Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019209 (hepatomegaly)
 5,798 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Supplementation of a closed formula, cereal based stock diet with excess L-histidine at a 5% or 8% level for 4 days reduced growth and induced hepatomegaly and an increase in plasma cholesterole levels in weanling rats. The enlargement of the liver was in part due to glycogen accumulation; plasma glucose concentration was unchanged. Feeding four different amino acids (L-phenylalanine, L-glutamic acid, glycine and L-tryptophan), at levels which caused reduction of growth comparable to the 5% and 8% L-histidine supplementation, did not effect liver weight or plasma cholesterol levels. L-Threonine added, at a 2% level, to the 8% L-histidine diet did not alleviate any of the histidine effects. Rats fed a diet containing 5% urocanic acid, the first metabolite of the histidine degradative pathway, grew at a normal rate but had higher plasma cholesterol levels compared to rats fed stock diet. When rats fed L-histidine-or urocanic acid-supplemented diets were returned to stock diet, a normal growth rate was resumed immediately and plasma cholesterol levels returned to normal within 6 days. These results suggest that L-histidine and/or urocanic acid induce a hypercholesterolemia which disappears several days after the supplementation ceases.
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PMID:Effect of excess dietary L-histidine on plasma cholesterol levels in weanling rats. 65 Feb 95

Two siblings had Leber's congenital amaurosis. The girl (Patient 1) showed blindness shortly after birth, absent pupillary light reflex, and multiple round, white spots in both fundi. Her serum threonine level was increased (2.0 to 5.3 mg/dl; normal, 0.78 to 1.82 mg/dl). She died of massive pericardial effusion four months after birth. Her brother (Patient 2) was nearly blind shortly after birth. He had a poor pupillary light reflex and a nearly extinguished electroretinographic response. He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly, and mental and physical retardation. We suspect a close relationship between hyperthreoninemia and Leber's congenital amaurosis in these siblings.
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PMID:Leber's congenital amaurosis associated with hyperthreoninemia. 308 84

To elucidate the effect of peroxisome proliferators on the signal-transduction pathway, we have compared the effect of ciprofibrate, an hypolipaemic agent, on the overall phosphoprotein level between rat and human well differentiated hepatic derived cell lines. The phosphorylation status of several phosphoproteins in the rat Fao cell line was increased by the drug while no changes were observed in the human HepG2 cell line. In rat Fao cells, this increase, which is concentration and time dependent, can be as much as eightfold for 20-kDa and 22-kDa proteins. Wy-14,643, a non-fibrate molecule and a more potent peroxisome proliferator than ciprofibrate, increased the phosphorylation status of the same phosphoproteins. Peroxisome proliferators may act by activating kinases inactive in control cells, by amplifying kinases already active in control cells or by inactivating phosphatases. The phosphoamino acid residues affected are essentially serine and threonine. This modification of the signal-transduction pathway by the peroxisome proliferators in rodent cells appears to be an early event or an independent mechanism of the peroxisome proliferation. These results support the accumulating evidence that the perturbation of this pathway may be a major cause of the hepatomegaly and the hepatocarcinogenesis induced by peroxisome proliferators in rodent species. In contrast, the lack of phosphorylation changes in the human HepG2 cell line supports the non-toxic effect of peroxisome proliferators also used as hypolipaemic agents in humans.
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PMID:Influence of peroxisome proliferators on phosphoprotein levels in human and rat hepatic-derived cell lines. 760 Nov 16

Glucosidase I is an important enzyme in N-linked glycoprotein processing, removing specifically distal alpha-1,2-linked glucose from the Glc3Man9GlcNAc2 precursor after its en bloc transfer from dolichyl diphosphate to a nascent polypeptide chain in the endoplasmic reticulum. We have identified a glucosidase I defect in a neonate with severe generalized hypotonia and dysmorphic features. The clinical course was progressive and was characterized by the occurrence of hepatomegaly, hypoventilation, feeding problems, seizures, and fatal outcome at age 74 d. The accumulation of the tetrasaccharide Glc(alpha1-2)Glc(alpha1-3)Glc(alpha1-3)Man in the patient's urine indicated a glycosylation disorder. Enzymological studies on liver tissue and cultured skin fibroblasts revealed a severe glucosidase I deficiency. The residual activity was <3% of that of controls. Glucosidase I activities in cultured skin fibroblasts from both parents were found to be 50% of those of controls. Tissues from the patient subjected to SDS-PAGE followed by immunoblotting revealed strongly decreased amounts of glucosidase I protein in the homogenate of the liver, and a less-severe decrease in cultured skin fibroblasts. Molecular studies showed that the patient was a compound heterozygote for two missense mutations in the glucosidase I gene: (1) one allele harbored a G-->C transition at nucleotide (nt) 1587, resulting in the substitution of Arg at position 486 by Thr (R486T), and (2) on the other allele a T-->C transition at nt 2085 resulted in the substitution of Phe at position 652 by Leu (F652L). The mother was heterozygous for the G-->C transition, whereas the father was heterozygous for the T-->C transition. These base changes were not seen in 100 control DNA samples. A causal relationship between the alpha-glucosidase I deficiency and the disease is postulated.
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PMID:A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency. 1078 35

