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)

In a full life cycle test, newly hatched eggs of zebra fish, Brachydanio rerio, were reared to sexual maturity under continuous exposure to 40, 80, 110, 130, and 150 micrograms/liter lindane, gamma-hexachlorocyclohexane. The effects of lindane were investigated by recording behavior and survival of the F0- and F1-generation as well as morphological alterations in liver ultrastructure of F0. Changes in peroxisomes were visualized by cytochemical staining for catalase activity with diaminobenzidine. Whereas behavioral changes can already be observed at 40 micrograms/liter, survival and number of eggs in F0 as well as survival and growth of F1 are unaffected by up to 80 micrograms/liter lindane. At concentrations greater than or equal to 110 micrograms/liter, survival of larvae is reduced already after 35 days, and mortality is 100% after 3 months. From 40 micrograms/liter, liver ultrastructure displays a microvesicular fatty vacuolation (steatosis) characterized by lipid deposition within the cisternae of the RER. At 40 micrograms/liter, this highly specific pathological change is accompanied by accumulation of hepatic macrovesicular triglyceride droplets, glycogen depletion, and the occurrence of club-shaped mitochondria. Additional alterations at 80 micrograms/liter comprise proliferation of SER in males and progressive fractionation of RER in females, stacking of club-shaped mitochondria, a conspicuous decrease in peroxisomal catalase activity, infiltration of macrophages into the liver parenchyma, and a significant stimulation of hepatocytic mitosis. Among several substances tested so far in zebra fish (4-nitrophenol, 4-chloroaniline 3,4-dichloroaniline, atrazine, lindane), lindane is the only compound inducing behavioral changes and hepatic steatosis in conjunction with a reduction in fertility. With regard to the relative sensitivity of the methods applied, behavioral and cytological studies appear more responsive to lindane exposure than survival studies.
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PMID:Hepatic steatosis in zebra fish (Brachydanio rerio) induced by long-term exposure to gamma-hexachlorocyclohexane. 169 56

Rats were fed a low protein diet deficient in and supplemented with lysine and threonine. Liver lipids contained more lecithin, sphingomyelin, and free fatty acids, and less amino phospholipids in the deficient rats. No variations in fatty acid composition of choline- and ethanolamine-containing phospholipids were found; only palmitic acid was increased in the serine-containing phospholipids of the deficient animals. The incorporation of acetate-(14)C into phospholipids, but not into other liver lipids, was lower in deficient rats. In the plasma of deficient rats the concentration of esterified fatty acids and phospholipids was lower, of free fatty acids higher, than in the controls. The fatty acid composition of depot fat differed from that of liver neutral fat both in deficient and supplemented animals. The results presented establish that multiple metabolic defects resulting from lysine and threonine deficiency accompany the fatty liver. The design of the experiments does not permit conclusions to be drawn regarding the causal relationship between the various alterations in lipid metabolism and the fatty liver.
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PMID:Lipid metabolism in fatty liver of lysine- and threonine-deficient rats. 596 90

Protein kinase C (PKC) activity was evaluated and the phosphorylation of its endogenous substrates was explored in fatty liver induced by administration of ethionine (an analogue of methionine) to cows in order to assess the relevance of PKC-dependent phosphorylation in the development of fatty liver. PKC activity was decreased in both the cytosolic and the total particulate fractions from fatty livers, compared to the corresponding fractions from control liver. The mode of activation by the PKC cofactors (1-oleoyl-2-acetyl-sn-glycerol, 12-O-tetradecanoylphorbol-13-acetate, phosphatidyl-serine and Ca2+) was similar in both control and fatty livers, suggesting a quantitative but not a qualitative change in PKC in fatty liver. At least three substrate proteins (34 kDa, 26 kDa and 19 kDa) were found in the cytosolic fraction and their phosphorylation was reduced in fatty liver. These results suggest that impairment of the signal transduction pathway mediated by PKC is involved in the pathogenesis of fatty liver in cows.
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PMID:Reduced protein kinase C activity and endogenous protein phosphorylation in ethionine-induced fatty liver in cows. 770 79

We studied the variations arising in plasma and liver lipids after intravenous (i.v.), intraperitoneal (IP), and intragastric (IG) administration of a fat overdose on the order of 4 g.kg-1 body wt.day-1 in the form of Intralipid (ITL) 20% to 33 New Zealand rabbits for 15 days. The control group was submitted for surgery but did not receive an ITL supplement. The results show weight gain in all animals and normal liver enzyme values. There was an increase in plasma lipids in groups supplemented by the parenteral route (i.v. and IP), and fatty acids showed a similar distribution, in terms of percentages, to that for ITL. In liver tissue, there was an increase in the fractions related to ethanolamine and a decrease in phospholipids of choline and serine. In the i.v. group, neutral lipids predominated compared with other groups. The livers of all supplemented animals (i.v., IP, and IG) showed a higher content of stearic and linoleic acid and a reduction in oleic acid. Study with optical microscopy showed a microvacuolization affecting the three areas of the hepatic acini in the i.v. group, seen with electron microscopy as vacuoles lacking membranes and surrounded by mitochondria. In conclusion, there is an increase in hepatic steatosis in parenteral groups and a greater deposit of neutral lipids in the i.v. group, related to the administration route, without biochemical signs of liver dysfunction.
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PMID:Liver lipid composition and intravenous, intraperitoneal, and enteral administration of intralipid. 819 19

