Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Mice lacking acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the terminal step in triacylglycerol synthesis, have enhanced insulin sensitivity and are protected from obesity, a result of increased energy expenditure. In these mice, factors derived from white adipose tissue (WAT) contribute to the systemic changes in metabolism. One such factor, adiponectin, increases fatty acid oxidation and enhances insulin sensitivity. To test the hypothesis that adiponectin is required for the altered energy and glucose metabolism in DGAT1-deficient mice, we generated adiponectin-deficient mice and introduced adiponectin deficiency into DGAT1-deficient mice by genetic crosses. Although adiponectin-deficient mice fed a high-fat diet were heavier, exhibited worse glucose tolerance, and had more hepatic triacylglycerol accumulation than wild-type controls, mice lacking both DGAT1 and adiponectin, like DGAT1-deficient mice, were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis. These findings indicate that adiponectin is required for normal energy, glucose, and lipid metabolism but that the metabolic changes induced by DGAT1-deficient WAT are independent of adiponectin and are likely due to other WAT-derived factors. Our findings also suggest that the pharmacological inhibition of DGAT1 may be useful for treating human obesity and insulin resistance associated with low circulating adiponectin levels.
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PMID:Effects of DGAT1 deficiency on energy and glucose metabolism are independent of adiponectin. 1659 53

Obesity is now prevailing worldwide, coincident with the increase of hepatic steatosis. Metabolic syndrome with obesity and hypertension, hyperlipidemia, and impaired glucose tolerance is one of the most frequent life-threatening diseases and non-alcoholic steatohepatitis is believed to be a hepatic expression of this syndrome. Non-alcoholic steatohepatitis is prevalent and well characterized in Caucasians, but little is known about non-alcoholic steatohepatitis in Asia-Oceania. Obesity will be a serious social problem in Asia-Oceania in the next two decades and we need to prevent the increase of this syndrome. Therefore, it is extremely important to know about non-alcoholic steatohepatitis based on racial differences, because this syndrome is likely to be a multi-factorial syndrome resulting from different combinations of susceptibility genes superimposed on different environmental factors. Because hepatic steatosis is the first step in the development of not only metabolic syndrome but also non-alcoholic steatohepatitis, the genetic background of Japanese NASH patients was investigated and a measure to assess fatty acid beta-oxidation in the liver in vivo was developed.
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PMID:In vivo imaging of hepatic fatty acid metabolism in patients with non-alcoholic steatohepatitis using semiquantitative 123I-labeled branched-chain fatty acid analog. 1695 79

FoxO1 plays an important role in mediating the effect of insulin on hepatic metabolism. Increased FoxO1 activity is associated with reduced ability of insulin to regulate hepatic glucose production. However, the underlying mechanism and physiology remain unknown. We studied the effect of FoxO1 on the ability of insulin to regulate hepatic metabolism in normal vs. insulin-resistant liver under fed and fasting conditions. FoxO1 gain of function, as a result of adenovirus-mediated or transgenic expression, augmented hepatic gluconeogenesis, accompanied by decreased glycogen content and increased fat deposition in liver. Mice with excessive FoxO1 activity exhibited impaired glucose tolerance. Conversely, FoxO1 loss of function, caused by hepatic production of its dominant-negative variant, suppressed hepatic gluconeogenesis, resulting in enhanced glucose disposal and improved insulin sensitivity in db/db mice. FoxO1 expression becomes deregulated, culminating in increased nuclear localization and accounting for its increased transcription activity in livers of both high fat-induced obese mice and diabetic db/db mice. Increased FoxO1 activity resulted in up-regulation of hepatic peroxisome proliferator-activated receptor-gamma coactivator-1beta, fatty acid synthase, and acetyl CoA carboxylase expression, accounting for increased hepatic fat infiltration. These data indicate that hepatic FoxO1 deregulation impairs the ability of insulin to regulate hepatic metabolism, contributing to the development of hepatic steatosis and abnormal metabolism in diabetes.
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PMID:Aberrant Forkhead box O1 function is associated with impaired hepatic metabolism. 1699 36