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a kind of inborn errors of metabolism, with the main clinic manifestations of jaundice, hepatomegaly, and abnormal liver function indices. As a mitochondrial solute carrier protein, citrin plays important roles in aerobic glycolysis, gluconeogenesis, urea cycle, and protein and nucleotide syntheses. Therefore citrin deficiency causes various and complicated metabolic disturbances, such as hypoglycemia, hyperlactic acidemia, hyperammonemia, hypoproteinemia, hyperlipidemia, and galactosemia. This paper reported a case of NICCD confirmed by mutation analysis of SLC25A13, the gene encoding citrin. The baby (male, 6 months old) was referred to the First Affiliated Hospital with the complaint of jaundice of the skin and sclera, which it had suffered from for nearly 6 months. Physical examination showed obvious jaundice and a palpable liver 5 cm below the right subcostal margin. Liver function tests revealed elevated enzymatic activities, like GGT, ALP, AST, and ALT, together with increased levels of TBA, bilirubin (especially conjugated bilirubin), and decreased levels of total protein/albumin and fibrinogen. Blood levels of ammonia, lactate, cholesterol, and triglyceride were also increased, and in particular, the serum AFP level reached 319,225.70 microg/L, a extremely elevated value that has rarely been found in practice before. Tandem mass analysis of a dried blood sample revealed increased levels of free fatty acids and tyrosine, methionine, citrulline, and threonine as well. UP-GC-MS analysis of the urine sample showed elevated galactose and galactitol. The baby was thus diagnosed with suspected NICCD based on the findings. It was then treated with oral arginine and multiple vitamins (including fat-soluble vitamins A, D, E, and K), and was fed with lactose-free and medium-chain fatty acids enriched formula instead of breast feeding. After half a month of treatment, the jaundice disappeared, and the laboratory findings, including liver function indices, blood levels of ammonia, lactate and AFP, were returned to normal level. The baby was followed up for 6 months. It developed well, and the abnormal laboratory findings, including MS-MS and UP-GC-MS analysis results, have been corrected, except a slightly elevated lactate level sometimes. SLC25A13 gene mutation analysis for the patient revealed a compound heterozygote of mutation 851del4 and 1638ins23 and therefore NICCD was definitely diagnosed.
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PMID:[A difficult and complicated case study: neonatal intrahepatic cholestasis caused by citrin deficiency]. 1661 6

unc-51-like autophagy activating kinase 1 and 2 (Ulk1/2) regulate autophagy initiation under various stress conditions. However, the physiological functions of these Ser/Thr kinases are not well characterized. Here, we show that mice with liver-specific double knockout (LDKO) of Ulk1 and Ulk2 (Ulk1/2 LDKO) are viable, but exhibit overt hepatomegaly phenotype. Surprisingly, Ulk1/2 LDKO mice display normal autophagic activity in hepatocytes upon overnight fasting, but are strongly resistant to acetaminophen (APAP)-induced liver injury. Further studies revealed that Ulk1/2 are also dispensable for APAP-induced autophagy process, but are essential for the maximum activation of c-Jun N-terminal kinase (JNK) signaling both in vivo and in isolated primary hepatocytes during APAP treatment. Mechanistically, APAP-induced inhibition of mechanistic target of rapamycin complex 1 releases Ulk1 from an inactive state. Activated Ulk1 then directly phosphorylates and increases the kinase activity of mitogen-activated protein kinase kinase 4 and 7 (MKK4/7), the upstream kinases and activator of JNK, and mediates APAP-induced liver injury. Ulk1-dependent phosphorylation of MKK7 was further confirmed by a context-dependent phosphorylation antibody. Moreover, activation of JNK and APAP-induced cell death was markedly attenuated in Mkk4/7 double knockdown hepatocytes reconstituted with an Ulk1-unphosphorylatable mutant of MKK7 compared to those in cells rescued with wild-type MKK7.
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PMID:Liver-specific deficiency of unc-51 like kinase 1 and 2 protects mice from acetaminophen-induced liver injury. 2939 64