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)

Ethanol and other alcohols stimulate adenylate cyclase activity in various tissues and potentiate its stimulation by some hormones. This effect, however, usually requires a high alcohol concentration. In some cases, an unknown substance, different from cyclic AMP, was formed from ATP in the presence of an alcohol and mimicked stimulation of adenylate cyclase. Ethanol inhibits phosphodiesterase activity in some tissues. In the brain, only the low affinity enzyme of pons-medulla region is inhibited. ATP levels and ATPase activities are affected by ethanol treatment and this can lead to secondary changes of the cyclic AMP levels. Cyclic AMP levels in the brain and liver are decreased by acute ethanol administration while levels in other organs are unchanged. High doses of ethanol inhibit the postdecapitation-induced rise of cyclic AMP level in the brain while low ethanol doses potentiate the postdecapitation rise of cyclic AMP in the lower brain stem. Chronic ethanol administration increases basal adenylate cyclase activity and cyclic AMP levels, and decreases stimulation of adenylate cyclase by norepinephrine in the brain. In contrast, the stimulation of cyclic AMP formation by norepinephrine and other biogenic amines is increased in the brain of ethanol-withdrawn animals. Chronic administration of ethanol affects also cyclic AMP levels and cyclic AMP formation in some peripheral organs. Cyclic AMP might be involved in ethanol-induced fatty liver, since it activates hepatic lipase and might also participate in the fatty acid oxidation.
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PMID:Interactions of ethanol with cyclic AMP. 16 56

The fatty liver often found in untreated kwashiorkor has been associated with highly variable concentration of circulating lipids. The effect on lipid metabolism of two isocaloric diets--one synthetic monomolecular (Vivonex) and one standard (Casilan)--which both initiated satisfactory clinical improvement was studied in 21 Ethiopian children with kwashiorkor during the first weeks of rehabilitation. Before treatment mean fasting values of all biochemical parameters were within normal ranges except for moderately elevated triglycerides--an unexpected finding-and low insulin. Individual values varied greatly; triglyceride between 0.39 and 3.49 mmol/1. FFA correlated both to glycerol, D-beta-hydroxybutyrate and triglyceride values. During treatment insulin, glucose and glycerol remained essentially unchanged and were similar in both dietary groups. In the Vivonex group only there was an initial marked, parallel fall of FFA and D-beta-hydroxybutyrate suggesting greater availability of carbohydrate and enhanced glucose utilization. This pattern of response seemed to occur without comparable inhibition of lipolysis. Triglycerides--like serum albumin--increased faster in the Casilan group. The highest mean triglyceride value was reached by day 8 in the Casilan group and by day 15 in the Vivonex group. Ten minutes following heparin injection triglycerides declined, FFA and glycerol increased indicating release of in vivo active lipase. LPL activity assayed in vitro was similar and unaffected by 2 weeks of dietary treatment in both groups. LPL activity was inversely correlated to triglycerides providing--beside the type of diet--another possible explanation for the wide variations seen in circulatory triglycerides.
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PMID:Dietary effects in the early recovery phase of kwashiorkor. Plasma levels of triglycerides, FFA, D-beta-hydroxybutyrate, glycerol, postheparin lipoprotein lipase (LPL), glucose and insulin. 127 67

