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)

Nonalcoholic steatohepatitis and chronic viral hepatitis C are the two dominant liver diseases in the Netherlands. Hepatic steatosis is usually innocuous but in twenty percent of patients it develops into steatohepatitis. One-fifth of these patients develop liver cirrhosis and hepatocellular carcinoma can also be a consequence of the disease. Nonalcoholic steatohepatitis is characterized by macrovesicular steatosis, necroinflammation, loss ofhepatocytes and fibrosis. Nonalcoholic steatohepatitis often is associated with type 2 diabetes mellitus, hypertension, dyslipoproteinemia and obesity. Insulin resistance plays a major role in the pathogenesis of this disease. Drugs against insulin resistance can ameliorate nonalcoholic steatohepatitis. Gradual weight loss, a diet including polyunsaturated fatty acids and exercise are other important treatment components of this condition.
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PMID:[Nonalcoholic steatohepatitis: diagnosis, pathogenesis, treatment and prognosis]. 1583 33

To increase our understanding of the effect of thiazolidinediones, a new class of antidiabetic drugs, on liver function as well as glycemic control, we investigated liver function before, during, and after treatment with troglitazone and pioglitazone. A total of 32 patients with type 2 diabetes were studied. Glycemic control and liver function were measured before, during, and after 4 to 12 weeks of treatment with troglitazone or pioglitazone. Glycemic control was assessed by fasting levels of plasma glucose, hemoglobin A 1c , and serum insulin, and liver function was assessed by asparatate aminotransferase (AST), alanine aminotransferase (ALT), and gamma -glutamyl transpeptidase ( gamma-GTP). Homeostasis model assessment for insulin resistance was used as an index of insulin resistance. During treatment with troglitazone, fasting plasma glucose and hemoglobin A 1c levels and homeostasis model assessment for insulin resistance were significantly decreased. Serum AST, ALT, and gamma-GTP levels were significantly decreased during treatment (AST, -17.4%; ALT, -27.2%; gamma-GTP, -47.9%) and returned to pretreatment levels after 4 weeks of withdrawal of the drug. A similar tendency was observed during treatment with pioglitazone (AST, -4.7%; ALT, -16.4%; gamma-GTP, -30.8%). These data suggest that, in contrast to the deterioration of liver function reported in a small subset of patients treated with troglitazone, treatment with thiazolidinediones was associated with a decrease in serum transaminases in most patients. The improvement in liver function parameters known to be associated with fatty liver in the present study, together with an improvement in fatty liver reported for another class of insulin sensitizers, biguanides, suggests that thiazolidinediones may have a beneficial effect on fatty liver.
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PMID:Improvement of liver function parameters in patients with type 2 diabetes treated with thiazolidinediones. 1579 62

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

Stearoyl-CoA desaturase (SCD), the rate-limiting enzyme in monounsaturated fatty acid synthesis, has recently been shown to be the critical control point regulating hepatic lipogenesis and lipid oxidation. As several manifestations of the metabolic syndrome and type 2 diabetes mellitus are associated with alterations in intracellular lipid partitioning, we propose that SCD1 may be a potential therapeutic target in the treatment of obesity and the metabolic syndrome. In support of this notion, we have shown that SCD1-deficient mice have increased energy expenditure, reduced body adiposity, increased insulin sensitivity and are resistant to diet-induced obesity and liver steatosis. Furthermore, SCD1 was found to be specifically repressed during leptin-mediated weight loss, and leptin-deficient ob/ob mice lacking SCD1 showed marked correction of the hypometabolic phenotype and hepatic steatosis. Much evidence indicates that the direct anti-steatotic effect of SCD1 deficiency stems from increased fatty acid oxidation and decreased lipid synthesis. All of these findings reveal that pharmacological manipulation of SCD activity might be of benefit in the treatment of obesity, diabetes, liver steatosis and other diseases of the metabolic syndrome.
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PMID:Stearoyl-CoA desaturase as a new drug target for obesity treatment. 1583 67

