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)

Mitochondrial dysfunctions of the muscle in diabetic amyotrophy and of the liver in diabetic fatty liver have been reported. We investigated mitochondrial gene mutations in three cases: (1) a patient with diabetic amyotrophy in the muscles of the lower extremities, and neuropathy; (2) 5 diabetics with myoatrophy, diabetic nephropathy, and chronic renal failure; and (3) an IDDM patient with a diabetic fatty liver. We identified a 5778-bp deletion (8214-13991) in mitochondrial DNA from the muscle and liver biopsy specimens by the primer shift PCR and PCR-direct sequence methods. It is speculated that 5778-bp deletion is due to homogeneous recombination in the 7-bp repeat sequence of TCCTAGA flanking the region deleted in the mitochondrial DNA. Determination of respiratory chain enzyme activities in fresh muscle mitochondria demonstrated the defect in complex I activity. The deletion covers areas coding ND3, ND4, ND4L, and ND5 in complex I. The 5778-bp deletion might cause a defect in mitochondrial oxidative phosphorylation and contribute to the pathogenesis of diabetic amyotrophy, myoatrophy with diabetic nephropathy, and chronic renal failure, as well as diabetic fatty liver in IDDM.
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PMID:A new mitochondrial DNA deletion associated with diabetic amyotrophy, diabetic myoatrophy and diabetic fatty liver. 760 16

Fatty liver dystrophy ( fld) is an autosomal recessive mutation in mice characterized by hypertriglyceridemia and fatty liver during neonatal development. The fatty liver in fld/fld mice spontaneously resolves between the age of 14-18 days, at which point the animals develop a neuropathy associated with abnormal myelin formation in peripheral nerve. We have investigated the morphological and biochemical alterations that occur in the fatty liver of neonatal fld/fld mice. Studies at the light and electron microscopic level demonstrated the accumulation of lipid droplets and hypertrophic parenchymal cells in fld neonates, with no apparent liver pathology after resolution of the fatty liver. To better characterize the biochemical basis for the development of fatty liver in fld mice, we compared protein expression patterns in the fatty liver of fld mice and in the liver of phenotypically normal (wild-type) littermates using quantitative two-dimensional gel electrophoresis. We detected 24 proteins with significantly altered expression levels (P < 0.001) in the fld fatty liver, 15 of which are proteins that are altered in abundance by peroxisome proliferating chemicals. As these compounds characteristically elicit changes in the expression of mitochondrial and peroxisomal enzymes involved in fatty acid oxidation, we quantitated rates of fatty acid oxidation in hepatocytes isolated from fld and wild-type mice. These studies revealed that hepatic fatty acid oxidation in fld neonates is reduced by 60% compared to wild-type littermates. In hepatocytes from adult fld mice that no longer exhibit a fatty liver, oxidation rates were similar to those in hepatocytes from age-matched wild-type mice. These findings indicate that altered expression of proteins involved in fatty acid oxidation is associated with triglyceride accumulation in the fld fatty liver.
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PMID:The fatty liver dystrophy mutant mouse: microvesicular steatosis associated with altered expression levels of peroxisome proliferator-regulated proteins. 979 7

The fatty liver dystrophy (fld) mutant mouse is characterized by neonatal fatty liver and hypertriglyceridemia that resolve at weaning, and neuropathy affecting peripheral nerve in adulthood. We now report additional significant manifestations of this single gene mutation, which include adipose tissue deficiency, glucose intolerance, and increased susceptibility to atherosclerosis. In adult fld/fld mice, both white and brown fat pads exhibit an 80% reduction in mass compared with wild-type controls, and consist of immature adipocytes as assessed by morphological and molecular criteria. The lack of lipid accumulation in fld/fld adipose tissue could be attributed, in part, to a failure to induce expression of lipoprotein lipase and enzymes involved in fatty acid synthesis, such as fatty acid synthase and acetyl-CoA carboxylase. Related to the deficiency of adipose tissue, fld/fld mice were also found to exhibit profound glucose intolerance, modest hyperinsulinemia, and reduced tissue response to insulin. As insulin resistance is a important risk factor in vascular disease, we examined susceptibility of fld/fld mice to diet-induced atherosclerosis. Mutant mice fed an atherogenic diet developed 2-fold greater aortic lesions than their wild-type counterparts, despite having a less atherogenic lipoprotein cholesterol profile. The fld adipose-deficient phenotype has both similarities to and distinctions from the group of rare human diseases known as lipodystrophies.
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PMID:Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene. 1088 87