In a previous report (Langner, C. A., Birkenmeier, E. H., Ben-Zeev, O., Schotz, M. C., Sweet, H. O., Davisson, M. T., and Gordon, J. I. (1989) J. Biol. Chem. 264, 7994-8003), we characterized the early developmental phenotype of mice that were homozygous for the autosomal recessive fatty liver dystrophy (fld) mutation. Shortly after birth, these mice can be distinguished from their +/? littermates by large pale livers, hypertriglyceridemia, elevations in hepatic apolipoprotein A-IV and apoC-II mRNA levels, and tissue-specific decreases in lipoprotein lipase and hepatic lipase activities. These traits resolve by the early weaning period. We have now characterized a second feature of this mutation: a peripheral neuropathy that becomes manifest by an abnormal gait at the end of the second postnatal week and persists through adulthood. Electron microscopic studies of sciatic nerves from 4-day-to 1-year-old fld/fld mice demonstrated a variety of abnormalities including thin, poorly compacted myelin sheaths, active myelin breakdown, and enlarged Schwann cell mitochondria and nuclei. Western blot analysis of sciatic nerve homogenates prepared from 1 to 3-month-old fld/fld mice and their +/? littermates indicated that homozygous animals have striking reductions in two peripheral nerve myelin-associated proteins, P0 and P2. The steady-state level of apoE, a protein induced during nerve regeneration, is markedly elevated. Furthermore, two axon-specific proteins, neurofilament 68K and growth-associated 43 protein, display altered expression in adult fld/fld sciatic nerves. High performance thin-layer chromatography revealed deficiencies in phospholipids, glycosphingolipids, and some neutral lipids in fld/fld sciatic nerves harvested during the first several months of life (compared to their +/? littermates). Cholesterol esters were elevated in homozygotes. By contrast, no differences in brain lipids were noted between fld/fld animals and their +/? littermates. These data suggest that the fld mutation is associated with an abnormality of myelin formation (dysmyelination) as well as demyelination and axonal degeneration that persists despite apparent resolution of the neonatal hypertriglyceridemia and associated lipase abnormalities. These findings establish the fld/fld mouse as an excellent model system for analyzing homeostatic mechanisms that modulate lipid metabolism in newborn mice and for examining the pathogenesis of peripheral neuropathies associated with dyslipidemias.
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PMID:Characterization of the peripheral neuropathy in neonatal and adult mice that are homozygous for the fatty liver dystrophy (fld) mutation. 205 Jun 89

Fatty liver was induced in Wistar rats by orotic acid and the recovery process was studied by enzyme histochemical staining for non specific esterase, lipase and by ultrastructural investigation. Enzyme histochemically, these enzyme activities were markedly decreased in orotic acid-induced fatty liver. However, during the recovery process after the end of orotic acid administration, these enzyme activities clearly appeared. Under these conditions, no significant ultrastructural alterations could be detected. Based on our data, pathogenesis of orotic acid-induced fatty liver was discussed.
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PMID:Enzyme histochemical and ultrastructural approach in orotic acid-induced fatty liver and their recovery process in Wistar rats. 246 50

An autosomal recessive mutation, termed fatty liver dystrophy (fld), can be identified in neonatal mice by their enlarged and fatty liver (Sweet, H. O., Birkenmeier, E. H., and Davisson, M. T. (1988) Mouse News Letter 81, 69). We have examined the underlying metabolic abnormalities in fld/fld mice from postnatal days 3-40. Serum and hepatic triglyceride levels were elevated 5-fold in suckling fld/fld mice compared to their +/? littermates but abruptly resolved at the suckling/weaning transition. Blot hybridization analysis of liver and intestinal RNAs revealed a liver-specific increase in apolipoprotein (apo) A-IV and C-II mRNA concentrations (100- and 6-fold, respectively) that was limited to the suckling and early weaning stages in fld/fld mice. Resolution of these differences during the weaning period could not be delayed by prolonging suckling to the 20th postnatal day nor could the mutant phenotype be elicited in young adult animals with a high fat diet. Lipoprotein lipase (LPL) activity was reduced 16-fold in the white adipose tissue of fld/fld mice until the onset of weaning. Heart activity was decreased less than 2-fold, but there were no deficits in brown adipose tissue or liver. Hepatic lipase (HL) mRNA levels and activity were significantly reduced in fld/fld livers and sera, respectively, during the suckling period. Mapping studies show the fld locus to be distinct from loci encoding LPL, HL, and apoA-IV, and those responsible for the combined lipase deficiencies in cld/cld and W/Wv mice. These data suggest that the fld mutation is associated with developmentally programmed tissue-specific defects in the neonatal expression of LPL and HL activities and provide evidence for a new regulatory locus which affects these lipase activities. This mutation could serve as a useful model for (i) analyzing the homeostatic mechanisms controlling lipid metabolism in newborn mice and (ii) understanding and treating certain inborn errors in human triglyceride metabolism.
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PMID:The fatty liver dystrophy (fld) mutation. A new mutant mouse with a developmental abnormality in triglyceride metabolism and associated tissue-specific defects in lipoprotein lipase and hepatic lipase activities. 272 72