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

Hepatic steatosis is the hallmark of nonalcoholic fatty liver disease (NAFLD), which is the consequence of multiple metabolic derangements among which insulin resistance plays a pivotal role. Steatosis is, also, a feature of hepatitis C virus (HCV) infection. However, in chronic hepatitis C, the prevalence of steatosis is 2.5-fold more elevated than that expected by a chance concurrence with NAFLD, suggesting that HCV may be implied in the development of steatosis. As observed in NAFLD, in patients infected with HCV genotype 1 steatosis is associated with an increased body mass index. On the other hand, in patients infected with genotype 3 the extent of steatosis strictly correlates with the viral load indicating that steatosis is mainly "virus-related". Regardless of the "metabolic" or "viral" etiology, hepatic steatosis in HCV contributes to the progression of liver fibrosis, to the development of hepatocellular carcinoma and to an impaired response to interferon treatment. Features such as obesity, insulin resistance and type 2 diabetes mellitus are shared by NAFLD and HCV-associated steatosis. In addition, HCV infection, directly or through steatosis, favors the development of type 2 diabetes mellitus. Hyperlipidemia is an independent predictor of the development of NAFLD, but not of HCV-associated steatosis. Arterial hypertension is common in nonalcoholic steatohepatitis patients, and HCV infection has recently been acknowledged as an independent risk factor for atherosclerosis. The role of iron in the progression of both NAFLD and HCV-associated steatosis remains controversial while lipoperoxidation and oxidative stress are pathogenic mechanisms shared by both. Some metabolic risk factors may be shared by both HCV-associated steatosis and NAFLD although the disease progression and pathophysiological background may be different. Preliminary data suggest that the therapeutic options for NAFLD may also be useful to improve HCV-associated steatosis.
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PMID:[Hepatitis C virus-associated and metabolic steatosis. Different or overlapping diseases?]. 1585 90

Although the target of hepatitis C virus (HCV) infection is the liver, it has become progressively more evident that HCV can induce diseases in numerous organs. Recently, much attention has been drawn to metabolic disorders in HCV infection. Initially, hepatic steatosis and disturbances in lipid metabolism were found to be characteristic of HCV infection, and, subsequently, a correlation was noted between HCV infection and diabetes. It is now evident that HCV, by itself, can induce insulin resistance by way of disturbing the intracellular signaling pathway of insulin by the function of HCV core protein. Insulin resistance, caused by HCV infection, evolves to type 2 diabetes when superimposed on a high-fat diet and obesity. The fact that HCV infection induces insulin resistance by the virus itself may influence the progression of chronic hepatitis and open up novel therapeutic approaches. When hepatitis C is compared with nonalcoholic steatohepatitis (NASH), there are a number of similarities and several differences. From the metabolic aspect, hepatitis C resembles NASH in numerous features, such as the presence of steatosis, serum dyslipidemia, and oxidative stress in the liver, suggesting that hepatitis C is a steatohepatitis. In contrast, there are noticeable differences between hepatitis C and NASH, in that HCV modulates cellular gene expression and intracellular signal transduction, including the activation of mitogen-activated protein (MAP) kinase and transcription factor activator protein (AP)-1, while such details have not been noted for NASH. This difference may explain the markedly higher incidence of HCC development in chronic hepatitis C compared with that in NASH. HCV infection needs to be viewed not only as a liver disease but also as a metabolic disease, and this viewpoint could open up a novel way to the molecular understanding of the pathogenesis of hepatitis C, as a virus-associated steatohepatitis (VASH).
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PMID:Metabolic aspects of hepatitis C viral infection: steatohepatitis resembling but distinct from NASH. 1586 69

