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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obesity is a principal causative factor in the development of metabolic syndrome. Here we report that increased oxidative stress in accumulated fat is an important pathogenic mechanism of obesity-associated metabolic syndrome. Fat accumulation correlated with systemic oxidative stress in humans and mice. Production of ROS increased selectively in adipose tissue of obese mice, accompanied by augmented expression of NADPH oxidase and decreased expression of antioxidative enzymes. In cultured adipocytes, elevated levels of fatty acids increased oxidative stress via NADPH oxidase activation, and oxidative stress caused dysregulated production of adipocytokines (fat-derived hormones), including adiponectin, plasminogen activator inhibitor-1, IL-6, and monocyte chemotactic protein-1. Finally, in obese mice, treatment with NADPH oxidase inhibitor reduced ROS production in adipose tissue, attenuated the dysregulation of adipocytokines, and improved diabetes, hyperlipidemia, and hepatic steatosis. Collectively, our results suggest that increased oxidative stress in accumulated fat is an early instigator of metabolic syndrome and that the redox state in adipose tissue is a potentially useful therapeutic target for obesity-associated metabolic syndrome.
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PMID:Increased oxidative stress in obesity and its impact on metabolic syndrome. 1559

We measured liver fat content by 3-Tesla magnetic resonance spectroscopy (MRS) in 34 non- to mild obese Japanese subjects with type 2 diabetes, who were not complicated with any liver diseases including clinical fatty liver (liver/spleen ratio of computed tomography [CT] < 0.9) and were not being treated with oral hypoglycemic agents, insulin, or lipid-lowering agents, and analyzed the relationship between liver fat content and body composition and plasma metabolite. The liver fat content is significantly correlated with variables relating to obesity (body mass index [BMI], body weight, fat mass, waist to hip ratio, visceral fat area, subcutaneous fat area, and serum triglyceride), insulin resistance (fasting plasma insulin and homeostasis model assessment of insulin resistance [HOMA-IR]), adipocytokines (serum plasminogen activator inhibitor-1 [PAI-1] and leptin), and serum cholinesterase, but not CT liver/spleen ratio, which is correlated only with fasting plasma glucose, BMI, and HOMA-IR. Multiple regression analysis revealed that the liver fat content is independently associated with serum PAI-1 level (p < 0.001) and BMI (p < 0.05), but not visceral fat area. MRS is a more sensitive method for quantifying liver fat content than CT in type 2 diabetic subjects with non- to mild obesity and without clinical fatty liver.
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PMID:Liver fat content measured by magnetic resonance spectroscopy at 3.0 tesla independently correlates with plasminogen activator inhibitor-1 and body mass index in type 2 diabetic subjects. 1580 72

Insulin resistance in humans is not always accompanied by obesity, since severe insulin resistance also characterizes patients lacking subcutaneous fat such as those with HAART- (highly-active antiretroviral therapy)-associated lipodystrophy. Both obese and lipodystrophic patients, however, have an increase in the amount of fat hidden in the liver. Liver fat content can be accurately quantified non-invasively by proton magnetic resonance spectroscopy. It is closely correlated with fasting insulin concentrations and direct measures of hepatic insulin sensitivity while the amount of subcutaneous adipose tissue is not. An increase in liver fat content has been shown to predict type 2 diabetes, independently of other cardiovascular risk factors. This is easily explained by the fact that the liver, once fatty, overproduces most of the known cardiovascular risk factors such as very low density lipoprotein (VLDL), glucose, C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1), fibrinogen and coagulation factors. The causes of inter-individual variation in liver fat content, independent of obesity, are largely unknown but could involve differences in signals from adipose tissue such as in the amount of adiponectin produced and differences in fat intake. Adiponectin deficiency characterizes both lipodystrophic and obese insulin-resistant individuals, and serum levels correlate with liver fat content. Liver fat content can be decreased by weight loss and by a low as compared to a high fat diet. In addition, treatment of both lipodystrophic and type 2 diabetic patients with peroxisome proliferators activator receptor-gamma (PPARgamma) agonists, but not metformin, decreases liver fat and markedly increases adiponectin levels. The fatty liver may help to explain why some but not all obese individuals are insulin resistant and why even lean individuals may be insulin resistant, and thereby at risk of developing type 2 diabetes and cardiovascular disease.
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PMID:Fat in the liver and insulin resistance. 1617 70

