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)

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

The World Health Organization estimates that around one billion people throughout the world are overweight and that over 300 million of these are obese and if current trends continue, the number of overweight persons will increase to 1.5 billion by 2015. The number of obese adults in Australia is estimated to have risen from 2.0 million in 1992/93 to 3.1 million in 2005. The prevalence of obesity has been increasing due to a convergence of factors--the rise of TV viewing, our preference for takeaway and pre-prepared foods, the trend towards more computer-bound sedentary jobs, and fewer opportunities for sport and physical exercise. Obesity is not only linked to lack of self esteem, social and work discrimination, but also to illnesses such as the metabolic syndrome and hyperinsulinaemia (which increases the risk of developing heart disease, diabetes, hypertension, fatty liver), cancer, asthma, dementia, arthritis and kidney disease. It has been estimated that the cost of obesity in Australia in 2005 was $1,721 million. Of this amount, $1,084 million were direct health costs, and $637 million indirect health costs (due to lost work productivity, absenteeism and unemployment). The prevalence cost per year for each obese adult has been estimated at $554 and the value of an obesity cure is about $6,903 per obese person. Government efforts at reducing the burden remain inadequate and a more radical approach is needed. The Australian government, for example, has made changes to Medicare so that GPs can refer people with chronic illness due to obesity to an exercise physiologist and dietitian and receive a Medicare rebate, but so far these measures are having no perceptible effect on obesity levels. There is a growing recognition that both Public Health and Clinical approaches, and Private and Public resources, need to be brought to this growing problem. Australian health economist, Paul Gross, from the Institute of Health Economics and Technology Assessment claims there is too much reliance on health workers to treat the problem, especially doctors, who have not been given additional resources to manage obesity outside a typical doctor's consultation. Gross has recommended that further changes should be made to Medicare, private health insurance, and workplace and tax legislation to give people financial incentives to change their behaviour because obesity should not just be treated by governments as a public health problem but also as a barrier to productivity and a drain on resources. A Special Report of the WMCACA (Weight Management Code Administration Council of Australia) (www.weightcouncil.org) on the "Health Economics of Weight Management" has been published in the Asia Pacific Journal of Clinical Nutrition in September 2006. This report explores the cost benefit analysis of weight management in greater detail.
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PMID:Health economics of weight management: evidence and cost. 1739 29

The incidence of obesity has increased dramatically during recent decades. Obesity will cause a decline in life expectancy for the first time in recent history due to numerous co-morbid disorders. Adipocyte and adipose tissue dysfunction belong to the primary defects in obesity and may link obesity to several health problems including increased risk of insulin resistance, type 2 diabetes, fatty liver disease, hypertension, dyslipidemia, atherosclerosis, dementia, airway disease and some cancers. However, not all obese individuals develop obesity related metabolic or cardiovascular disorders potentially due to a preserved normal adipose tissue architecture and function. The majority of patients with obesity have an impaired adipose tissue function caused by the interaction of genetic and environmental factors which lead to adipocyte hypertrophy, hypoxia, a variety of stresses and inflammatory processes within adipose tissue. Ectopic fat accumulation including visceral obesity may be considered as a consequence of adipose tissue dysfunction, which is further characterized by changes in the cellular composition, increased lipid storage and impaired insulin sensitivity in adipocytes, and secretion of a proinflammatory, atherogenic, and diabetogenic adipokine pattern. This review focuses on the discussion of mechanisms causing or maintaining impaired adipose tissue function in obesity and potentially linking obesity to its associated disorders. A model is proposed how different pathogenic factors and mechanisms may cause dysfunction of adipose tissue.
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PMID:Adipose tissue dysfunction in obesity. 1935 89