Lipin-alpha and -beta are the alternatively spliced gene products of the Lpin1 gene, whose product lipin is required for adipocyte differentiation. Lipin deficiency causes lipodystrophy, fatty liver, and insulin resistance in mice, whereas adipose tissue lipin overexpression results in increased adiposity but improved insulin sensitivity. To assess lipin expression and its relation to insulin resistance in humans, we examined lipin-alpha and -beta mRNA levels in subjects with normal or impaired glucose tolerance. We found higher expression levels of both lipin isoforms in lean, insulin-sensitive subjects. When compared with normal glucose-tolerant subjects, individuals with impaired glucose tolerance were more insulin resistant, demonstrated higher levels of intramyocellular lipids (IMCLs), and expressed approximately 50% lower levels of lipin-alpha and -beta. In addition, there was a strong inverse correlation between adipose tissue lipin expression and muscle IMCLs but no evidence for an increase in muscle lipid oxidation. After treatment of the impaired glucose-tolerant subjects with insulin sensitizers for 10 weeks, pioglitazone (but not metformin) resulted in a 60% increase in the insulin sensitivity index (Si) and a 32% decrease in IMCLs (both P < 0.01), along with an increase in lipin-beta (but not lipin-alpha) expression by 200% (P < 0.005). Lipin expression in skeletal muscle, however, was not related to obesity or insulin resistance. Hence, high adipose tissue lipin expression is found in insulin-sensitive subjects, and lipin-beta expression increases following treatment with pioglitazone. These results suggest that increased adipogenesis and/or lipogenesis in subcutaneous fat, mediated by the LPIN1 gene, may prevent lipotoxicity in muscle, leading to improved insulin sensitivity.
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PMID:Lipin expression is attenuated in adipose tissue of insulin-resistant human subjects and increases with peroxisome proliferator-activated receptor gamma activation. 1700 47

Liver fatty acid-binding protein (L-Fabp) regulates murine hepatic fatty acid trafficking in response to fasting. In this study, we show that L-Fabp(-/-) mice fed a high-fat Western diet for up to 18 weeks are less obese and accumulate less hepatic triglyceride than C57BL/6J controls. Paradoxically, both control and L-Fabp(-/-) mice manifested comparable glucose intolerance and insulin resistance when fed a Western diet. Protection against obesity in Western diet-fed L-Fabp(-/-) mice was not due to discernable changes in food intake, fat malabsorption, or heat production, although intestinal lipid secretion kinetics were significantly slower in both chow-fed and Western diet-fed L-Fabp(-/-) mice. By contrast, there was a significant increase in the respiratory exchange ratio in L-Fabp(-/-) mice, suggesting a shift in energy substrate use from fat to carbohydrate, findings supported by an approximately threefold increase in serum lactate. Microarray analysis revealed increased expression of genes involved in lipid synthesis (fatty acid synthase, squalene epoxidase, hydroxy-methylglutaryl coenzyme A reductase), while genes involved in glycolysis (glucokinase and glycerol kinase) were decreased in L-Fabp(-/-) mice. Fatty acid synthase expression was also increased in the skeletal muscle of L-Fabp(-/-) mice. In conclusion, L-Fabp may function as a metabolic sensor in regulating lipid homeostasis. We suggest that L-Fabp(-/-) mice are protected against Western diet-induced obesity and hepatic steatosis through a series of adaptations in both hepatic and extrahepatic energy substrate use. (HEPATOLOGY 2006;44:1191-1205.).
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PMID:Protection against Western diet-induced obesity and hepatic steatosis in liver fatty acid-binding protein knockout mice. 1705 18

The present study examined a new model of impaired glucose tolerance (IGT) in a nonhuman primate fed with a high-fructose and high-fat (HFF) diet that contained 15% lard, 31% fructose, and 1% cholesterol. Female cynomolgus monkeys (age, 3-4 years) were divided into two groups: 1) those fed with normal control diet (N = 5) and 2) those fed with HFF diet (N = 5). In the HFF diet group, total cholesterol and low-density lipoprotein cholesterol in blood were significantly increased four- to fivefold when compared with the normal control diet group. No difference in the blood glucose, insulin, hemoglobin A1c, and triglyceride levels was detected between the two groups. Plasma levels of adiponectin, but not of resistin, were significantly higher in HFF diet at 20 weeks after HFF diet feeding. Oral glucose tolerance test was performed before HFF diet feeding and at 12 and 24 weeks after HFF diet feeding, but no significant changes in glucose sensitivity were observed even 24 weeks after HFF diet feeding. Twenty-four weeks after HFF diet feeding, accumulated foam cells and infiltrated macrophages were histologically detected in the thoracic aorta, in addition to a fatty liver. Interestingly, the pancreatic beta cells appeared normal in the HFF diet group. These results show that a chronic HFF diet does not induce IGT but can cause atherosclerotic lesions in conjunction with the generation of a fatty liver phenotype in cynomolgus monkey; however, the present results are very preliminary and they need to be validated in larger-scale studies in the future.
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PMID:Effect of fructose-rich high-fat diet on glucose sensitivity and atherosclerosis in nonhuman primate. 1720 Jul 27

