Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Choline is required to make certain phospholipids which are essential components of all membranes. It is a precursor for biosynthesis of the neurotransmitter acetylcholine and also is an important source of labile methyl groups. Much attention has been given to the effect of supplemental choline upon brain function, i.e., enhancement of acetylcholine synthesis and release. In addition, choline supplements administered to rats in utero or shortly after birth permanently after brain function. The mechanisms for this effect is unknown and under investigation at this time. Healthy humans fed diets deficient in choline, and humans fed parenterally have decreased plasma choline concentrations and develop liver dysfunction that is similar to that seen in choline-deficient animals. In experimental animals, fatty liver occurs in choline deficiency because phosphatidylcholine synthesis is required for very low-density lipoprotein secretion. This accumulation of lipids in liver may explain why choline-deficient rats spontaneously develop hepatocarcinoma. We found that choline deficiency was associated with the accumulation of 1,2-diacylglycerol, an activator of protein kinase C. Several lines of evidence indicate that cancers might develop secondary to abnormalities in protein kinase C-mediated signal transduction.
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PMID:Choline: an important nutrient in brain development, liver function and carcinogenesis. 145 45

Ethionine, an ethyl analogue of methionine, induces fatty liver in rats. The effects of ethionine administration on protein kinase C (PKC) in rat liver was examined. By a single administration at a dose of 0.5 mg/g body wt., liver PKC activity was increased in both cytosolic and total particulate fractions. The increase in cytosol was significant, even at 4 h after administration, when compared with control rat liver cytosol. On the other hand, a 4-day consecutive administration (0.5 mg/g per day) resulted in decreased PKC activity, particularly in cytosol, when compared with the control. Protein phosphorylation in liver catalyzed by PKC was found to be enhanced by ethionine, irrespective of the mode of administration. The enhanced phosphorylation was observed in both cytosolic and total particulate fractions. The change of PKC activity, and the phosphorylation of its endogenous substrates, are postulated to be involved in the pathogenesis of ethionine-induced fatty liver of rats.
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PMID:Altered protein kinase C activity and its endogenous protein phosphorylation in rat liver after administration of ethionine. 160 39

Protein kinase (PK) C activity in the liver of cattle with fatty liver syndrome was evaluated and compared with that in liver of healthy cattle. The PKC activities in cytosolic and particulate fractions were reduced in fatty livers, compared with those in livers from healthy cattle. The decrease of PKC activity was more distinct in cytosolic (P = 0.0016) than particulate (P = 0.069) fractions. Protein kinase activities other than PKC were not substantially changed. Seemingly, PKC was involved in the pathogenesis of fatty liver syndrome in cattle.
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PMID:Decreased protein kinase C activity in fatty liver from cattle. 280 19

Rats fed a choline deficient diet develop foci of enzyme-altered hepatocytes with subsequent formation of hepatic tumors. This is the only nutritional deficiency that, in itself, causes cancer. We suggested that carcinogenesis is triggered, in part, because of abnormalities in cell signals which regulate cell proliferation and cell death. Because choline deficient rats develop fatty liver (choline is needed for hepatic secretion of certain lipoproteins), we examined whether an important lipid second messenger involved in proliferative signaling, 1,2-sn-diacylglycerol, accumulated in liver and resulted in the prolonged activation of protein kinase C. We observed that 1,2-sn-diacylglycerol accumulated in the plasma membrane from the non-tumor portion of livers of rats fed a choline deficient diet, and that unsaturated free fatty acids, another activator of protein kinase C, also accumulated in deficient livers. Protein kinase C in the hepatic plasma membrane and nucleus of choline deficient rats was elevated for months; this is the only model system which exhibits such prolonged activation of protein kinase C. Premalignant, abnormal hepatic foci were detected only in the deficient rats, and 15% of deficient rats (none of the controls) had hepatocellular carcinoma at 1 year on the diet. In rats, an early event in choline deficiency is an increase in the rate of cell death. In liver from choline deficient rats, we observed an increase in the numbers of liver cells with fragmented DNA (characteristic of programmed cell death; apoptosis). We used a cell culture model (immortalized rat hepatocytes) to study the effects of choline deficiency on apoptosis. Liver cells grown in a choline deficient medium became depleted of choline, accumulated triacylglycerol and 1,2-sn-diacylglycerol, and had increased DNA fragmentation and other morphologic and biochemical changes associated with apoptosis. This model has great potential as a tool for studying the underlying link between choline deficiency and the regulation of the balance between cell proliferation and cell death. We suggest that choline deficiency altered the cell proliferation signals mediated by protein kinase C within liver, and altered cell apoptosis. These changes in cell signaling may be the triggering events which result in hepatic carcinogenesis.
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PMID:Choline and hepatocarcinogenesis in the rat. 764 29

