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)

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor, which controls adipocyte differentiation. We targeted with homologous recombination the PPAR gamma 2-specific exon B, resulting in a white adipose tissue knockdown of PPAR gamma. Although homozygous (PPAR gamma hyp/hyp) mice are born with similar weight as the WT mice, the PPAR gamma hyp/hyp animals become growth retarded and develop severe lipodystrophy and hyperlipidemia. Almost half of these PPAR gamma hyp/hyp mice die before adulthood, whereas the surviving PPAR gamma hyp/hyp animals overcome the growth retardation, yet remain lipodystrophic. In contrast to most lipodystrophic models, the adult PPAR gamma hyp/hyp mice only have mild glucose intolerance and do not have a fatty liver. These metabolic consequences of the lipodystrophy are relatively benign because of the induction of a compensatory gene expression program in the muscle that enables efficient oxidation of excess lipids. The PPAR gamma hyp/hyp mice unequivocally demonstrate that PPAR gamma is the master regulator of adipogenesis in vivo and establish that lipid and glucose homeostasis can be relatively well maintained in the absence of white adipose tissue.
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PMID:Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPAR gamma hypomorphic mice. 1460 33

The ability of insulin to stimulate glucose disposal varies more than six-fold in apparently healthy individuals. The one third of the population that is most insulin resistant is at greatly increased risk to develop cardiovascular disease (CVD), type 2 diabetes, hypertension, stroke, nonalcoholic fatty liver disease, polycystic ovary disease, and certain forms of cancer. Between 25-35% of the variability in insulin action is related to being overweight. The importance of the adverse effects of excess adiposity is apparent in light of the evidence that more than half of the adult population in the United States is classified as being overweight/obese, as defined by a body mass index greater than 25.0 kg/m(2). The current epidemic of overweight/obesity is most-likely related to a combination of increased caloric intake and decreased energy expenditure. In either instance, the fact that CVD risk is increased as individuals gain weight emphasizes the gravity of the health care dilemma posed by the explosive increase in the prevalence of overweight/obesity in the population at large. Given the enormity of the problem, it is necessary to differentiate between the CVD risk related to obesity per se, as distinct from the fact that the prevalence of insulin resistance and compensatory hyperinsulinemia are increased in overweight/obese individuals. Although the majority of individuals in the general population that can be considered insulin resistant are also overweight/obese, not all overweight/obese persons are insulin resistant. Furthermore, the cluster of abnormalities associated with insulin resistance - namely, glucose intolerance, hyperinsulinemia, dyslipidemia, and elevated plasma C-reactive protein concentrations -- is limited to the subset of overweight/obese individuals that are also insulin resistant. Of greater clinical relevance is the fact that significant improvement in these metabolic abnormalities following weight loss is seen only in the subset of overweight/obese individuals that are also insulin resistant. In view of the large number of overweight/obese subjects at potential risk to be insulin resistant/hyperinsulinemic (and at increased CVD risk), and the difficulty in achieving weight loss, it seems essential to identify those overweight/obese individuals who are also insulin resistant and will benefit the most from weight loss, then target this population for the most-intensive efforts to bring about weight loss.
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PMID:Obesity, insulin resistance, and cardiovascular disease. 1474 3

Patients with hypopituitarism develop a phenotype similar to metabolic syndrome with central obesity and diabetes. Similarly, patients with hypothalamic damage may develop central obesity, insulin resistance, and hyperphagia. We sought to examine the clinical associations between hypopituitarism, hypothalamic dysfunction, and nonalcoholic fatty liver disease (NAFLD). A case series of patients seen at our institution with diagnoses of hypopituitarism, hypothalamic obesity, or craniopharyngioma and NAFLD was undertaken. Clinical, laboratory, and liver biopsy features were reviewed. Twenty-one patients were identified. NAFLD was diagnosed 6.4 +/- 7.5 years (median 3 years) after the diagnosis of hypothalamic/pituitary dysfunction. Mean gain in body mass index (BMI) between diagnoses of hypothalamic/pituitary disease and NAFLD was 11.3 +/- 8.9 kg/m(2) at an average yearly rate of 2.2 +/- 2.2 kg/m(2). The majority of patients developed elevated glucose levels and dyslipidemia by time of diagnosis of NAFLD. Of the 10 patients biopsied, six were cirrhotic, two had nonalcoholic steatohepatitis (NASH) with fibrosis, and two had simple steatosis. Long-term follow-up of 66 +/- 33 months (range 12-120) was available for 18 patients. Two required liver transplantation. Six patients died, two from liver related causes. In conclusion, patients with hypothalamic and/or pituitary disease are at risk of excessive weight gain, impaired glucose tolerance, and dyslipidemia with subsequent development of NAFLD. This group has a high prevalence of cirrhosis placing them at risk for liver-related death. The novel evidence that hypothalamic/pituitary dysfunction may be accompanied by progressive NAFLD has important implications for the work-up and management of patients with hypothalamic/pituitary disease.
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PMID:Nonalcoholic fatty liver disease among patients with hypothalamic and pituitary dysfunction. 1505 93

