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)

Among Asians, including Japanese, obesity is related to dyslipidemia and insulin resistance at a lower level of body mass index (BMI) compared with non-Hispanic whites (NHW). We hypothesize that this ethnic difference in the relationship between BMI and metabolic risks is partly associated with the ethnic difference in fat distribution, namely, liver fat as well as visceral adipose tissue. To compare liver fat content among Japanese vs NHW men, regional computed tomographic images were taken to measure liver computed tomographic density in population-based samples of 313 Japanese and 288 NHW men aged 40 to 49 years, along with the assessment of metabolic parameters. Liver fat content was higher in Japanese than NHW men (liver to spleen attenuation ratio [lower value means higher liver fat content]: 1.01 +/- 0.16 vs 1.07 +/- 0.15, respectively; P < .01), despite a lower mean BMI in Japanese men (BMI: 23.6 +/- 2.9 vs 27.8 +/- 4.2 kg/m(2), P < .01). Moreover, Japanese men had a greater disposition for fatty liver with a small increase in BMI than NHW (P < .01), whereas both groups had a similar relationship between visceral adipose tissue and BMI. In both groups, liver fat content correlated with triglycerides, homeostasis model assessment of insulin resistance, and C-reactive protein. Liver fat content is higher among Japanese than NHW; and this ethnic difference becomes more robust with a small increase in BMI, suggesting that fatty liver is a sensitive marker for the failure of the adipose tissue to expand to accommodate an increased energy influx, and is associated with similar metabolic risk in Japanese despite lower BMI compared with NHW men.
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PMID:Higher liver fat content among Japanese in Japan compared with non-Hispanic whites in the United States. 1942 36

There is increasing evidence of a causal relationship between sleep-disordered breathing and metabolic dysfunction. Metabolic syndrome (MetS), a cluster of risk factors that promote atherosclerotic cardiovascular disease, comprises central obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension, manifestations of altered total body energy regulation. Excess caloric intake is indisputably the key driver of MetS, but other environmental and genetic factors likely play a role; in particular, obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), may induce or exacerbate various aspects of MetS. Clinical studies show that OSA can affect glucose metabolism, cholesterol, inflammatory markers, and nonalcoholic fatty liver disease. Animal models of OSA enable scientists to circumvent confounders such as obesity in clinical studies. In the most widely used model, which involves exposing rodents to IH during their sleep phase, the IH alters circadian glucose homeostasis, impairs muscle carbohydrate uptake, induces hyperlipidemia, and upregulates cholesterol synthesis enzymes. Complicating factors such as obesity or a high-fat diet lead to progressive insulin resistance and liver inflammation, respectively. Mechanisms for these effects are not yet fully understood, but are likely related to energy-conserving adaptations to hypoxia, which is a strong catabolic stressor. Finally, IH may contribute to the morbidity of MetS by inducing inflammation and oxidative stress. Identification of OSA as a potential causative factor in MetS would have immense clinical impact and could improve the management and understanding of both disorders.
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PMID:Metabolic consequences of sleep-disordered breathing. 1950 16

Although the atherogenic role of dietary cholesterol has been well established, its diabetogenic potential and associated metabolic disturbances have not been reported. Diet-induced hamster models of insulin resistance and dyslipidemia were employed to determine lipogenic and diabetogenic effects of dietary cholesterol. Metabolic studies were conducted in hamsters fed diets rich in fructose (40%), fat (30%), and cholesterol (0.05-0.25%) (FFC) and other test diets. Short-term feeding of the FFC diet induced insulin resistance, glucose intolerance, hypertriglyceridemia, and hypercholesterolemia. Prolonged feeding (6-22 wk) of the FFC diet led to severe hepatic steatosis, glucose intolerance, and mild increases in fasting blood glucose, suggesting progression toward type 2 diabetes, but did not induce beta-cell dysfunction. Metabolic changes induced by the diet, including dyslipidemia and insulin resistance, were cholesterol concentration dependent and were only markedly induced on a high-fructose and high-fat dietary background. There were significant increases in hepatic and plasma triglyceride with FFC feeding, likely due to a 10- to 15-fold induction of hepatic stearoyl-CoA desaturase compared with chow levels (P < 0.03). Hepatic insulin resistance was evident based on reduced tyrosine phosphorylation of the insulin receptor-beta, IRS-1, and IRS-2 as well as increased protein mass of protein tyrosine phosphatase 1B. Interestingly, nuclear liver X receptor (LXR) target genes such as ABCA1 were upregulated on the FFC diet, and dietary supplementation with an LXR agonist (instead of dietary cholesterol) worsened dyslipidemia, glucose intolerance, and upregulation of target mRNA and proteins similar to that of dietary cholesterol. In summary, these data clearly implicate dietary cholesterol, synergistically acting with dietary fat and fructose, as a major determinant of the severity of metabolic disturbances in the hamster model. Dietary cholesterol appears to induce hepatic cholesterol ester and triglyceride accumulation, and diet-induced LXR activation (via cholesterol-derived oxysterols) may possibly be one key underlying mechanism.
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PMID:Metabolic effects of dietary cholesterol in an animal model of insulin resistance and hepatic steatosis. 2000 38