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear transcription factor that comprises the primary molecular target for thiazolidinedione (TZD) insulin-sensitizing drugs. Whilst expressed in many tissues in humans, its abundant expression in adipose tissue is believed to be the focal point through which TZDs regulate genes involved in glucose and lipid metabolism and via which these agents ultimately improve the hyperglycemia of type 2 diabetes. However, TZDs exhibit many additional properties, not least an array of effects which suggest a broad attack on the inflammatory process. Thus, TZDs have been shown to reduce plasma levels of the chemokine, monocyte chemotactic protein-1 (MCP-1), the anti-fibrinolytic protein, plasminogen activator inhibitor-1 (PAI-1), the endothelial cell adhesion molecules, e-selectin and inter-cellular adhesion molecule-1 (ICAM-1), the leucocyte-activating molecule, CD40L, and the tissue-remodeling enzyme, matrix metalloproteinase-9 (MMP-9). Further tangible evidence of a reduction by TZDs of systemic inflammation in patients with the classical metabolic syndrome stems from falls in the white blood cell count, P-selectin-positive platelets and in the acute-phase inflammatory proteins, C-reactive protein, serum amyloid A and fibrinogen. At the tissue level, TZDs improve vascular endothelial function, and reduce the rate of progression of intimal-medial thickening of the carotid artery and the microalbuminuria of type 2 diabetes. Further, TZDs have been shown to be efficacious in inflammatory diseases as wide-ranging as psoriasis, ulcerative colitis and non-alcoholic steatohepatitis (NASH). In the case of the latter, a broad spectrum of TZD-related properties is visible. Here, these drugs improve insulin sensitivity for glucose metabolism, reduce hyperinsulinemia, hepatic steatosis, inflammation and fibrosis, and lower the circulating levels of liver transaminases (ALT, AST), alkaline phosphatase and gamma glutamyl transferase. These effects in humans are also well-supported by investigative animal and in vitro studies. The ameliorative effects on liver fibrosis are of particular interest since they suggest that TZDs are able to activate a program of corrective tissue-remodeling. The basis for this action may be partly an ability to inhibit matrix protein secretion by hepatic stellate cells. An analogous action has also been seen in kidney mesangial cells. In conclusion, TZDs are important new drugs, presently indicated for the treatment of type 2 diabetes but with a spectrum of properties which suggests their potential for treating a number of degenerative inflammatory diseases, including NASH. However, full-scale, long-term clinical trials are needed with TZDs to test their potential to treat NASH, not least because of the (hepatotoxic) legacy of the prototype TZD, troglitazone, but also in view of the escalating burden of liver disease which is accompanying the increasing global prevalence of clinical obesity and type 2 diabetes.
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PMID:Thiazolidinediones: Pleiotropic drugs with potent anti-inflammatory properties for tissue protection. 1619 19