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

The metabolic syndrome is strongly associated with insulin resistance and has been recognized as a cluster of risk factors for cardiovascular diseases such as visceral obesity, hypertension, and diabetes. There is a growing body of evidence to show that nonalcoholic steatohepatitis (NASH) is the hepatic manifestation of insulin resistant patients with the metabolic syndrome. Indeed, insulin resistance increases adipocyte lipolysis and subsequently elevates circulating free fatty acids, thus stimulating the accumulation of fatty acids in the liver (hepatic steatosis). Fatty acids elicit reactive oxygen species generation, thereby promoting disease progression to NASH by both lipid peroxidation and inflammatory cytokine production. Postprandial hyperglycemia, one of the characteristic features of insulin resistance, also induces oxidative stress generation, being involved in dysfunction of pancreatic beta cells and vascular wall cells in the metabolic syndrome. Recently, STOP-NIDDM trial revealed that acarbose (Glucobay), an alpha-glucosidase inhibitor, improved postprandial hyperglycemia and subsequently reduced the risk of development of type 2 diabetes and newly diagnosed hypertension in patients with impaired glucose tolerance. In this study, acarbose treatment was also found to reduce body mass index and waist circumference in these patients. Furthermore, a meta-analysis of seven long-term studies has also shown that intervention with acarbose improved triglyceride levels, body weight and systolic blood pressure and subsequently prevented myocardial infarction in type 2 diabetic patients. Since acarbose improves postprandial hyperglycemia by delaying the release of glucose from complex carbohydrates in the absence of an increase in insulin secretion, the beneficial aspects of acarbose could be ascribed to improvement of insulin sensitivity in these patients. Given the pathological link between NASH and insulin resistance, we would like to hypothesize here that acarbose may become a promising therapeutic strategy for the treatment of patients with NASH. Does acarbose treatment improve steatohepatitis histologically? Is the extent of histological improvement by acarbose parallel to that of insulin sensitivity in these patients? Large clinical trials will provide us with more definite information whether acarbose treatment can improve insulin sensitivity and resultantly reduce the risk of progression of liver diseases in patients with NASH.
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PMID:Acarbose is a promising therapeutic strategy for the treatment of patients with nonalcoholic steatohepatitis (NASH). 1592 16

Liver X receptor (LXR) agonists have been proposed to act as anti-diabetic drugs. However, pharmacological LXR activation leads to severe hepatic steatosis, a condition usually associated with insulin resistance and type 2 diabetes mellitus. To address this apparent contradiction, lean and ob/ob mice were treated with the LXR agonist GW-3965 for 10 days. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp studies. Hepatic glucose production (HGP) and metabolic clearance rate (MCR) of glucose were determined with stable isotope techniques. Blood glucose and hepatic and whole body insulin sensitivity remained unaffected upon treatment in lean mice, despite increased hepatic triglyceride contents (61.7 +/- 7.2 vs. 12.1 +/- 2.0 nmol/mg liver, P < 0.05). In ob/ob mice, LXR activation resulted in lower blood glucose levels and significantly improved whole body insulin sensitivity. GW-3965 treatment did not affect HGP under normo- and hyperinsulinemic conditions, despite increased hepatic triglyceride contents (221 +/- 13 vs. 176 +/- 19 nmol/mg liver, P < 0.05). Clamped MCR increased upon GW-3965 treatment (18.2 +/- 1.0 vs. 14.3 +/- 1.4 ml x kg(-1) x min(-1), P = 0.05). LXR activation increased white adipose tissue mRNA levels of Glut4, Acc1 and Fasin ob/ob mice only. In conclusion, LXR-induced blood glucose lowering in ob/ob mice was attributable to increased peripheral glucose uptake and metabolism, physiologically reflected in a slightly improved insulin sensitivity. Remarkably, steatosis associated with LXR activation did not affect hepatic insulin sensitivity.
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PMID:Differential effects of pharmacological liver X receptor activation on hepatic and peripheral insulin sensitivity in lean and ob/ob mice. 1594 83


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