Long term intake of high-glucose diet (HGD) may induce many diseases such as dyslipidemia, fatty liver and diabetes disease. Most of the research for molecular mechanisms of the association between HGD and the above diseases focus on the metabolism of glucose and lipid. However, there are few studies on molecular mechanism of the effect of HGD on digestion and absorption. We used HGD (containing 20% glucose) to feed C57BL/6J mice for 4 weeks, detected the expressions of 13,098 genes in jejunums of C57BL/6J mice with DNA microarray. Microarray analysis showed the expression of genes related to digestive enzyme, gastrointestinal peptide and nutrient transporters were significantly changed, which indicated that HGD induced the suppression of digestive enzyme gene expression, attenuation of alimentary tract movement and nutrient transportation. In one word, the microarray analysis suggested that HGD impaired the function of digestion and absorption in jejunum of C57BL/6J mice. We validated our microarray findings by conducting real-time RT-PCR assays on selected genes and detecting the activities of disaccharidases such as lactase, maltase and sucrase in jejunum of C57BL/6J mice.
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PMID:Microarray analysis of high-glucose diet-induced changes in mRNA expression in jejunums of C57BL/6J mice reveals impairment in digestion, absorption. 1961 90

The worldwide epidemic of obesity and the metabolic syndrome has made nonalcoholic fatty liver disease (NAFLD), one of the most important liver diseases of our time. NAFLD is now the commonest cause of abnormal liver test results in industrialized countries and its incidence is rising. The current treatment of nonalcoholic steatohepatitis (NASH) has focused on lifestyle modification to achieve weight loss and modification of risk factors, such as insulin resistance, dyslipidemia, and hyperglycemia associated with the metabolic syndrome. With our increasing understanding of the pathogenesis of NASH, have come a plethora of new pharmacologic options with great potential to modify the natural history of NAFLD and NASH. This article focuses on a number of novel molecular targets for the treatment of NASH as well as the evidence for currently available therapy. It should be noted, however, that in part because of the long natural history of NASH and NAFLD, no therapy to date has been shown to unequivocally alter liver-related morbidity and mortality in these patients.
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PMID:Current and novel therapies for the treatment of nonalcoholic steatohepatitis. 1966 29

In addition to its enormous impacts on an individual's quality of life, obesity is a daunting health problem in the world today and the increasing rate of obesity is now causing a severe burden on health care systems. Fortunately, the normalization or reduction of increased body fat reverses the obesity-associated morbidities, such as hypertension, glucose intolerance, dyslipidemia, and fatty liver diseases. However, the modification of lifestyle in a case of established clinical obesity is very difficult to achieve. Recent breakthroughs in relation to the molecular mechanism regulating body weight and energy metabolism give us hopes for the development of anti-obesity drugs. Even with the high social demand for an effective treatment for obesity and extensive researches, both in academia and the pharmaceutical industry, only two weight-loss drugs, sibutramine and orlistat, have been approved by the FDA for long-term treatment. In addition, the current bottleneck in drug discovery shows that a more detailed understanding of the pathogenesis of obesity is an essential element for the development of efficacious treatment. In this review article, we focus on the structural origin of chemical entities for anti-obesity treatment along with the rationale for drug discovery, rather than categorizing the clinical efficacy or pharmacological target of obesity. For the clarification of the structural origin, we formed a collection with 4 major groups, including natural products, natural product mimetics, synthetic small molecules, and peptides/hormones. This analysis might provide strategic plans for medicinal chemists, biologists, and physicians to begin an optimistic era with a new class of pharmaceutical adjuncts for obesity therapy.
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PMID:Anti-obesity agents: a focused review on the structural classification of therapeutic entities. 1968 61

Aurricularia aurricula, hawthorn (Crataegus pinnatifida), and Pueraria radix are well known for both traditional food and folk medicine. Each of the above 3 plants possesses a distinct pathway contributing to treat dyslipidemia. To develop a health-promoting diet against dyslipidemia, the polysaccharides from A. aurricula, polyphenol from hawthorn, and P. radix were combined to postulate as a functional formula diet (AHP) in the present study and its pharmaceutical effects and underlying mechanisms were elucidated in vivo. The dyslipidemia model associated with fatty liver was induced by cholesterol-enriched diet (CED) for up to 12 wk in male ICR mice. Mice were randomly divided into 5 groups, that is, regular diet (RD), CED, Xuezhikang treatment (positive control group, PG), low and high (150 or 450 mg/kg/d) of AHP treatment groups. Compared with the CED group, AHP groups maintained lipid profiles through lowering serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C), inhibiting the accumulation of hepatic TC and triglyceride (TG). AHP could also improve both serum and hepatic biochemical activity profiles including antioxidant status, serum nitric oxide (NO), and hepatic 3-hydroxy-3-methylglutary CoA (HMG-CoA) reductase levels. Hepatic histopathological examinations showed markedly decreased fatty deposits in the liver of AHP-treated mice, illustrating the ability to reverse a condition of fatty liver. Our study indicated that this functional formula diet would be a potent alternative as a health-promoting diet, simultaneously targeting on the complexity and redundancy of dyslipidemia.
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PMID:Dietary intervention with AHP, a functional formula diet, improves both serum and hepatic lipids profile in dyslipidemia mice. 1972 4