Non alcoholic fatty liver disease is a disease of emerging identity and importance. It is frequently associated with obesity, especially visceral fat, and is intimately related to fatty liver and markers of insulin resistance. Both the prevalence and the severity of liver steatosis are related to body mass index, waist circumference, hyperinsulinaemia, hypertriglyceridaemia and impaired glucose tolerance or type 2 diabetes. The identification fatty liver disease in obese patients, is very important in order to prevent complications such as steathohepatitis and cirrhosis. The pathogenesis of non alcoholic fatty liver disease is very complex, there are mitochondrial morphologic and functional alterations, as well as, high sensitivity to injurious stimulus, an increased inflammatory activity, and modifications in cellular metabolism at post-receptor level. Weight reduction is one of the first steps in the treatment of patients with non alcoholic fatty liver disease, as well as the management of associated conditions such as obesity, diabetes mellitus and hyperlipidaemia. Antioxidants, and others drugs such as ursodeoxycholic acid may be beneficial in the treatment of non alcoholic fatty liver disease. These medications, however, need first to be tested in well-controlled trials with clinically relevant end-points and extended follow-up. In this review, we analyze the new concepts in epidemiology, pathophysiology and treatment of this disease.
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PMID:[An update on non-alcoholic fatty liver disease]. 1514 45

Metabolic syndrome also can be named insulin resistance syndrome. The main clinical manifestations include metabolic disorders of glucose and lipid and some diseases caused by the metabolic disorder, such as impaired glucose tolerance or diabetes, obesity, hyperlipemia, fatty liver, hypertension, coronary heart disease, microalbuminuria, etc. According to the theory of zang-fu organs (viscera) in traditional Chinese medicine, these diseases all result from the deficiency of spleen-qi. They are characterized by deficiency in the Ben (root) and excess in the Biao (branch). The Ben (root) is the failure of the spleen in transportation, and the Biao (branch) is stagnation of qi, blood, phlegm, fire, dampness and food. In the prevention and treatment of metabolic syndrome, it is advocated that the intervention of medicine should be used as early as possible, so as to slow down the occurrence and development of insulin resistance, and that emphasis should be transferred from decreasing blood glucose alone to comprehensive prevention of risk factors, especially to the prevention of cardiovascular events. The effect of traditional Chinese herbs is not as good as the western drugs in decreasing the blood pressure and glucose. However, the traditional Chinese herbs have distinctive superiority in ameliorating the insulin resistance, protecting the injury of vascular endothelial cells, regulating the metabolism of lipid, inhibiting the hypercoagulability, and treating the inflammation. Moreover, they are relatively safe. Therefore, the integration of the traditional Chinese medicine and western medicine is worth further research.
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PMID:[Prevention and treatment of metabolic syndrome with integrated traditional Chinese and western medicine]. 1538 69