Metabolic syndrome (MetS) is a cluster of metabolic abnormalities including abdominal obesity, impaired fasting glucose, hypertension and dyslipidemia. It seems to affect about one-fourth to one-fifth of the Mediterranean population, and its prevalence increases with age, being similar for both sexes and depending on the region and the definition used, with the National Cholesterol Education Program-Adult Treatment Panel-III (NCEP-ATPIII) definition being the most effective in the identification of glucose intolerance and cardiovascular risk. Except for these, MetS is associated with fatty liver disease, some forms of cancer, hypogonadism, and vascular dementia. The Mediterranean diet seems to be an ideal diet in patients with MetS, being rich in fibre, monounsaturated and polyunsaturated fats, and low in animal protein; and decreases the prevalence of MetS and cardiovascular disease risk. Except for weight loss, multifactorial intervention including insulin resistance reduction and normoglycemia, management of dyslipidemia, optimizing blood pressure and administration of low-dose aspirin for patients at high or moderately high cardiovascular disease (CVD) risk are additional targets. The present review provides current understanding about MetS in the Mediterranean region, focusing on its prevalence, clinical significance, and therapeutic strategy.
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PMID:Metabolic syndrome in the Mediterranean region: Current status. 2227 55

Obesity significantly increases the risk of developing type 2 diabetes, hypertension, coronary heart disease, stroke, fatty liver disease, dementia, obstructive sleep apnea and several types of cancer. Adipocyte and adipose tissue dysfunction represent primary defects in obesity and may link obesity to metabolic and cardiovascular diseases. Adipose tissue (AT) dysfunction manifests by a proinflammatory adipokine secretion pattern that mediate auto/paracrine and endocrine communication and by inflammatory cell infiltration, particularly in intra-abdominal fat. Impaired AT function is caused by the interaction of genetic, behavioral and environmental factors which lead to adipocyte hypertrophy, ectopic fat accumulation, hypoxia, AT stresses, impaired AT mitochondrial function and inflammatory processes within adipose tissue. Recently, increased autophagy has been linked to obesity and AT dysfunction and may represent a mechanism to compensate for AT stresses. A better understanding of mechanisms causing or maintaining AT dysfunction may provide new therapeutic strategies in the treatment of obesity-induced metabolic diseases.
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PMID:Adipose tissue dysfunction contributes to obesity related metabolic diseases. 2373 79

High fructose intake is associated with increased plasma triglyceride concentration, hepatic steatosis, impaired glucose tolerance, insulin resistance, and high blood pressure. In addition, increased fructose intake has recently been supposed to be a risk factor for dementia. However, direct effects of fructose on the brain function remain to be clarified. The localization of glucose transporter 5 (Glut5), a representative transporter of fructose, was immunohistochemically examined in the brains of humans, rats, and mice to clarify whether fructose was transported from the blood into the brain. Glut5 immunoreactivity was demonstrated to be located in the epithelial cells of the choroid plexus and the ependymal cells in the brains of humans and rats using commercial antibodies for Glut5. In addition, mRNA expression of mouse Glut5 was confirmed in the brains of mice. Immunohistochemical examination using a custom-made antibody against two regions of amino acid sequences of mouse Glut5 revealed that Glut5 immunoreactivity was also seen in the epithelial cells of the choroid plexus and the ependymal cells in the brains of mice. These findings show that Glut5 immunoreactivity is located in the epithelial cells of the choroid plexus and the ependymal cells, suggesting the possibility of the direct transportation of intravascular fructose into the brain parenchyma.
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PMID:Immunoreactivity of glucose transporter 5 is located in epithelial cells of the choroid plexus and ependymal cells. 2436 38

Leptin has key roles in the regulation of energy balance, body weight, metabolism, and endocrine function. Leptin levels are undetectable or very low in patients with lipodystrophy, hypothalamic amenorrhea, and congenital leptin deficiency (CLD) due to mutations in the leptin gene. For these patients, leptin replacement therapy with metreleptin (a recombinant leptin analog) has improved or normalized most of their phenotypes, including normalization of endocrine axes, decrease in insulin resistance, and improvement of lipid profile and hepatic steatosis. Remarkable weight loss has been observed in patients with CLD. Due to its effects, leptin therapy has also been evaluated in conditions where leptin levels are normal or high, such as common obesity, diabetes (types 1 and 2), and Rabson-Mendenhall syndrome. A better understanding of the physiological roles of leptin may lead to the development of leptin-based therapies for other prevalent disorders such as obesity-associated nonalcoholic fatty liver disease, depression and dementia.
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PMID:Leptin treatment: facts and expectations. 2515 86