Insulin-mediated glucose disposal varies widely in apparently healthy human beings, and the more insulin resistant an individual, the more insulin they must secrete in order to prevent the development of type 2 diabetes. However, the combination of insulin resistance and compensatory hyperinsulinemia increases the likelihood that an individual will be hypertensive, and have a dyslipidemia characterized by a high plasma triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentration. These changes increase risk of cardiovascular disease (CVD), and in 1988, this cluster of related abnormalities was designated as comprising a syndrome (X). Several other clinical syndromes are now known to be associated with insulin resistance and compensatory hyperinsulinemia. For example, polycystic ovary syndrome appears to be secondary to insulin resistance and compensatory hyperinsulinemia. More recently, studies have shown that the prevalence of insulin resistance/hyperinsulinemia is increased in patients with nonalcoholic fatty liver disease, and there are reports that certain forms of cancer are more likely to occur in insulin resistant/hyperinsulinemic persons. Finally, there is substantial evidence of an association between insulin resistance/hyperinsulinemia, and sleep disordered breathing. Given the rapid increase in the number of clinical syndromes and abnormalities associated with insulin resistance/hyperinsulinemia, it seems reasonable to suggest that the cluster of these changes related to the defect in insulin action be subsumed under the term of the insulin resistance syndrome. In addition to the identification of additional clinical syndromes related to insulin resistance/hyperinsulinemia, a number of new risk factors have been recognized that would increase CVD risk in these individuals. Thus, in addition to a high TG and a low HDL-C, the atherogenic lipoprotein profile in insulin resistant/hyperinsulinemic individuals also includes the appearance of smaller and denser low density lipoprotein particles, and the enhanced postprandial accumulation of remnant lipoproteins; changes identified as increasing risk of CVD. Elevated plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) have been shown to be associated with increased CVD, and there is evidence of a significant relationship between PAI-1 and fibrinogen levels and both insulin resistance and hyperinsulinemia. Evidence is also accumulating that sympathetic nervous system (SNS) activity is increased in insulin resistant, hyperinsulinemic individuals, and, along with the salt sensitivity associated with insulin resistance/hyperinsulinemia, increases the likelihood that these individuals will develop essential hypertension. The first step in the process of atherogenesis is the binding of mononuclear cells to the endothelium, and mononuclear cells isolated from insulin resistant/hyperinsulinemic individuals adhere with greater avidity. This process is modulated by adhesion molecules produced by endothelial cells, and there is a significant relationship between degree of insulin resistance and the plasma concentration of the several of these adhesion molecules. Further evidence of the relationship between insulin resistance and endothelial dysfunction is the finding that asymmetric dimethylarginine, an endogenous inhibitor of the enzyme nitric oxide synthase, is increased in insulin resistant/hyperinsulinemic individuals. Finally, plasma concentrations of several inflammatory markers are elevated in insulin resistant subjects. It is obvious that the cluster of abnormalities associated with insulin resistance and compensatory hyperinsulinemia contains many well-recognized CVD risk factors, choosing which one, or ones, that are primarily responsible for the accelerated atherogenesis that characterizes this syndrome is not a simple task. Indeed, efforts to try to do so by the use of multiple regression analysis of epidemiological data may be more misleading than helpful.
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PMID:Insulin resistance, the insulin resistance syndrome, and cardiovascular disease. 1648 19

Recent progress in adipocyte biology delineates that adipocytes not only store excess energy, but also respond to metabolic signals by secreting proteins that exert local, central, and peripheral effects. Among these adipokines are free fatty acids, plasminogen activator inhibitor-1, angiotensinogen, TNFa, leptin and adiponectin. Dysregulation of production of these adipokines and/or imbalance of their actions lead to a wide array of liver and systemic pathophysiology related to NASH such as 1) development of systemic and hepatic insulin resistance, 2) progression from benign fatty liver to steatohepatitis and 3) activation of hepatic fibrogenesis. This review deals with the emerging concept of the adipokine interrelationship with the liver.
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PMID:[Adipokine interrelationship with the liver]. 1676 13

Overweight and obesity, particularly abdominal adiposity, increase the risk for type 2 diabetes mellitus and cardiovascular disease (CVD). Metabolic syndrome, a constellation of risk factors that includes elevated triglycerides, low high-density lipoprotein cholesterol, elevated blood pressure, elevated fasting glucose, and abdominal obesity, predicts the development of CVD and diabetes to an even greater degree. Excess abdominal adipose tissue is associated with insulin resistance, the precursor to type 2 diabetes, and creates an atherogenic inflammatory milieu, characterized by high levels of C-reactive protein and other inflammatory markers (e.g., fibrinogen, plasminogen activator inhibitor-1, cytokines, and adhesion molecules). High levels of these biomarkers correlate with an increased incidence of diabetes and CVD. Recent evidence suggests that patients with nonalcoholic fatty liver disease have an increased incidence of obesity, metabolic syndrome, and insulin resistance and/or type 2 diabetes. Relatively small reductions in body weight may significantly reduce abdominal adipose tissue, reduce insulin resistance, lower triglycerides and low-density lipoprotein cholesterol, reduce inflammation, and decrease overall cardiometabolic risk.
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PMID:Abdominal adiposity and cardiometabolic risk: do we have all the answers? 1772 Mar 54

