Isolated liver RNA was used for transcriptional profiling by micro array analysis.
2016-06-01 | E-MTAB-3943 | biostudies-arrayexpress
Project description:Adaptive responses to hypoxia regulate hepatic lipid metabolism, but their consequences in nonalcoholic fatty liver disease (NAFLD) are largely unknown. Here, we show that hypoxia inducible factor-1 (HIF-1), a key determinant of hypoxic adaptations, prevents excessive hepatic lipid accumulation in the progression of NAFLD. When exposed to a choline-deficient diet (CDD) for 4 weeks, the loss of hepatic Hif-1? gene accelerated liver steatosis with enhanced triglyceride accumulation in the liver compared to wild-type (WT) livers. Expression of genes involved in peroxisomal fatty acid oxidation was suppressed significantly in CDD-treated WT livers, whereas this reduction was further enhanced in Hif-1?-deficient livers. A lack of induction and nuclear accumulation of lipin1, a key regulator of the PPAR?/PGC-1? pathway, could be attributed to impaired peroxisomal ?-oxidation in Hif-1?-deficient livers. The lipin1-mediated binding of PPAR? to the acyl CoA oxidase promoter was markedly reduced in Hif-1?-deficient mice exposed to a CDD. Moreover, forced Lipin1 expression restored the aberrant lipid accumulation caused by Hif-1? deletion in cells incubated in a choline-deficient medium. These results strongly suggest that HIF-1 plays a crucial role in the regulation of peroxisomal lipid metabolism by activating the expression and nuclear accumulation of lipin1 in NAFLD.
| S-EPMC6155071 | biostudies-literature
Project description:Choline kinase and phosphocholine cytidylytransferase catalyse the rate-limiting steps of the cytidine pathway for the synthesis of phosphatidylcholine [Infante (1977) Biochem. J. 167, 847--849]. Essential-fatty acid deficiency induces a 3.5-fold increase in the specific activity of choline kinase, whereas the specific activity of the cytidylytransferase remains unchanged in rat liver. This change in specific activity accounts for the calculated increase in flux through the cytidine pathway produced in vivo by the same dietary state [Trewhella & Collins (1973 Biochim. Biophys. Acta 296, 34--50], thus confirming the fact that choline kinase has a regulatory role in the cytidine pathway for the synthesis of phosphatidylcholine.
| S-EPMC1186279 | biostudies-other
Project description:Non-alcoholic fatty liver disease is the most common liver disorder in developed countries, and its incidence is increasing in all population groups. As an antioxidant, vitamin E is effective in the treatment of non-alcoholic fatty liver disease, although the mechanism is still unclear. Methionine-choline deficient Wistar rats (n = 5) used as an experimental model of non-alcoholic fatty liver disease were fed a vitamin E-enriched diet (500 mg/kg) for 4 weeks. The effects were assessed by measuring lipid peroxidation, ?-tocopherol levels, and the expression of ?-tocopherol-related proteins in the liver. In vitamin E-treated methionine-choline deficient rats, lipid peroxidation was reduced, but liver histopathological changes were not improved. Hepatic ?-tocopherol levels in these rats were significantly elevated compared to normal rats treated with vitamin E. Expression of liver ?-tocopherol transfer protein in vitamin E-treated methionine-choline deficient rats was significantly repressed compared to methionine-choline deficient rats. The expression of liver cytochrome P450 4F2 and ATP-binding cassette transporter protein 1, involved in metabolism and transport of ?-tocopherol, respectively, was significantly repressed in vitamin E-treated methionine-choline deficient rats. In methionine-choline deficient rats, vitamin E treatment altered the hepatic ?-tocopherol-related protein expression, which may affect ?-tocopherol status in the liver, leading to reduced lipid peroxidation.
| S-EPMC4042150 | biostudies-literature
Project description:Non-alcoholic fatty liver disease (NAFLD) is emerging as the most common chronic liver disease worldwide. In addition, NAFLD may increase the risk of cardiovascular and liver-related diseases, and displays features of metabolic syndrome. In NAFLD, oxidative stress is primarily caused by excessive free fatty acids. The oxidation of fatty acids is usually caused by β-oxidation of mitochondria under normal conditions, resulting in the production of energy. However, when the inflow of fatty acids in NAFLD becomes excessive, the β-oxidation of mitochondria becomes saturated and the oxidation process increases at sites including peroxisomes and microsomes, thereby increasing production of reactive oxygen species (ROS). Thus, hepatic mitochondrial ROS play an important role in the pathogenesis of NAFLD. Eliminating mitochondrial ROS may improve NAFLD, but the underlying mechanism remains unclear. We examined the effect of mitochondrial ROS on NAFLD by focusing on peroxiredoxin (Prx), an antioxidant protein that can remove hydrogen peroxide. The protective effect and pathological phenomenon of mitochondrial peroxiredoxin in methionine-choline deficient diet (MCD)-induced liver injury was assessed in a mouse model of NAFLD. In these mice, mitochondrial peroxiredoxin deficiency significantly increased hepatic steatosis and fibrosis. In addition, ablation of Prx III enhances susceptibility to MCD diet-induced oxidative stress and exacerbates NAFLD progression by promoting inflammation. The binding assay results also showed that Prx III-deficient mice had more severe liver damage than Prx III-abundant mice in MCD diet liver injury models. The present data suggest that mitochondrial peroxiredoxin III could be a therapeutic target for preventing and suppressing diet-induced NAFLD.