A limited number of studies have reported associations of markers of liver injury, including elevated concentrations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), with prospective risk of type 2 diabetes. However, only one study has adjusted for a detailed measure of insulin sensitivity (insulin sensitivity index [S(i)]), which is important given associations of obesity and S(i) with nonalcoholic fatty liver disease (NAFLD). Our objective was to investigate the associations of elevated AST and ALT with incident type 2 diabetes among 906 participants in the Insulin Resistance Atherosclerosis Study who were nondiabetic at baseline. S(i) and acute insulin response (AIR) were measured directly from the frequently sampled intravenous glucose tolerance test among black, Hispanic, and non-Hispanic white participants aged 40-69 years. After 5.2 years, 148 individuals had developed type 2 diabetes. Baseline AST and ALT were positively correlated with fasting insulin (r = 0.22 and r = 0.35, respectively), waist circumference (r = 0.18 and r = 0.34), and fasting glucose (r = 0.13 and r = 0.29) and inversely with S(i) (r = -0.18 and r = -0.30; all P < 0.0001). In separate logistic regression models adjusting for age, sex, ethnicity, clinical center, and alcohol consumption, participants in the highest quartiles (Q4) of AST and ALT were at significantly increased risk of incident type 2 diabetes compared with those in the lowest three quartiles (Q1-Q3): AST: odds ratio (OR) 1.73 (95% CI 1.17-2.57); ALT: OR 2.32 (1.36-3.75). After further adjustment for smoking, waist circumference, triglyceride, HDL, impaired glucose tolerance, S(i), and AIR, both AST and ALT remained significantly associated with incident type 2 diabetes: AST, Q4 vs. Q1-Q3: OR 1.98 (1.23-3.17); ALT, Q4 vs. Q1-Q3: OR 2.00 (1.22-3.28). There were no interactions of sex, ethnicity, obesity, impaired glucose tolerance, or S(i) with AST or ALT in the prediction of type 2 diabetes. When entered into the same model with adjustment for demographic variables, both C-reactive protein and ALT independently predicted type 2 diabetes. In addition, AST and ALT were positively associated with incident type 2 diabetes after excluding former and moderate to heavy drinkers. In conclusion, AST and ALT independently predict type 2 diabetes. Baseline elevations of these markers may reflect NAFLD or related pathologies.
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PMID:Elevations in markers of liver injury and risk of type 2 diabetes: the insulin resistance atherosclerosis study. 1544 93

Adipocyte hyperplasia is characteristic of some forms of human obesity, but the role of adipocyte number in obesity and how normal adipocyte number is established are unclear. Preadipocytes proliferate and then differentiate to become mitotically quiescent adipocytes. This involves exit from the cell cycle, a process regulated by cell cycle inhibitors such as the cyclin-dependent kinase inhibitors (CDKIs) p27 and p21. 3T3-L1 preadipocytes show marked changes in p27 and p21 during differentiation, suggesting CDKIs may regulate establishment of adipocyte number in vivo. To study the role of these CDKIs in adipogenesis, we analyzed adult p27 knockout (p27KO), p21 knockout (p21KO), p27/p21 double knockout (DBKO), and wild-type (WT) mice. Adult DBKO mice weighed 100% more and had fourfold increases in body fat percentage compared with WT. Fat pad weights were increased 80, 90, and 500% in p27KO, p21KO, and DBKO mice, respectively, compared with WT. Adipocyte numbers of p27KO, p21KO, and DBKO mice were 1.9-, 1.7-, and 6.1-fold, respectively, that of WT; adipocyte size was not increased. DBKO mice showed glucose intolerance, insulin insensitivity, hepatic steatosis and dyslipidemia; gradations of these effects occurred in p27KO and p21KO mice. In conclusion, p27KO and p21KO mice are obese because of adipocyte hyperplasia, and DBKO mice have further increases in obesity and adipocyte hyperplasia, indicating that their functions in establishing adipocyte number are not redundant. p27 and p21 are major regulators of adipocyte number in vivo, and knockouts lacking one or both of these proteins provide models for producing adipocyte hyperplasia and understanding its metabolic consequences.
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PMID:Loss of cyclin-dependent kinase inhibitors produces adipocyte hyperplasia and obesity. 1546 64