Fatty liver represents the liver component of metabolic syndrome and may be involved in plasminogen activator inhibitor-1 (PAI-1) synthesis. We studied plasma PAI-1 levels and relationships with risk factors for metabolic syndrome, including fatty liver, in 170 patients. Liver ultrasound scan was performed on all patients, and a liver biopsy was performed on those patients with chronically elevated transaminase levels. Plasma PAI-1 levels correlated significantly (P < .05) with body mass index, degree of steatosis, insulin resistance, insulin level, waist circumference, triglycerides, and high-density lipoprotein (HDL) -cholesterol. However, only body mass index (beta = .455) and HDL-cholesterol (beta = .293) remained predictors of PAI-1 levels. Liver biopsy revealed a significant correlation (P < .05) between insulin resistance (r = 0.381) or insulin level (r = 0.519) and liver fibrosis. In patients presenting features of metabolic syndrome, plasma PAI-1 levels were mainly conditioned by the whole-body fat content.
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PMID:Plasma plasminogen activator inhibitor-1 levels and nonalcoholic fatty liver in individuals with features of metabolic syndrome. 1816 Jun

This study determined the effects of alpha- and gamma-tocopherol supplementation on metabolic control and oxidative stress in type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Blood glucose, haemoglobin A1c (HbA1c), urinary protein, plasma free fatty acid, triacylglycerol and plasminogen activator inhibitor-1 (PAI-1) levels in OLETF rats were significantly higher than in non-diabetic control Long-Evans Tokushima Otsuka (LETO) rats. Alpha-tocopherol inhibited the increase in urinary protein, blood glucose, HbA1c and PAI-1 levels, but gamma-tocopherol did not. Plasma and hepatic lipid peroxidation and hepatic steatosis were increased in OLETF rats. alpha-Tocopherol decreased lipid peroxidation. Mitochondrial reactive oxygen species production and uncoupling protein 2 (UCP2) expression were significantly increased in the heart and aorta of OLETF rats compared with LETO rats. Endothelial NO synthase and aortic nitrotyrosine were increased in OLETF rats. In contrast, the expression of phosphorylated vasodilator-stimulated phosphoprotein and glucose transporter 4 in the aorta was significantly decreased in OLETF rats. These abnormalities were reversed by alpha-tocopherol. These findings suggest that alpha-tocopherol may prevent cardiovascular tissues from oxidative stress and insulin signalling disorder resulting from diabetes mellitus.
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PMID:Supplementation of alpha-tocopherol improves cardiovascular risk factors via the insulin signalling pathway and reduction of mitochondrial reactive oxygen species in type II diabetic rats. 1834 21

We assessed the differential contribution of nonalcoholic steatohepatitis (NASH) and visceral adiposity to nontraditional cardiovascular risk biomarkers in adult men. We enrolled 45 consecutive, overweight, male patients with biopsy-proven NASH, 45 overweight male patients without ultrasound-diagnosed hepatic steatosis, and 45 healthy male volunteers. All participants were matched for age; NASH and overweight patients were also matched for BMI and visceral adiposity (as estimated by abdominal ultrasonography). Nontraditional cardiovascular risk biomarkers were measured in all participants. Plasma concentrations of high-sensitivity C-reactive protein (hs-CRP), fibrinogen, plasminogen activator inhibitor-1 (PAI-1) activity, and adiponectin were markedly different among the groups; the lowest values (the highest for adiponectin) were in nonobese healthy subjects, intermediate in overweight nonsteatotic patients, and the highest (the lowest for adiponectin) in those with biopsy-proven NASH. The marked differences in these cardiovascular risk biomarkers that were observed between overweight and NASH patients were only slightly weakened after adjustment for age, BMI, smoking, plasma triglycerides, and insulin resistance (IR) as assessed by homeostasis model assessment (HOMA). In multivariate regression analysis, NASH and visceral adiposity predicted cardiovascular risk biomarkers independently of potential confounders. In conclusion, our results suggest that NASH can predict a more atherogenic risk profile in a manner that is partly independent from the contribution of visceral adiposity in adult men.
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PMID:NASH predicts plasma inflammatory biomarkers independently of visceral fat in men. 1932 44


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