Hepatic steatosis frequently complicates total parenteral nutrition (TPN). Some of the mechanisms responsible were examined in rats receiving calories as dextrose (CHO-TPN) or dextrose plus lipid emulsion (Lipid-TPN). Hepatic triglyceride content increased approximately threefold after CHO-TPN and twofold after Lipid-TPN (P less than 0.02). Hepatic triglyceride fatty acid composition reflected endogenous synthesis. Hepatic acetyl-Coenzyme A carboxylase specific activity increased fourfold after CHO-TPN and twofold after Lipid-TPN, and it correlated positively with hepatic lipid content (r = 0.82). The activities of the microsomal enzymes of complex lipid synthesis were unchanged in the TPN groups. Both TPN regimens suppressed hepatic triglyceride secretion, measured by the rise in plasma triglyceride and the incorporation of [14C]palmitic acid into plasma triglyceride after intravenous Triton. Hepatic triglyceride secretion correlated negatively with total hepatic lipid content (r = -0.89). CHO-TPN increased the uptake of a radiolabeled triglyceride emulsion and increased hepatic lipase activity, whereas Lipid-TPN decreased both. Both adipose and cardiac lipase were higher for Lipid-TPN animals than for CHO-TPN or control animals. Hepatic 14C-triglyceride content was increased in both TPN groups as compared with controls after the injection of 1-[14C]-palmitic acid. This increment was proportional to the decreased hepatic secretion. Triglyceride fatty acid oxidation was significantly suppressed by CHO-TPN, less so by Lipid-TPN. Free fatty acid oxidation was suppressed only by CHO-TPN. The results suggest that the steatosis induced by TPN in rats was due to enhanced hepatic synthesis of fatty acid and reduced triglyceride secretion. Reduced hepatic triglyceride uptake, enhanced fatty acid oxidation, and enhanced peripheral tissue plasma triglyceride lipolysis when CHO-TPN is supplemented with lipid may modulate the accumulation of hepatic triglyceride and, along with reduced synthesis of fatty acid, lead to a lower hepatic triglyceride content.
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PMID:Pathogenesis of hepatic steatosis in the parenterally fed rat. 643 55

Neutral lipid storage disease (NLSD) is an autosomal recessive disorder in which excess triacylglycerol (TG) accumulates in most cells. Although it has been hypothesized that the TG accumulation is caused by a functional defect in cytosolic lipase activity, we were able to expose TG hydrolysis in NLSD cells by using triacsin C, an inhibitor of acyl-CoA synthetase that blocks the reincorporation of hydrolyzed fatty acids into glycerolipids. Our data suggest that TG lipolysis in NLSD cells is masked by rapid TG resynthesis, occurring because released acylglycerols cannot be used for phospholipid synthesis. In uptake studies, triacsin C blocked the incorporation of [3H]glycerol into glycerolipids, incorporation of [14C]oleate into TG, but not incorporation of [14C]oleate into phospholipid. Thus, the drug inhibited both de novo synthesis of glycerolipids via the glycerol-3-phosphate pathway and the synthesis of TG from diacylglycerol. The drug did not appear to block reacylation of lysophospholipids. Triacsin C caused a loss of about 60% of the TG mass from both NLSD and oleate-loaded control cells. Rates of TG lipolysis were similar in NLSD cells and oleate-loaded control cells labeled with [6-(7-nitro-2,1,3-benzoxadiazol-4-yl)-amino]hexanoic acid or labeled with [14C]oleate or [3H]glycerol and chased in the presence of triacsin C. During a 96-h chase, [14C]oleate reincorporation into the different phospholipid species increased only in control cells. Similar results were observed when NLSD, and control cells were chased after labeling with [3H]glycerol. These data strongly suggest that normal human fibroblasts mobilize stored TG for phospholipid synthesis and that recycling to PC occurs via a TG-derived mono- or diacylglycerol intermediate. Normal recycling to phosphatidylethanolamine may primarily involve TG-derived acyl groups rather than an acylglycerol precursor. NLSD cells appear to have a block in this recycling pathway with the result that both hydrolyzed fatty acids and the acylglycerol backbone are re-esterified to form TG. Because the NLSD phenotype includes ichthyosis, fatty liver, myopathy, cardiomyopathy, and mental retardation, the recycling pathway appears to be critical for the normal function of skin, liver, muscle, heart, and the central nervous system.
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PMID:Acylglycerol recycling from triacylglycerol to phospholipid, not lipase activity, is defective in neutral lipid storage disease fibroblasts. 866 20