Lipogenesis occurs primarily in the liver, where dietary carbohydrates control the expression of key enzymes in glycolytic and lipogenic pathways. We have recently discovered that the transcription factor XBP1, best known as a key regulator of the unfolded protein response (UPR), is required for de novo fatty acid synthesis in the liver, a function unrelated to its role in the UPR.(1) XBP1 protein expression is induced in the liver by a high carbohydrate diet and directly controls the induction of critical genes involved in fatty acid synthesis. Specific deletion of XBP1 in adult liver using an inducible approach results in profound hypocholesterolemia and hypotriglyceridemia, which could be attributed to diminished production of lipids in the liver. Notably, this phenotype is not associated with fatty liver (hepatic steatosis) or significant compromise in protein secretion. XBP1 joins an already rich field of transcriptional regulatory proteins in the control of hepatic lipogenesis. Its function in lipogenesis appears to be highly significant as evidenced by the phenotype of the genetic mutant strain. A more complete understanding of the mechanisms by which XBP1 accelerates de novo fatty acid synthesis in the liver while preserving normal hepatic lipid composition is highly relevant to the treatment of diseases such as atherosclerosis and metabolic syndrome that are associated with dyslipidemia. Since excess fat accumulation in the liver could result from increased hepatic fatty acid synthesis, compounds that inhibit XBP1 activation may also be useful therapeutics for the treatment of human alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), increasingly common causes of morbidity and mortality in the United States.
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PMID:From sugar to fat: How the transcription factor XBP1 regulates hepatic lipogenesis. 1975 10

Excess lipid accumulation in nonadipose tissues may occur in the setting of high levels of plasma free fatty acids or triglycerides (TGs) in a process called "lipotoxicity". Evidence from human studies and animal models suggests that lipid accumulation in the heart, skeletal muscle, pancreas, and liver play an important role in the pathogenesis of heart failure, obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). During the past few years, several studies have shown that n-3 polyunsaturated fatty acids (PUFA) have potentially cardioprotective effects, especially in high-risk patients with dyslipidemia, and might therefore be expected to be of benefit in T2DM. Moreover, new information has demonstrated the beneficial effects of consuming n-3 PUFA in preventing the complications of lipotoxicity. n-3 PUFA dietary intake thus had positive effects on fatty liver in patients with non-alcoholic fatty liver disease (NAFLD), with an improvement in liver echotexture and a significant regression of hepatic brightness, associated with improved liver hemodynamics. The n-3 PUFA also had beneficial effects on ectopic fat accumulation inside the heart, with stabilization of cardiac myocytes and antiarrhythmic effects. On the other hand, recent data from animal models suggest that oral dosing of eicosapentaenoic acid (EPA) could contribute to protect against beta-cell lipotoxicity. This review discusses the latest hypotheses regarding lipotoxicity, concentrating on the impact of the n-3 PUFA that contribute to ectopic lipid storage, affecting organ function. Further human studies are needed to test the evidence and elucidate the mechanisms involved in this process.
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PMID:n-3 PUFA and lipotoxicity. 1978 63

A subset of HIV-1-infected patients undergoing antiretroviral treatment develops a lipodystrophy syndrome. It is characterized by loss of peripheral subcutaneous adipose tissue (face, limbs, buttocks), visceral fat accumulation, and, in some cases, lipomatosis, especially in the dorsocervical area. In addition, these patients show metabolic alterations reminiscent of the metabolic syndrome, particularly dyslipidemia and insulin resistance. These alterations lead to enhanced cardiovascular risk in patients and favor the development of diabetes. Although a complex combination of HIV-1 infection and drug treatment-related events triggers the syndrome, lipotoxicity appears to contribute to the development of the syndrome. Active lipolysis in subcutaneous fat, combined with impaired fat storage capacity in the subcutaneous depot, drive ectopic deposition of lipids, either in the visceral depot or in nonadipose sites. Both hepatic steatosis and increased lipid content in skeletal muscle take place and surely contribute to systemic metabolic alterations, especially insulin resistance. Pancreatic function may also be affected by the exposure to high levels of fatty acids; together with direct effects of antiretroviral drugs, this may contribute to impaired insulin release and a prodiabetic state in the patients. Addressing lipotoxicity as a pathogenic actor in the lipodystrophy syndrome should be considered in strategies for treating and/or preventing the morphological alterations and systemic metabolic disturbances associated with lipodystrophy.
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PMID:Drug-induced lipotoxicity: lipodystrophy associated with HIV-1 infection and antiretroviral treatment. 1980 25


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