Previously we have reported on siblings with severe hypercholesterolemia, xanthomas, and premature atherosclerosis without any impairment of low-density lipoprotein receptor in their fibroblasts as a first characterization of autosomal recessive hypercholesterolemia (ARH). Recently, mutations were identified for this disease in a gene encoding a putative adaptor protein. The purpose of this study was to examine the molecular pathogenesis of ARH in Japanese siblings. A novel insertion mutation was discovered in the ARH gene of the siblings. An insertion of an extra cytosine residue was identified in a locus comprising eight consecutive cytosines at positions 599 through 606 in exon 6, resulting in a sequence of nine cytosines and generating an early stop codon at 657-659. The mother was heterozygous for this mutation. Neither transcription product nor protein of ARH was detected in the fibroblasts of the homozygous patients. A single nucleotide polymorphism was discovered among the normal control subjects at position 604 (cytosine to thymine: ARH-604C to ARH-604T), which changes the proline residue at 202 to serine. Interestingly, ARH is caused by a mutation of cytosine to adenine at this same position. Both siblings exhibited fatty liver, which may also be related to this mutation.
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PMID:Clinical features and genetic analysis of autosomal recessive hypercholesterolemia. 1278 51

Insulin resistance and increased cytochrome P450 2E1 (CYP2E1) expression are both associated with and mechanistically implicated in the development of nonalcoholic fatty liver disease. Although currently viewed as distinct factors, insulin resistance and CYP2E1 expression may be interrelated through the ability of CYP2E1-induced oxidant stress to impair hepatic insulin signaling. To test this possibility, the effects of in vitro and in vivo CYP2E1 overexpression on hepatocyte insulin signaling were examined. CYP2E1 overexpression in a hepatocyte cell line decreased tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2 in response to insulin. CYP2E1 overexpression was also associated with increased inhibitory serine 307 and 636/639 IRS-1 phosphorylation. In parallel, the effects of insulin on Akt activation, glycogen synthase kinase 3, and FoxO1a phosphorylation, and glucose secretion were all significantly decreased in CYP2E1 overexpressing cells. This inhibition of insulin signaling by CYP2E1 overexpression was partially c-Jun N-terminal kinase dependent. In the methionine- and choline-deficient diet mouse model of steatohepatitis with CYP2E1 overexpression, insulin-induced IRS-1, IRS-2, and Akt phosphorylation were similarly decreased. These findings indicate that increased hepatocyte CYP2E1 expression and the presence of steatohepatitis result in the down-regulation of insulin signaling, potentially contributing to the insulin resistance associated with nonalcoholic fatty liver disease.
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PMID:Hepatocyte CYP2E1 overexpression and steatohepatitis lead to impaired hepatic insulin signaling. 1563 82

Plasma free fatty acid (FFA) levels are elevated in obesity. FFA, by causing insulin resistance in muscle, liver, and endothelial cells, contributes to the development of type 2 diabetes mellitus (T2DM), hypertension, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD). The mechanism through which FFA induces insulin resistance involves intramyocellular and intrahepatocellular accumulation of triglycerides and diacylglycerol, activation of several serine/threonine kinases, reduction in tyrosine phosphorylation of the insulin receptor substrate (IRS)-1/2, and impairment of the IRS/phosphatidylinositol 3-kinase pathway of insulin signaling. FFA also produces low-grade inflammation in skeletal muscle and liver through activation of nuclear factor-kappaB, resulting in release of several proinflammatory and proatherogenic cytokines. Thus, elevated FFA levels (due to obesity or to high-fat feeding) cause insulin resistance in skeletal muscle and liver, which contributes to the development of T2DM, and produce low-grade inflammation, which contributes to the development of atherosclerotic vascular diseases and NAFLD.
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PMID:Fatty acid-induced inflammation and insulin resistance in skeletal muscle and liver. 1689 68