The incidence and risk factors of nonalcoholic fatty liver disease (NAFLD) have never been prospectively determined. To determine the frequency and risk factors of NAFLD and chronological ordering between NAFLD, weight gain, and features of insulin resistance, a historical cohort study was conducted in a Japanese workplace. A cohort free of previous liver injury, alcohol consumption of more than 140 g/wk, and hepatitis B or C infection (529 of 1537 subjects), and a subcohort of 287 subjects free of insulin resistance-related features were identified. Elevated aminotransferases in nonalcoholics were used as a surrogate for NAFLD. High aminotransferases together with weight gain of more than 2 kg and insulin resistance-related features in the subcohort were sought for up to 5 years. The incidence of high aminotransferases was 31 per 1000 person-years (71 events). A significant interaction occurred between age and sex in the development of high aminotransferases. In subjects younger than age 40 years, male sex (hazard ratio [HR]: 4.6), elevated body mass index (HR: 2.1), hypertension (HR: 2.6), and low high-density lipoprotein cholesterol (HR: 2.8) increased the risk of high aminotransferases, whereas age (HR: 0.6 for each 5 years) decreased the risk. In subjects older than age 40 years, glucose intolerance (HR: 5.3) was the only significant risk factor. In the subcohort, weight gain preceded high aminotransferases and other insulin resistance-related features, which appeared sequentially in order of low high-density lipoprotein cholesterol, hypertriglyceridemia/hypertransaminasemia/hypertension, and glucose intolerance. In conclusion, this cohort study clearly showed chronological ordering and an association between development of elevated aminotransferases and risk factors of NAFLD.
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PMID:Chronological development of elevated aminotransferases in a nonalcoholic population. 1569 Apr 83

Hepatic insulin resistance is a critical component in the development of type 2 diabetes mellitus. In many cases, insulin resistance in liver is associated with reduced expression of both major insulin receptor substrate (IRS) proteins, IRS-1 and IRS-2. To investigate the specific functions of IRS-1 and IRS-2 in regulating liver function in vivo, we developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) are used to knock down IRS-1, IRS-2, or both, by 70-80% in livers of WT mice. The knockdown of IRS-1 resulted in an upregulation of the gluconeogenic enzymes glucose-6 phosphatase and phosphoenolpyruvate carboxykinase, as well as a marked increase in hepatic nuclear factor-4 alpha. Decreased IRS-1 was also associated with a decrease in glucokinase expression and a trend toward increased blood glucose, whereas knockdown of IRS-2 resulted in the upregulation of lipogenic enzymes SREBP-1c and fatty acid synthase, as well as increased hepatic lipid accumulation. The concomitant injection of IRS-1 and IRS-2 adenoviral shRNAs resulted in systemic insulin resistance, glucose intolerance, and hepatic steatosis. The alterations in the dual-knockdown mice were associated with defective Akt activation and Foxo1 phosphorylation. Taken together, our results demonstrate that hepatic IRS-1 and IRS-2 have complementary roles in the control of hepatic metabolism, with IRS-1 more closely linked to glucose homeostasis and IRS-2 more closely linked to lipid metabolism.
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PMID:Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. 2780 76

Angiopoietin-like protein 4 (ANGPTL4) is a circulating protein predominantly expressed in adipose tissue and liver. Several recent studies demonstrated that ANGPTL4 is the target gene of peroxisome proliferation activators, the agonists of which are widely used as the antidiabetic and lipid-lowering drugs. Here we provide evidence that ANGPTL4 is a blood-borne hormone directly involved in regulating glucose homeostasis, lipid metabolism, and insulin sensitivity. Adenovirus-mediated expression of ANGPTL4 potently decreased blood glucose and improved glucose tolerance, whereas it induced hyperlipidemia, fatty liver, and hepatomegaly in C57 mice. In db/db diabetic mice, ANGPTL4 treatment reduced hyperglycemia to a normal level, and markedly alleviated glucose intolerance and hyperinsulinemia. Ex vivo studies on primary rat hepatocytes revealed that ANGPTL4 significantly decreased hepatic glucose production and enhanced insulin-mediated inhibition of gluconeogenesis. Serum levels of ANGPTL4 in human subjects inversely correlated with plasma glucose concentrations and HOMA IR, the homeostasis model assessment of insulin resistance. In patients with type 2 diabetes, serum levels of ANGPTL4 were significantly lower than those in healthy subjects, suggesting that the decreased ANGPTL4 could be a causative factor of this disease. These results collectively indicate that ANGPTL4 exerts distinct effects on glucose and lipid metabolism, and that its beneficial effect on glucose homeostasis might be useful for the treatment of diabetes.
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PMID:Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice. 1583 23


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