Naturally occurring mutations in the mouse provide a unique resource for identifying genes and characterizing proteins involved in lipid metabolism. Spontaneous mouse mutations have been described that affect various aspects of lipid metabolism, including cellular cholesterol homeostasis, fatty acid metabolism, serum lipoprotein levels, serum and tissue lipase activities, and lipid composition of tissues such as liver, nerve, kidney, and adrenal gland. Here we briefly describe the phenotypes and genetics of several mutants with blood and tissue lipid abnormalities, and then provide a more in-depth discussion of two mutations, fatty liver dystrophy (fld) and combined lipase deficiency (cld). Mice homozygous for the fld mutation exhibit fatty liver and hypertriglyceridemia during neonatal development, and a peripheral neuropathy that progresses throughout the lifetime of the animal. Combined lipase deficiency is characterized by a nearly complete absence of lipoprotein lipase and hepatic lipase activity resulting in neonatal lethality. Although the underlying genes for these two disorders have yet to be identified, candidates that have been implicated through the molecular and biochemical characterization of the mutants are discussed.
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PMID:Naturally occurring mutations in mice affecting lipid transport and metabolism. 882 13

Fasting induces pancreatic secretory lipase, possibly through an increased utilization of fatty acids and/or ketone bodies by the acinar cells. To test this hypothesis, the effects of L-aminocarnitine (ACA), an inhibitor of mitochondrial beta-oxidation and ketone body formation, on the pancreatic enzyme composition were studied in rats. The characteristics and reversibility of the hepatic steatosis produced by ACA in fasted animals were also investigated. In fasted rats, ACA decreased the plasma levels of beta-hydroxybutyrate, glucose and insulin, but increased that of glucagon. Fasting for 3 days increased the pancreatic lipase content by 80%. Administration of ACA (3, 10 or 30 mg kg(-1) daily) for 3 days to fasted rats led to dose-related decreases in pancreatic lipase content, the fasting-induced increase was prevented even by the lowest dose. Nevertheless, ACA in the fasted rats likewise decreased the pancreatic contents of protein, amylase and trypsinogen to varying degrees, suggesting a general defect of protein synthesis. The 3-day treatment with ACA during fasting led to dose-related, marked increases in hepatic weight and triglyceride content. Light and electron microscopy revealed lipid vesicles of varying sizes in the hepatocytes; the fat deposition was predominant in the periportal zones of the hepatic lobules. By means of electron microscopy, lipid vacuoles were observed in the centroacinar cells, but not in the acinar cells of the pancreas. In rats treated with 30 mg kg(-1) of ACA daily for 3 days while they were fasted, cessation of ACA treatment and refeeding with normal chow led to normalization of the pancreatic enzyme contents within 6 days, and gradual and complete disappearance of the hepatic steatosis within 24 days. Microscopy also demonstrated complete recovery in both the liver and the pancreas. The results indicate that pancreatic secretory lipase induction during the adaptive phase of starvation is dependent on an unhindered mitochondrial beta-oxidation of fatty acids and ketogenesis. The dose-related degree of hepatic triglyceride accumulation which can be produced readily by administration of ACA during short-term starvation in the rat may serve as a new, convenient experimental model for studies of fatty liver.
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PMID:Effect of L-aminocarnitine, an inhibitor of mitochondrial fatty acid oxidation, on the exocrine pancreas and liver in fasted rats. 1060 Feb 64

Biochemical mechanisms which may control fat deposition in liver and/or peripheral tissues have been studied in Poland and Landes geese. Post-prandial plasma substrates and post-heparin lipoprotein-lipase (LPL) activity were measured in 10-week-old animals. At 23 weeks of age, geese were overfed for 14 days then slaughtered. Hepatic steatosis was more important in Landes geese, while muscle and subcutaneous adipose tissue were less developed. In this breed, fatty liver weight negatively scaled to LPL activity, suggesting that a low LPL activity is a limiting factor of peripheral fat deposition. Consequently, non-catabolized VLDL may return to liver and increase hepatic steatosis. In Poland geese, such a mechanism does not exist. On the other hand, fatty liver weight was positively correlated to very low density lipoproteins (VLDL) and triacylglycerols measured in overfed Poland geese, suggesting that lipids synthetized by liver are better transferred from liver to extrahepatic tissues. Kinetics of post-prandial plasma glucose, triacylglycerols, phospholipids and uric acid were similar in the two breeds. However, the marked decrease in post-prandial plasma glycerol in Poland geese suggests that an extrahepatic tissue lipolysis inhibition could contribute to the higher peripheral fattening in overfed Poland geese and could be a limiting factor of hepatic steatosis in this breed.
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PMID:Metabolism in two breeds of geese with moderate or large overfeeding induced liver-steatosis. 1090 56


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