Statins reduce cardiovascular mortality and morbidity as well as cardiovascular events in patients with a very high risk of cardiovascular disease (CVD) and also in subjects with high or moderate risk by reducing the levels of low-density lipoprotein cholesterol (LDL-C). Although they are considered to be drugs with a very good safety profile, because of their wide use there are many concerns that their adverse effects might compromise their proven beneficial effects. Therefore this article reviews all the data and provides an evidence- based insight what are the proven adverse effects of statins and what are the "myths" about them. The most important side effects include myopathy and rhabdomyolysis. Another side effect is increased activity of liver tests which occurs occasionally and is reversible. However, recent studies even suggest that statin therapy can improve hepatic steatosis. It is beyond any doubt that statins do slightly increase the incidence of type 2 diabetes mellitus in people with two or more components of metabolic syndrome but the cardiovascular benefits of such a treatment by far exceed this risk. Statin therapy has also been associated with some adverse renal effects, eg. acute renal failure, but recent data suggest even a possible protective effect of these drugs on renal dysfunction. Concerns that statins might increase cancer have not been proven. On the contrary, several studies have indicated a possible benefit of these drugs in patients with different types of cancer. Early concerns about cognitive dysfunction and memory loss associated with statins use could not be proven and most recent data even suggest a possible beneficial effect of statins in the prevention of dementia. Systematic reviews and clinical guidelines suggest that the cardiovascular benefits of statins by far out-weight non-cardiovascular harms in patients with cardiovascular risk.
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PMID:Adverse effects of statins - myths and reality. 2531 33

Chitotriosidase (CHIT1) belongs to chitinase family. So far this enzyme has been the best investigated human chitinase regarding its biological activity and association with various disorders. In a healthy population, CHIT1 activity is very low and originates in the circulating polymorphonuclear cells. Conversely, during the development of acute/chronic inflammatory disorders, the enzymatic activity of CHIT1 increases significantly. Recently, CHIT1 has also been involved in the pathogenesis of diabetes mellitus (DM). Mounting evidence from experimental studies revealing the increase of CHIT1 levels in pathological conditions, such as atherosclerosis, coronary artery disease, acute ischemic stroke, cerebrovascular dementia, nonalcoholic fatty liver disease, and osteolytic processes suggest its critical role in the evolutions and complications of DM. This review is addressed to provide mechanistic insights by highlighting the relationship between CHIT1 and diabetes, and their contribution in the exacerbation of this disease.
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PMID:Chitotriosidase: A New Inflammatory Marker in Diabetic Complications. 2711 85

Obesity and its multiple metabolic sequelae, including type 2 diabetes, cardiovascular disease, and fatty liver disease, are becoming increasingly widespread in both the developed and developing world. There is an urgent need to identify new approaches for the prevention and treatment of these costly and prevalent metabolic conditions. Accomplishing this will require the use of appropriate animal models for preclinical and translational investigations in metabolic disease research. Although studies in rodent models are often useful for target/pathway identification and testing hypotheses, there are important differences in metabolic physiology between rodents and primates, and experimental findings in rodent models have often failed to be successfully translated into new, clinically useful therapeutic modalities in humans. Nonhuman primates represent a valuable and physiologically relevant model that serve as a critical translational bridge between basic studies performed in rodent models and clinical studies in humans. The purpose of this review is to evaluate the evidence, including a number of specific examples, in support of the use of nonhuman primate models in metabolic disease research, as well as some of the disadvantages and limitations involved in the use of nonhuman primates. The evidence taken as a whole indicates that nonhuman primates are and will remain an indispensable resource for evaluating the efficacy and safety of novel therapeutic strategies targeting clinically important metabolic diseases, including dyslipidemia and atherosclerosis, type 2 diabetes, hepatic steatosis, steatohepatitis, and hepatic fibrosis, and potentially the cognitive decline and dementia associated with metabolic dysfunction, prior to taking these therapies into clinical trials in humans.
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PMID:Use and Importance of Nonhuman Primates in Metabolic Disease Research: Current State of the Field. 2921 41


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