Peroxisome proliferator-activated receptor (PPAR) and retinoid x receptor (RXR) play important roles in fatty acid metabolism. The present study examined the regulation of retinoic acid receptor (RAR alpha, beta, and gamma), RXR (alpha, beta, and gamma), PPAR, cytochrome P450 2E1 (CYP2E1), catalase, and beta-actin gene expression in chronic alcoholic liver disease in the rat. The results demonstrated that the expression of genes for RAR and RXR isoforms and catalase were not altered by ethanol in the fatty liver. In contrast, the levels of PPAR and CYP2E1 mRNAs were down- and up-regulated by ethanol in the liver, respectively. The levels of CYP2E1 mRNAs correlated positively with blood alcohol levels (BAL). In addition, ethanol induced expression of beta-actin mRNA was also proportional to the BAL. The level of PPAR mRNA and the content of polyunsaturated fatty acid decreased in ethanol-fed rat livers. Decreased PPAR gene expression in ethanol-fed rats might result from a decrease in the content of polyunsaturated fatty acid in the liver. However, the activities of enzymes involved in hepatic lipid metabolism, including acyl CoA synthetase, acyl CoA oxidase, catalase, and protein kinase C, were not changed by ethanol treatment. The significance of down-regulation of PPAR gene in alcohol liver disease is discussed.
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PMID:Expression of the peroxisome proliferator-activated receptor gene is decreased in experimental alcoholic liver disease. 783 30

Parenchymal cells were isolated from the liver of male calves, and monolayer cultures formed were treated with glucocorticoids to examine whether haptoglobin, appearance of which is associated with hepatic lipidosis (fatty liver) in cattle, is induced by steroid hormones. Without addition of dexamethasone, only trace amounts of haptoglobin were detected in culture medium. With addition of dexamethasone (10(-12) to 10(-4) M), considerable amounts of haptoglobin were released into the medium. Maximal release was observed at concentrations of 10(-8) to 10(-6) M dexamethasone. Haptoglobin release was similarly induced by cortisol, although the effect was less potent than that of dexamethasone. Actinomycin D (a known protein synthesis inhibitor) dose-dependently reduced amounts of haptoglobin released in response to 10(-8) M dexamethasone. Dexamethasone also induced annexin I, which is known to be synthesized in response to glucocorticoids. Dexamethasone treatment resulted in reduced protein kinase C activity in the cell cytosol, which has been shown to be an early event in dexamethasone-treated cells. Other than glucocorticoids, estradiol induced haptoglobin release, whereas progesterone was less effective. The association of haptoglobin with hepatic lipidosis can be reasonably explained by the fact that haptoglobin production by the liver is induced by glucocorticoids and estradiol, and these steroid hormones are triggers for development of hepatic lipidosis in cattle.
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PMID:Dexamethasone-induced haptoglobin release by calf liver parenchymal cells. 797 46

Haptoglobin (Hp), an acute-phase protein, is detected in serum of cows with hepatic lipidosis (fatty liver). To assess the relevance of Hp in fatty liver, induction of Hp was examined, using conditions similar to those involving development of fatty liver in cows. Induction of Hp was achieved by a combination of dexamethasone administration (0.1 mg/kg of body weight) and 2 days' starvation. Haptoglobin appearance in serum was not associated with the increase of alpha 1-acid glycoprotein (a marker for inflammation). This treatment increased serum nonesterified fatty acids concentration and decreased serum triglycerides concentration. Protein kinase C activity was decreased in the cytosolic fractions of liver and mononuclear cells. Reduction of protein kinase C-catalyzed endogenous protein phosphorylation also was observed, particularly in the cytosolic fractions of the tissue and cells. Detection of Hp in serum of cows with fatty liver appears to be explained by the fact that Hp is induced by dexamethasone administration and starvation, which are similar to the condition responsible for fatty liver development. The change of protein kinase C-catalyzed phosphorylation was suggested to be involved in the induction of Hp in cows.
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PMID:Possible involvement of protein kinase C with induction of haptoglobin in cows by treatment with dexamethasone and by starvation. 831 60

