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)

Adiponectin has recently been shown to be a promising candidate for the treatment of obesity-associated metabolic syndromes. Replenishment of recombinant adiponectin in mice can decrease hyperglycemia, reverse insulin resistance, and cause sustained weight loss without affecting food intake. Here we report its potential roles in alcoholic and nonalcoholic fatty liver diseases in mice. Circulating concentrations of adiponectin decreased significantly following chronic consumption of high-fat ethanol-containing food. Delivery of recombinant adiponectin into these mice dramatically alleviated hepatomegaly and steatosis (fatty liver) and also significantly attenuated inflammation and the elevated levels of serum alanine aminotransferase. These therapeutic effects resulted partly from the ability of adiponectin to increase carnitine palmitoyltransferase I activity and enhance hepatic fatty acid oxidation, while it decreased the activities of two key enzymes involved in fatty acid synthesis, including acetyl-CoA carboxylase and fatty acid synthase. Furthermore, adiponectin treatment could suppress the hepatic production of TNF-alpha and plasma concentrations of this proinflammatory cytokine. Adiponectin was also effective in ameliorating hepatomegaly, steatosis, and alanine aminotransferase abnormality associated with nonalcoholic obese, ob/ob mice. These results demonstrate a novel mechanism of adiponectin action and suggest a potential clinical application of adiponectin and its agonists in the treatment of liver diseases.
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PMID:The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. 1284 63

Adiponectin has antilipogenic and anti-inflammatory effects, while tumor necrosis factor alpha (TNF-alpha) reduces insulin sensitivity and has proinflammatory effects. We examined (1) the extent to which hypoadiponectinemia and TNF-alpha activation are features of nonalcoholic steatohepatitis (NASH) and (2) whether serum levels of these markers correlate with the severity of histological changes in 109 subjects with nonalcoholic fatty liver disease (NAFLD), including 80 with NASH and 29 with simple steatosis. By multivariate analysis, subjects with NASH had reduced adiponectin level and increased TNF-alpha and soluble TNF receptor 2 (sTNFR2)-but not leptin levels, compared with controls matched by age, sex, and body mass index; these differences were independent of the increased insulin resistance (by homeostasis model [HOMA-IR]) in NASH. When compared with simple steatosis, NASH was associated with lower adiponectin levels and higher HOMA-IR, but there were no significant differences in the levels of TNF-alpha and sTNFR2. The majority of subjects with steatohepatitis (77%) had adiponectin levels less than 10 microg/mL and HOMA-IR greater than 3 units, but only 33% of those with pure steatosis had these findings. HOMA-IR and low serum adiponectin were also independently associated with increased grades of hepatic necroinflammation. In conclusion, hypoadiponectinemia is a feature of NASH independent of insulin resistance. Reduced adiponectin level is associated with more extensive necroinflammation and may contribute to the development of necroinflammatory forms of NAFLD.
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PMID:Beyond insulin resistance in NASH: TNF-alpha or adiponectin? 1566 Apr 29

Adiponectin, secreted specifically from adipocytes, is thought to play a key role in the metabolic syndrome. Plasma adiponectin concentrations were studied in 36 typical nonalcoholic fatty liver (NAFL) women which is commonly associated with the metabolic syndrome. They were diagnosed as NAFL by ultrasound brightness, slightly elevated serum ALT levels and the exclusion of history of alcohol abuse and other known liver diseases. Compared with 64 control women, NAFL had a significant increase in the variables of the metabolic syndrome, other hepatic enzymes and leptin levels, while a reduction in AST/ALT ratio and adiponectin before (mean +/- SE: 7.2 +/- 0.5 vs 9.0 +/- 0.4 microg/ml, p < 0.005) and after adjustment for body fat mass (0.24 +/- 0.02 vs 0.34 +/- 0.02, p < 0.0001), atherogenic Index [(total cholesterol - HDLC)/HDLC: 3.2 +/- 0.3 vs 4.6 +/- 0.3, p < 0.005] or calculated insulin resistance (HOMA-R) (6.6 +/- 1.9 vs 8.6 +/- 0.9, p < 0.005). BMI and amylase were positive, and adiponectin/BMI was negative significant independent determinants of ALT value in multiple regression model. In conclusion, while hypoadiponectinemia was observed in NAFL, hypoadiponectinemia provides the possibility of fat accumulation in the liver.
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PMID:Plasma adiponectin decrease in women with nonalcoholic Fatty liver. 1564 78