Nucleoside analogues represent the cornerstones of antiretroviral regimens. A range of drug- or tissue-specific toxicities, such as peripheral neuropathy, myopathy, pancreatitis and lactic acidosis with hepatic steatosis, has been documented with these agents. The fat atrophy seen on long term antiretroviral therapy may also be related to nucleoside analogues. The mechanisms by which nucleoside analogues cause toxicity are not clearly established. In vitro, the triphosphates of these agents are weak to modest substrates for human DNA polymerases, showing the greatest affinity for mitochondrial DNA polymerase gamma. Short term exposure in vitro to some nucleoside analogues has been demonstrated to cause increased lactate production or falls in mitochondrial DNA suggestive of mitochondrial toxicity. However, stavudine and to a lesser extent zidovudine are poor substrates for mitochondrial thymidine kinase type 2, the predominant form in cells that are not actively mitotic such as neurons, myocytes and adipocytes. These are the cell types where the proposed mitochondrial toxicities neuropathy, myopathy and lipoatrophy are observed. Thus, active concentrations of phosphorylated products of stavudine and zidovudine may not be present in mitochondria. The familial mitochondrial diseases do not have identical presentations to nucleoside analogue toxicities. These disorders most commonly involve the CNS, typically with seizures or dementia, and occasionally the kidneys. Although nucleoside analogues are known to penetrate the CNS and are commonly renally excreted unchanged, mitochondrial toxicities at these sites have not been documented. Furthermore, toxicity caused by nucleoside or nucleotide analogues does not always appear to arise through the mitochondrial route. Cidofovir appears to cause renal tubular dysfunction via a toxic intracellular metabolite, and zidovudine-related anaemia appears to be related to decreased globin RNA synthesis. In vitro or animal models suggest that zidovudine myopathy, stavudine-related (but not zalcitabine- or didanosine-related) neuropathy and didanosine-related pancreatitis may all be not related, or not exclusively related, to mitochondrial dysfunction. The integration of nucleoside analogues into nuclear DNA, best documented with zidovudine but likely to occur with other agents, represents an alternative but potentially delayed pathway to cytotoxicity and cell apoptosis. This is the mechanism of cell death during therapy with antineoplastic nucleoside analogues, and may have contributed to the multisystem toxicities observed with the anti-hepatitis B drug fialuridine. New research evaluating the effects of long term exposure of cell lines is required to address the possibility that nuclear genotoxicity plays a role in long term nucleoside analogue toxicity.
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PMID:Toxicity of antiretroviral nucleoside and nucleotide analogues: is mitochondrial toxicity the only mechanism? 1114 57

Since the adoption of highly active antiretroviral therapy (HAART) in the mid-1990s, certain metabolic toxicities have been increasingly recognized. These include a fat redistribution syndrome (lipohypertrophy, lipoatrophy), hyperlipidaemia, altered glucose metabolism and insulin resistance, mitochondrial toxicity (presenting as anaemia, myopathy, pancreatitis, neuropathy, hepatic steatosis and lactic acidosis), and bone density abnormalities (osteoporosis and osteonecrosis). Metabolic complications are principally reported with protease inhibitors and nucleoside reverse transcriptase inhibitors, but may be seen with all classes of antiretroviral therapy. In this review, we summarize the epidemiology, pathogenesis and management of these various toxicities.
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PMID:The metabolic toxicities of antiretroviral therapy. 1151 63

The introduction of newer and more potent agents has diverted attention away from the importance of nucleoside analogue reverse transcriptase inhibitors (NRTIs) in modern antiretroviral drug regimens. As a class, these proviral chain terminators lack the virological potency of either non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) drugs, due largely to their competitive mode of inhibition and requirement for metabolic activation. However, neither NNRTIs nor PIs alone can maintain the complete suppression of HIV replication required for extended therapy, and both suffer from serious class cross-resistance on therapeutic failure. Thus, the NRTIs will remain essential components of highly active antiretroviral therapy (HAART) for the foreseeable future, both for their contribution to a regimen's virological potency and the subsequent preservation of the more potent drug classes used with them. However, it has become apparent in recent years that the current NRTIs exhibit duration-dependent adverse events as a class, which may limit the length of time for which they can be safely used. An independent contribution to peripheral fat wasting in lipodystrophy syndrome has been established for the use of NRTI drugs. Of greater clinical concern is their established association with potentially fatal lactic acidaemia and hepatic steatosis. Both these class events, as well as several individual drug events, such as peripheral; neuropathy, can be linked to progressive mitochondrial destruction with a greater or lesser degree of confidence. Mitochondrial toxicity, due in large part to the high affinity of several NRTI agents for uptake by mitochondrial DNA polymerase gamma, has been demonstrated both in vitro and in vivo. New chain-terminating agents are urgently needed that address issues of improved virological potency, greater efficacy in NRTI-experienced individuals, and greater long-term safety. The nucleotide class of reverse transcriptase inhibitor (NtRTI), currently under clinical development, addresses improved potency by abbreviating the intracellular activation pathway to allow a more rapid and complete conversion to the active agent. These nucleoside monophosphate analogues are taken as masked prodrugs bearing labile lipophilic groups to facilitate penetration of target cell membranes. Subsequent unmasking by endogenous chemolytic enzymes releases a partially activated nucleoside analogue metabolite. The NtRTI furthest along the developmental process is tenofovir disoproxil fumarate (TDF), an orally available acyclic adenine phosphonate analogue, currently in Phase III clinical trials. This agent has shown high potency and an unusually durable response in trials of single-agent therapy intensification in highly treatment-experienced individuals, and its active metabolite, tenofovir diphosphate, exhibits a long intracellular half-life in both resting and activated peripheral blood mononuclear cells that permits once daily dosing. Tenofovir diphosphate also exhibits a very low affinity for DNA polymerase gamma in vitro, suggesting a low degree of in vivo mitochondrial toxicity may be observed on long-term follow-up, although clinical data to support this inference are not yet available. The introduction of TDF and other NtRTIs as 'second-generation' nucleoside analogues carefully evaluated for potential long-term toxicity, can be expected to significantly improve the therapeutic options for both those currently on HAART and those yet to begin.
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PMID:An introduction to nucleoside and nucleotide analogues. 1167 69