| S-EPMC9855157 | biostudies-literature
Project description:Chronic feeding of methyl-donor (methionine, choline, folic acid, and vitamin B12) deficient diet induces hepatocellular carcinoma formation in rats. Previous studies have shown that promoter CpG islands in various cancer-related genes are aberrantly methylated in this model. Moreover, the global genome in methyl-donor-deficient diet fed rats contains a lesser amount of 5-methylcytosine than control livers. It is speculated that more than 90% of all 5-methylcytosines lie within the CpG islands of the transposons, including the long/short interspersed nucleotide elements (LINE and SINE). It is considered that the 5-methylcytosines in LINE-1 limit the ability of retrotransposons to be activated and transcribed; therefore, the extent of hypomethylation of LINE-1 could be a surrogate marker for aberrant methylation in other tumor-related genes as well as genome instability. Additionally, LINE-1 methylation status has been shown to be a good indicator of genome-wide methylation. In this study, we determined cytosine methylation status in the LINE-1 repetitive sequences of rats fed a choline-deficient (CD) diet for various durations and compared these with rats fed a choline-sufficient (CS) diet. The methylation status of LINE-1 was assessed by the combined bisulfite restriction analysis (COBRA) method, where the amount of bisulfite-modified and RsaI-cleaved DNA was quantified using gel electrophoresis. Progressive hypomethylation was observed in LINE-1 of CD livers as a function of feeding time; that is, the amount of cytosine in total cytosine (methylated and unmethylated) increased from 11.1% (1 week) to 19.3% (56 weeks), whereas in the control CS livers, it increased from 9.2% to 12.9%. Hypomethylation in tumor tissues was slightly higher (6%) than the nontumorous surrounding tissue. The present result also indicates that age is a factor influencing the extent of cytosine methylation.
| S-EPMC1479888 | biostudies-literature
Project description:Methionine-choline-deficient (MCD) diets cause steatohepatitis in rodents and are used to study the pathophysiology of fatty liver disease in human beings. The most widely used commercial MCD formulas not only lack methionine and choline but also contain excess sucrose and fat. The objective of this study was to determine whether dietary sucrose in the MCD formula plays a role in the pathogenesis of MCD-related liver disease. We prepared two custom MCD formulas, one containing sucrose as the principal carbohydrate and the other substituting sucrose with starch. Mice fed the sucrose-enriched formula developed typical features of MCD-related liver disease, including hepatic steatosis, hepatocellular apoptosis, alanine aminotransferase elevation, lipid peroxidation, and hepatic inflammation. In contrast, mice fed MCD-starch were significantly protected against liver injury. MCD-sucrose and MCD-starch mice displayed identical diet-related abnormalities in hepatic fatty acid uptake and triglyceride secretion. Hepatic de novo lipogenesis and triglyceride synthesis, however, were 2 times higher in MCD-sucrose mice than MCD-starch mice (P < 0.01). Hepatic lipid analysis revealed accumulation of excess saturated fatty acids in MCD-sucrose mice that correlated with hepatocellular injury. Overall, the results indicate that dietary sucrose is critical to the pathogenesis of MCD-mediated steatohepatitis. They suggest that saturated fatty acids, which are products of de novo lipogenesis, are mediators of hepatic toxicity in this model of liver disease.
| S-EPMC2739762 | biostudies-literature
Project description:Specific deletion of the tumor suppressor TRAF3 from B lymphocytes in mice leads to the prolonged survival of mature B cells and expanded B cell compartments in secondary lymphoid organs. In the current study, we investigated the metabolic basis of TRAF3-mediated regulation of B cell survival by employing metabolomic, lipidomic, and transcriptomic analyses. We compared the polar metabolites, lipids, and metabolic enzymes of resting splenic B cells purified from young adult B cell-specific Traf3 -/- and littermate control mice. We found that multiple metabolites, lipids, and enzymes regulated by TRAF3 in B cells are clustered in the choline metabolic pathway. Using stable isotope labeling, we demonstrated that phosphocholine and phosphatidylcholine biosynthesis was markedly elevated in Traf3 -/- mouse B cells and decreased in TRAF3-reconstituted human multiple myeloma cells. Furthermore, pharmacological inhibition of choline kinase ?, an enzyme that catalyzes phosphocholine synthesis and was strikingly increased in Traf3 -/- B cells, substantially reversed the survival phenotype of Traf3 -/- B cells both in vitro and in vivo. Taken together, our results indicate that enhanced phosphocholine and phosphatidylcholine synthesis supports the prolonged survival of Traf3 -/- B lymphocytes. Our findings suggest that TRAF3-regulated choline metabolism has diagnostic and therapeutic value for B cell malignancies with TRAF3 deletions or relevant mutations.
| S-EPMC6946882 | biostudies-literature