Plasma levels of adiponectin are decreased in patients with nonalcoholic fatty liver disease (NAFLD), but the relationship among plasma adiponectin, insulin sensitivity, and histological features is unclear. In 174 NAFLD patients and 42 controls, we examined plasma adiponectin concentrations in relation to 1) lipid profile, indices of insulin resistance, and features of the metabolic syndrome (n = 174); 2) hepatic insulin resistance (clamp technique with tracer infusion) (10 patients); and 3) histological features at liver biopsy (n = 116). When the data from all subjects were combined, plasma adiponectin levels were positively associated with increased age, female gender, and plasma high-density lipoprotein levels, and negatively associated with waist circumference, body mass index, triglycerides, indices of insulin resistance, and aminotransferase levels, and also predicted the presence of the metabolic syndrome. In step-wise regression, increased age, female gender, waist circumference, triglyceride levels, and homeostasis model assessment independently associated with adiponectin (adjusted R(2), 0.329). In NAFLD, adiponectin was only associated with increased age, female gender, and triglycerides (adjusted R(2), 0.245). When the measured histological parameters were included in the model, plasma adiponectin levels were also inversely proportional to the percentage of hepatic fat content (adjusted R(2), 0.221), whereas necroinflammation and fibrosis did not fit in the model. Adiponectin was negatively correlated with insulin-suppressed endogenous glucose production during the clamp (P = 0.011). The results demonstrate that decreased levels of circulating adiponectin in NAFLD are related to hepatic insulin sensitivity and to the amount of hepatic fat content. Hypoadiponectinemia in NAFLD is part of a metabolic disturbance characterized by ectopic fat accumulation in the central compartment.
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PMID:Plasma adiponectin in nonalcoholic fatty liver is related to hepatic insulin resistance and hepatic fat content, not to liver disease severity. 1579 48

Obesity is not necessary to observe insulin resistance in humans since severe insulin resistance also characterizes patients lacking subcutaneous fat such as those with HAART (highly-active antiretroviral therapy) - associated lipodystrophy. Both the obese and the lipodystrophic patients have, however, an increase in the amount of fat hidden in the liver. Liver fat content can be non-invasively accurately quantified by proton magnetic resonance spectroscopy. It is closely correlated with fasting insulin and direct measures of hepatic insulin sensitivity while the amount of subcutaneous adipose tissue is not. The causes of interindividual 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. In addition, treatment of both lipodystrophic and type 2 diabetic patients with PPARgamma agonists but not metformin decreases liver fat and increases adiponectin levels. Markers of liver fat such as serum alanine aminotransferase activity have been shown to predict type 2 diabetes in several studies independent of obesity. The fatty liver thus 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:The fatty liver and insulin resistance. 1589 48

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

There is increasing evidence that visceral adipose tissue is a causative risk factor for fatty liver and nonalcoholic steatohepatitis. Adipose tissue-derived secretory proteins are collectively named adipocytokines. Obesity and mainly visceral fat accumulation impair adipocyte function and adipocytokine secretion and the altered release of these proteins contributes to hypertension, impaired fibrinolysis and insulin resistance. This review summarizes recent findings on the role of the adipocytokines adiponectin, leptin and resistin in the context of hepatic insulin resistance, fatty liver and liver fibrosis. Elevated levels of resistin antagonize hepatic insulin action and raise plasma glucose levels. Leptin exerts insulin-sensitizing effects, but obesity has been linked to leptin resistance and low levels of circulating leptin receptor, indicating that high levels of leptin cannot mediate its beneficial effects. Adiponectin improves insulin sensitivity; however, low circulating adiponectin is found in the obese state. Adiponectin is an anti-inflammatory protein, whereas leptin augments inflammation and fibrogenesis. Disturbed adipocytokine secretion might, therefore, promote hepatic steatosis and the development of nonalcoholic steatohepatitis. The beneficial effects of the therapeutic approaches so far tested in the treatment of fatty liver disease and fibrosis might be due to the modulation of these adipocytokines.
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PMID:Mechanisms of disease: adipocytokines and visceral adipose tissue--emerging role in nonalcoholic fatty liver disease. 1626 8