Three categories of highly active antiretroviral therapy (HAART)-associated major toxic effects have been identified: nucleoside-related toxic effects (e.g., neuropathy, myopathy, pancreatitis, hepatic steatosis, lactic acidosis, and possibly lipoatrophy), metabolic complications (e.g., fat redistribution, insulin resistance, and hyperlipidemia), and bone disease (e.g., osteopenia and/or osteoporosis). The toxic effects caused by nucleosides are hypothesized to be a result of mitochondrial injury and include myopathy, pancreatitis, liver failure, and lactic acidosis. Alterations in lactic acid metabolism range from common instances of asymptomatic lactic acidemia to rare occurrences of life-threatening lactic acidosis with hepatic steatosis. A metabolic syndrome consisting of lipodystrophy (i.e., fat redistribution), hyperlipidemia and insulin resistance has been observed, particularly with protease inhibitor treatment. Some additive interaction between protease inhibitors and nucleosides has also been described. The potential relationship of these metabolic abnormalities to increased risk of cardiovascular disease and diabetes has broad implications on long-term patient management. Lipodystrophy associated with HAART is generally accompanied by potentially serious abnormalities, including dyslipidemia (i.e., hypercholesterolemia and hypertriglyceridemia) and altered glucose metabolism (i.e., insulin resistance). Regimens of HAART may have adverse effects on bone metabolism, as indicated by emerging reports of osteopenia, osteoporosis, and avascular necrosis.
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PMID:Long-term exposure to lifelong therapies. 1183 99

HAART has resulted in dramatic declines in morbidity and mortality among patients infected with HIV. Increased experience with HAART has led to the detection of drug related toxicities that may compromise adherence and necessitate discontinuation of treatment and alteration of otherwise effective regimens. This article considers the major long-term complications associated with nucleoside reverse transcriptase inhibitor (NRTI) use--hyperlactatemia and lactic acidosis/hepatic steatosis, other hepatotoxicities, pancreatitis, lipodystrophy, lipoatrophy, neuropathy, and hematologic toxicities. Mechanisms by which NRTIs may produce these effects are discussed, as are differential effects of agents in this class and management options.
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PMID:Long-term complications of nucleoside reverse transcriptase inhibitor therapy. 1274 68

Mitochondrial fatty acid oxidation disorders (FAOD) are recessively inherited errors of metabolism. Newborns with FAOD typically present with hypoketotic hypoglycemia, metabolic acidosis, hepatic failure, and cardiomyopathy. Late presentations include episodic myopathy, neuropathy, retinopathy, and arrhythmias. Sudden unexpected death can occur at any age and can be confused with sudden infant death syndrome. Some FAOD are associated with intrauterine growth restriction, prematurity, and pregnancy complications in the heterozygous mother, such as severe preeclampsia, acute fatty liver of pregnancy (AFLP), or hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Maternal pregnancy complications occur primarily in mothers carrying a fetus with long-chain l-3-hydroxyacyl CoA dehydrogenase deficiency or general trifunctional protein deficiencies. FAOD as a group represent the most common inborn errors of metabolism, and presymptomatic diagnosis of FAOD is the key to reduce morbidity and avoid mortality. The application of tandem mass spectrometry to newborn screening provides an effective means to identify most FAOD patients presymptomatically. At the beginning of 2005, 36 state newborn screening programs have mandated or adopted this technology resulting in a marked increase in the number of asymptomatic neonates with FAOD diagnosed. To ensure the long-term benefits of such screening programs, pediatricians and other health care providers must be educated about these disorders and their treatment.
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PMID:Fetal fatty acid oxidation disorders, their effect on maternal health and neonatal outcome: impact of expanded newborn screening on their diagnosis and management. 1581 98

Advances in anti-retroviral therapy (ART) has led to improved survival of patients infected with the human immunodeficiency virus (HIV). ART for HIV patients is composed of a combination of nucleoside reverse transcriptase inhibitors (NRTI) and/or a non-nucleoside reverse transcriptase inhibitor (NNRTI), and/or a protease inhibitor (PI). The long-term exposure to ART and HIV are causing mitochondrial toxicities, such as myopathies, neuropathy, myelopoiesis, pancreatitis, lactic acidosis, hepatic steatosis, and lipodystrophy. The mitochondrial pathogenesis has been believed to be due exclusively to NRTI-induced inhibition of DNA polymerase-gamma; it is now apparent that the etiology is far more complex, involving multiple mechanisms as well as an effect by HIV per se. Current therapy for patients includes interruption or change in medications and mitochondrial co-factors.
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PMID:Mitochondrial dysfunction in AIDS and its treatment. 1612 Apr 31


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