Choline deficiency, via deprivation of labile methyl groups, is associated with a greatly increased incidence of hepatocarcinoma in experimental animals. This dietary deficiency also causes fatty liver, because choline is needed for hepatic secretion of lipoproteins. We hypothesized that fatty liver might be associated with the accumulation of 1,2-sn-diradylglycerol and subsequent activation of protein kinase C. Several lines of evidence indicate that cancers might develop secondary to abnormalities in protein kinase C-mediated signal transduction. We observed that rats fed a choline-deficient diet for 1, 6, or 27 weeks had increased hepatic concentrations of 1,2-diradylglycerol. At 1 and 6 weeks, hepatic plasma membrane from choline-deficient rats had increased concentrations of 1,2-sn-diacylglycerol and 1-alkyl, 2-acylglycerol, with the latter accounting for 20-26% of membrane 1,2-sn-diradylglycerol (as compared with only 2-5% in controls). Protein kinase C activity was increased in hepatic plasma membrane at 1 week of choline deficiency. By Western blotting there was an increase in the amount of protein kinase C zeta and a decrease in the amount of protein kinase C delta in liver at 1 week. By 6 weeks of choline deficiency, hepatic plasma membrane and cytosolic protein kinase C (PKC) activities were increased significantly, with increased amounts of hepatic plasma membrane protein kinase C alpha, and delta detected by Western blotting. Glycogen synthase activity in liver was diminished after 1 week of choline deficiency; this enzyme is inhibited by PKC-mediated phosphorylation. We suggest that choline deficiency perturbed PKC-mediated transmembrane signaling within liver and that this contributed to the development of hepatic cancer in these animals.
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PMID:Accumulation of 1,2-sn-diradylglycerol with increased membrane-associated protein kinase C may be the mechanism for spontaneous hepatocarcinogenesis in choline-deficient rats. 842 Sep 80

High intracellular 1,2,-sn-diacylglycerol (DAG) usually activates protein kinase C (PKC). In choline-deficient Fischer 344 rats, we previously showed that fatty liver was associated with elevated hepatic DAG and sustained activation of PKC. Steatosis is a sequelae of many liver toxins, and we wanted to determine whether fatty liver is always associated with accumulation of DAG with activation of PKC. Obese Zucker rats had 11-fold more triacylglycerol in their livers and 2-fold more DAG in their hepatic plasma membrane than did lean control Zucker rats. However, this increased diacylglycerol was not associated with translocation or activation of PKC in hepatic plasma membrane (activity in obese rats was 897 pmol/mg protein X min(-1) vs. 780 pmol/mg protein X min(-1) in lean rats). No differences in PKC isoform expression were detected between obese and lean rats. In additional studies, we found that choline deficiency in the Zucker rat did not result in activation of PKC in liver, unlike our earlier observations in the choline deficient Fischer rat. This dissociation between fatty liver, DAG accumulation and PKC activation in Zucker rats supports previous reports of abnormalities in PKC signaling in this strain of rats.
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PMID:Hepatic protein kinase C is not activated despite high intracellular 1,2-sn-diacylglycerol in obese Zucker rats. 929 24

Acute ethanol administration induces significant modifications both in secretive and formative membranes of rat liver Golgi apparatus. The decrease in glycolipoprotein secretion and their retention into the hepatocyte contribute to the pathogenesis of alcohol-induced fatty liver. Molecular and cellular mechanisms behind the ethanol-induced injury of the liver secretory pathway are not yet completely defined. In this study on intact livers from ethanol-treated rats, the involvement of the Golgi compartment in the impairment of hepatic glycolipoprotein secretion has been correlated with changes in the expression level, subcellular distribution and enzymatic activity of protein kinase C (PKC) isoforms. Acute ethanol exposure determined a translocation of classic PKCs and delta isoform from the cytosol to cis and trans Golgi membranes, the site of glycolipoprotein retention in the hepatic cell. A marked stimulation of cytosolic epsilon PKC activity was observed throughout the period of treatment. The presence of activated PKC isozymes at the Golgi compartment of alcohol-treated rat livers may play a role in hepatic secretion and protein accumulation. Direct and indirect effects of ethanol consumption on PKC isozymes and Golgi function are discussed.
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PMID:Ethanol-induced effects on expression level, activity, and distribution of protein kinase C isoforms in rat liver Golgi apparatus. 974 54


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