Maternal pregravid obesity is a significant risk factor for adverse outcomes during pregnancy. In early pregnancy there is an increased risk of spontaneous abortion and congenital anomalies. In later gestation maternal metabolic manifestations of the metabolic syndrome, such as gestational hypertensive disorders and diabetes, become clinically recognized because of the increased insulin resistance in obese compared with nonobese women. In women with pregestational glucose intolerance, hypertension, central obesity, and lipid disorders, the physiologic changes in pregnancy increase the risk of problems previously not routinely encountered during pregnancy. These include chronic cardiac dysfunction, proteinuria, sleep apnea, and nonalcoholic fatty liver disease. At parturition the obese patient is at an increased risk of cesarean delivery and associated complications of anesthesia, wound disruption, infection, and deep venous thrombophlebitis. For the fetus there are short-term risks of fetal macrosomia, more specifically obesity, and long-term risks of adolescent components of the metabolic syndrome. Although preliminary results of bariatric surgery are encouraging, the procedure is expensive and not for all obese women, and we recognize that long-term follow-up data on offspring of obese women who have undergone bariatric surgery before pregnancy are lacking. In the interim, we need to encourage obese women to lose weight before conception, using lifestyle changes if possible. During pregnancy, weight gain should be limited to Institute of Medicine guidelines (currently under review) and encouragement given for physical activity.
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PMID:Management of obesity in pregnancy. 1726 45

Both diabetes and chronic hepatitis C virus (HCV) infection are common conditions that often coexist in the same subject. Studies seem to confirm the presence of an association between them. Mechanisms leading to HCV-induced insulin resistance and glucose intolerance are beginning to be elucidated. Insulin resistance in the setting of chronic HCV infection could be related etiologically to viral factors but is also often seen with concomitant nonalcoholic fatty liver disease, the hepatic manifestation of the metabolic syndrome. Insulin resistance decreases the likelihood of response to interferon-based therapies and may be an independent risk factor for the progression of HCV-related liver disease.
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PMID:Mechanisms of glucose intolerance in patients with chronic hepatitis C: implications for treatment. 1732 47

Urocortin 3 (Ucn 3), a member of the corticotropin-releasing factor (CRF) family of peptides, is strongly expressed in mammalian pancreatic beta cells and has been shown to stimulate insulin secretion. Here we report the investigation of the hypothesis that endogenous Ucn 3 regulates insulin secretion, particularly in the presence of nutrient excess. Secretion of Ucn 3-like immunoreactivity from cultured beta cells was stimulated by high glucose and insulin secretagogs such as GLP-1; furthermore, 5 pancreatic Ucn 3 mRNA levels in vivo were increased during the positive energy balance caused by high-fat diet and by the absence of leptin. Immunoneutralization of Ucn 3 or pharmacologic blockade of its receptor, the type 2 CRF receptor (CRFR2), attenuated high but not low glucose-induced insulin secretion from isolated islets in vitro. Cultured islets isolated from Ucn 3-null mice also secreted less insulin in response to high glucose concentrations. Consistently, peripheral injection of a selective CRFR2 antagonist before the administration of a glucose challenge significantly attenuated glucose-induced insulin secretion in vivo. Ucn 3-null mice were relatively protected from the hyperinsulinemia, hyperglycemia, glucose intolerance, hepatic steatosis, and hypertriglyceridemia induced by high-fat diet. Additionally, we found that aged Ucn 3-null mice maintained better glucose tolerance than age-matched wild-type littermates. These results suggest that endogenous Ucn 3 in the pancreas is induced under excessive caloric conditions and acts locally to augment insulin production, which in the long-term may contribute to reduced insulin sensitivity and harmful metabolic consequences.
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PMID:Urocortin 3 regulates glucose-stimulated insulin secretion and energy homeostasis. 1736 May 1

Adipokines and ghrelin play role in insulin resistance, the key pathophysiological abnormality in patients with nonalcoholic fatty liver diseases. In the present study, relationship between nonalcoholic steatohepatitis (NASH) and serum adipokine and ghrelin levels was investigated. Thirty seven patients with biopsy-proven NASH and 25 age- and sex-matched controls were enrolled. Ten of NASH patients (27%) had diabetes mellitus (n = 5) or impaired glucose tolerance (n = 5). Body mass index (BMI) was less than 30 kg/m(2) in 67.6% of patients, while in the remaining 32.4% it was more than 30 kg/m(2). Serum adiponectin, leptin, TNF-alpha, and ghrelin were determined. Serum leptin (15.49 +/- 4.84 vs 10.31 +/- 2.53) and TNF-alpha (12.1 +/- 2.7 vs 10.31 +/- 2.56) levels were significantly higher in the NASH group compared to in the control group (P < .001 for each). Nevertheless, adiponectin (11.1 +/- 2.1 vs 17.3 +/- 2.8) and ghrelin (6.46 +/- 1.1 vs 7.8 +/- 1.1) levels were lower in the NASH group than in the control group (P < .001 for each). Serum levels of the adipokines and ghrelin, however, were comparable in the subgroups of patients regardless of whether BMI was < 30 or > 30 or glucose tolerance was impaired or not (P > .05). Additionally, neither adipokines nor ghrelin was correlated with histopathological grade and stage (P > .05). In conclusion; there is a significant relationship between NASH and adipokines and ghrelin independent from BMI and status of the glucose metabolism. These cytokines that appear to have role in the pathogenesis of NASH, however, do not have any effect upon the severity of the histopathology.
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PMID:Serum adipokine and ghrelin levels in nonalcoholic steatohepatitis. 1739 82


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