Mitochondrial dysfunction is involved in the three stages of the transition from lack of exercise and excessive food intake to insulin resistance, diabetes and non-alcoholic steatohepatitis (NASH). In muscle, lack of exercise, a fat-rich diet, a polymorphism in peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1), and possibly age-related mitochondrial DNA (mtDNA) mutations may variously combine their effects to decrease PGC-1 expression, mitochondrial biogenesis and fat oxidation. Together with excessive food intake, insufficient fat oxidation causes fat accumulation and cellular stress in myocytes. The activation of Jun N-terminal kinase and protein kinase C-theta triggers the serine phosphorylation and inactivation of the insulin receptor substrate, and hampers the insulin-mediated translocation of glucose transporter-4 to the plasma membrane. Initially, the trend for increased blood glucose increases insulin secretion by pancreatic beta-cells. High plasma insulin levels compensate for insulin resistance in muscle and maintain normal blood glucose levels. Eventually, however, increased uncoupling protein-2 expression and possibly acquired mtDNA mutations in pancreatic beta-cells can blunt glucose-mediated adenosine triphosphate (ATP) formation and insulin secretion, to cause diabetes in some patients. High plasma glucose and/or insulin levels induce hepatic lipogenesis and cause hepatic steatosis. In fat-engorged hepatocytes, several vicious cycles involving tumor necrosis factor-alpha, reactive oxygen species (ROS), peroxynitrite, and lipid peroxidation products alter respiratory chain polypeptides and mtDNA, thus partially blocking the flow of electrons in the respiratory chain. The overreduction of upstream respiratory chain complexes increases mitochondrial ROS and peroxynitrite formation. Oxidative stress increases the release of lipid peroxidation products and cytokines, which together trigger the liver lesions of NASH.
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PMID:Role of mitochondria in non-alcoholic fatty liver disease. 1756 59

Insulin resistance, a hallmark of type 2 diabetes and obesity, is associated with increased activity of MAP and stress-activated protein (SAP) kinases, which results in decreased insulin signaling. Our goal was to investigate the role of MAP kinase phosphatase-4 (MKP-4) in modulating this process. We found that MKP-4 expression is up-regulated during adipocyte and myocyte differentiation in vitro and up-regulated during fasting in white adipose tissue in vivo. Overexpression of MKP-4 in 3T3-L1 cells inhibited ERK and JNK phosphorylation and, to a lesser extent, p38MAPK phosphorylation. As a result, the phosphorylation of IRS-1 serine 307 induced by anisomycin was abolished, leading to a sensitization of insulin signaling with recovery of insulin-stimulated IRS-1 tyrosine phosphorylation, IRS-1 docking with phosphatidylinositol 3-kinase, and Akt phosphorylation. MKP-4 also reversed the effect of TNF-alpha to inhibit insulin signaling; alter IL-6, Glut1 and Glut4 expression; and inhibit insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Overexpression of MKP-4 in the liver of ob/ob mice decreased ERK and JNK phosphorylation, leading to a reduction in fed and fasted glycemia, improved glucose intolerance, decreased expression of gluconeogenic and lipogenic genes, and reduced hepatic steatosis. Thus, MKP-4 has a protective effect against the development of insulin resistance through its ability to dephosphorylate and inactivate crucial mediators of stress-induced insulin resistance, such as ERK and JNK, and increasing MKP-4 activity might provide a therapy for insulin-resistant disorders.
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PMID:Overexpression of the dual-specificity phosphatase MKP-4/DUSP-9 protects against stress-induced insulin resistance. 1829 38

Liver plays a major role in regulating energy homeostasis in mammals. During feeding conditions, excessive glucose is converted into a preferred storage form of energy sources as triacylglycerol in liver via a collective metabolic pathway termed lipogenesis. Sterol regulatory element-binding protein 1c is a master regulator for this process by activating number of enzyme genes, such as Fasn or Acaca, that are involved in this pathway at the transcriptional level. Here we show that the salt-inducible kinase (SIK) family of proteins regulates the hepatic lipogenesis by modulating SREBP-1c activity. Overexpression of SIK1 inhibits hepatic expression of lipogenic genes, such as Fasn, whereas knockdown of SIK1 in liver greatly enhances their expression. Regulation of the Fasn gene by SIK kinases is mediated at the level of transcription via phosphorylation and inactivation of nuclear SREBP-1c. Among candidate sites for SIK-dependent regulation of SREBP-1c, the serine 329 residue is shown to be a critical regulatory site for SIK-mediated repression of SREBP-1c activity by in vitro kinase assay and reverse transcription-PCR analysis in primary hepatocytes. Finally, reduced hepatic triacylglycerol levels and lipogenic gene expression by adenoviral SIK1 transgenic expression are restored to normal levels by co-infection of mutant SREBP-1c, suggesting that SIK-dependent regulation of hepatic lipogenesis is indeed mediated through the phosphorylation of SREBP-1c in vivo. The process for the development of nonalcoholic fatty liver involves de novo lipogenesis via the activation of SREBP-1c. Modulation of SREBP-1c activity by SIK proteins would provide an attractive means for the regulation of such diseases.
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PMID:Salt-inducible kinase regulates hepatic lipogenesis by controlling SREBP-1c phosphorylation. 1924 31


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