Adiponectin is an abundant adipose-specific protein, which acts as an anti-diabetic, anti-atherogenic, and anti-inflammatory adipokine. Although recent advances in the field of adiponectin have been made by the identification of adiponectin receptors and by the understanding about relationship between its multimerization and functions, detailed molecular background remains unclear. Our established anti-human adiponectin antibodies, ANOC 9103 and ANOC 9104, blocked some adiponectin functions such as the growth inhibition of B-lymphocytes on stromal cells and the inhibition of acetylated LDL uptake in macrophages, suggesting that they may recognize important functional regions of adiponectin. As a result of epitope mapping based on the ability to bind to the deleted adiponectin mutants, we identified that these antibodies recognize amino-terminal region of adiponectin before the beginning of the collagen-like domain. Notably, a peptide fragment (DQETTTQGPGVLLPLPKGACTGWMA) corresponding to amino acid residues 17-41 of human adiponectin could bind to restricted types of cells and block adiponectin-induced cyclooxygenase-2 gene expression and prostaglandin E2 production in MS-5 stromal cells. Moreover, the deletion of its amino-terminal region reduced the abilities to inhibit not only collagen-induced platelet aggregation but also diet-induced hepatic steatosis. These data indicate that amino-terminal region of adiponectin is a physiologically functional domain and that a novel receptor, which recognizes amino-terminal region of adiponectin, may exist on some types of cells. Further investigations will contribute to the understanding of molecular mechanisms about adiponectin functions as well as to the designing of novel strategies for the treatment of patients with insulin-resistance, vascular dysfunction, and chronic inflammation.
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PMID:Identification of amino-terminal region of adiponectin as a physiologically functional domain. 1640 69

Adiponectin is a multifunctional adipokine that circulates as several oligomeric complexes in the blood stream. However, the molecular basis that regulates the production of the adiponectin oligomers remains largely elusive. We have shown previously that several conserved lysine residues (positions 68, 71, 80, and 104) within the collagenous domain of adiponectin are modified by hydroxylation and glycosylation (Wang, Y., Xu, A., Knight, C., Xu, L. Y., and Cooper, G. J. (2002) J. Biol. Chem. 277, 19521-19529). Here, we investigated the potential roles of these post-translational modifications in oligomeric complex formation of adiponectin. Gel filtration chromatography revealed that adiponectin produced from mammalian cells formed trimeric, hexameric, and high molecular weight (HMW) oligomeric complexes. These three oligomeric forms were differentially glycosylated, with the HMW oligomer having the highest carbohydrate content. Disruption of hydroxylation and glycosylation by substitution of the four conserved lysines with arginines selectively abrogated the intracellular assembly of the HMW oligomers in vitro as well as in vivo. In type 2 diabetic patients, both the ratios of HMW to total adiponectin and the degree of adiponectin glycosylation were significantly decreased compared with healthy controls. Functional studies of adiponectin-null mice revealed that abrogation of lysine hydroxylation/glycosylation markedly decreased the ability of adiponectin to stimulate phosphorylation of AMP-activated protein kinase in liver tissue. Chronic treatment of db/db diabetic mice with wild-type adiponectin alleviated hyperglycemia, hypertriglyceridemia, hepatic steatosis, and insulin resistance, whereas full-length adiponectin without proper post-translational modifications and HMW oligomers showed substantially decreased activities. Taken together, these data suggest that hydroxylation and glycosylation of the lysine residues within the collagenous domain of adiponectin are critically involved in regulating the formation of its HMW oligomeric complex and consequently contribute to the insulin-sensitizing activity of adiponectin in hepatocytes.
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PMID:Post-translational modifications of the four conserved lysine residues within the collagenous domain of adiponectin are required for the formation of its high molecular weight oligomeric complex. 1662 99

Adiponectin is a fat cell-secreted hormone with antidiabetic and anti-inflammatory activities. The reduced adiponectin levels are associated with obesity-related metabolic syndrome. Replenishment of this hormone into animal models can improve insulin sensitivity, decrease blood glucose and lipid levels, and prevent the development of atherosclerosis and fatty liver injury. Despite these findings, the underlying molecular mechanisms remain largely unknown. Here, we have used affinity chromatography to purify the protein complexes that are associated with adiponectin in human serum. The nature of these adiponectin-binding proteins was analyzed by MS/MS. Eight proteins from the adiponectin-containing protein mixtures have been identified. Many of them, including thrombospondin-1 (TSP-1), histidine-rich glycoprotein, kininogen 1, and alpha 2 macroglobulin (alpha2M), are well-known glycoproteins involved in the regulation of inflammation, angiogenesis, and tissue remodeling. Coimmunoprecipitation and radioligand competitive-binding assays confirmed the direct interactions between adiponectin and alpha2M, or TSP-1. Moreover, these specific bindings were also detected in the serum samples derived from both healthy human subjects and patients with type 2 diabetes. In summary, our study demonstrated that, in the circulation, adiponectin forms protein complexes with other serum proteins. These proteins might serve as the physiological-binding partners of adiponectin and regulate its bioavailability and biological activities.
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PMID:Proteomic characterization of human serum proteins associated with the fat-derived hormone adiponectin. 1676 90


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