Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adipokine resistin has been implicated in obesity and insulin resistance. Liver cirrhosis is associated with decreased body fat mass and insulin resistance. We determined plasma resistin levels in 57 patients with cirrhosis, 13 after liver transplantation, and 30 controls and correlated these with hemodynamic as well as hepatic and systemic metabolic parameters. Patients with cirrhosis had, dependent on the clinical stage, an overall 86% increase in resistin levels (P < 0.001) with hepatic venous resistin being higher than arterial levels (P < 0.001). Circulating resistin was significantly correlated with plasma TNF-alpha levels (r = 0.62, P < 0.001). No correlation was observed between resistin and hepatic hemodynamics, body fat mass, systemic energy metabolism, and the degree of insulin resistance. However, plasma resistin in cirrhosis was negatively associated with hepatic glucose production (r = -0.47, P < 0.01) and positively with circulating free fatty acids (FFA; r = 0.40, P < 0.01) and ketone bodies (r = 0.48, P < 0.001) as well as hepatic ketone body production (r = 0.40, P < 0.01). After liver transplantation, plasma resistin levels remained unchanged, whereas insulin resistance was significantly improved (P < 0.01). These data provide novel insights into the role of resistin in the pathophysiological background of a catabolic disease in humans and also indicate that resistin inhibition may not represent a suitable therapeutic strategy for the treatment of insulin resistance and diabetes in patients with liver cirrhosis.
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PMID:Elevated resistin levels in cirrhosis are associated with the proinflammatory state and altered hepatic glucose metabolism but not with insulin resistance. 1647 79

Most acute and chronic liver diseases are characterized by inflammatory processes with enhanced expression of various pro- and anti-inflammatory cytokines in the liver. These cytokines are the driving force of many inflammatory liver disorders often resulting in fibrosis and cirrhosis. Severe alcoholic hepatitis is a prototypic tumor necrosis factor-alpha (TNF-alpha)-associated disease. This knowledge has recently led to pilot studies with promising results investigating specific anti-TNF drugs such as infliximab or etanercept in the treatment of this disease, although a recently performed controlled French study did show a potential detrimental effect of this approach. Anti-TNF treatment strategies might also improve chronic hepatitis C infection as shown by one controlled trial using etanercept administered subcutaneously for 24 weeks. Furthermore, several case reports suggest that TNF-alpha neutralization is not harmful to patients chronically infected with this virus. In contrast, neutralization of TNF-alpha worsens and might even be associated with fatalities in chronic hepatitis B infection. Anti-inflammatory cytokines such as interleukin-10 (IL-10) have also been tried in patients with chronic liver diseases. Whereas IL-10 administered to patients with chronic hepatitis C virus infection shows indeed anti-inflammatory effects in the liver, it seems to act as a proviral agent thereby limiting its clinical utility. Another cytokine with major anti-inflammatory potential is the adipokine adiponectin, as its administration is beneficial in many experimental models of liver injury. Interference with cytokine pathways and/or administration of anti-inflammatory cytokines will be of major interest in the future therapy of many liver diseases.
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PMID:How to modulate inflammatory cytokines in liver diseases. 1703 2

Obesity has become epidemic in the United States, in Europe, and in many urban areas in the developing world. The globalization of certain 'fast foods' and 'soft drinks' may, in part, be contributing to this epidemic. Diets high in saturated fatty acids and trans fats as well as drinks that have high fructose corn syrup levels may be particularly harmful. Recent research suggests that fat is a dynamic endocrine organ and that visceral fat is associated with the metabolic syndrome. Central obesity leads to organ steatosis and altered serum adipokines including reduced adiponectin and markedly elevated leptin. This abnormal adipokine milieu results in increased tissue infiltration of monocytes and macrophages which produce proinflammatory cytokines that alter organ function. Over many years, the combination of steatosis and local inflammation leads to fibrosis and eventually to cancer. Nonalcoholic fatty liver disease (NAFLD) is a precursor for nonalcoholic steatohepatitis (NASH). NAFLD and NASH (1) lead to cirrhosis and hepatocellular carcinoma, (2) increase the risk of liver resection, and (3) compromise the outcome of liver transplantation. Similarly, in the pancreas nonalcoholic fatty pancreas disease (NAFPD) may lead to nonalcoholic steatopancreatitis (NASP). NAFPD and NASP may (1) promote the development of chronic pancreatitis and pancreatic cancer, (2) exacerbate the severity of acute pancreatitis, and (3) increase the risk of pancreatic surgery. In the gallbladder nonalcoholic fatty gallbladder disease (NAFGBD, cholecystosteatosis) may lead to steatocholecystitis. Cholecystosteatosis may be an explanation for (1) the increased incidence of chronic acalculous cholecystitis and (2) the increased number of cholecystectomies.
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PMID:Hepato-pancreato-biliary fat: the good, the bad and the ugly. 1833 22

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of referral to liver clinics, and its progressive form, non-alcoholic steatohepatitis (NASH), can lead to cirrhosis and end-stage liver disease. The main risk factors for NAFLD/NASH are the metabolic abnormalities commonly observed in metabolic syndrome: insulin resistance, visceral obesity, dyslipidemia and altered adipokine profile. At present, the causes of progression from NAFLD to NASH remain poorly defined, and research in this area has been limited by the availability of suitable animal models of this disease. In the past, the main models used to investigate the pathogenesis of steatohepatitis have either failed to reproduce the full spectrum of liver pathology that characterizes human NASH, or the liver pathology has developed in a metabolic context that is not representative of the human condition. In the last few years, a number of models have been described in which the full spectrum of liver pathology develops in an appropriate metabolic context. In general, the underlying cause of metabolic defects in these models is chronic caloric overconsumption, also known as overnutrition. Overnutrition has been achieved in a number of different ways, including forced feeding, administration of high-fat diets, the use of genetically hyperphagic animals, or a combination of these approaches. The purpose of the present review is to critique the liver pathology and metabolic abnormalities present in currently available animal models of NASH, with particular focus on models described in approximately the last 5 years.
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PMID:Animal models of NASH: getting both pathology and metabolic context right. 1875 64

Liver cirrhosis is a catabolic disease associated with a high incidence of insulin resistance and diabetes mellitus. Pre-B cell colony-enhancing factor/ nicotinamide phosphoribosyltransferase/visfatin has been characterized as a novel adipokine with a potential role in glucose metabolism and nicotinamide dinucleotide (NAD) generation. We studied plasma levels and metabolic relevance of visfatin in 19 patients with cirrhosis and 19 body mass index-, age-, and sex-matched controls. In addition, hepatic mRNA expression was assessed by qPCR in livers of seven patients with cirrhosis and four controls. Circulating visfatin was 78% lower in cirrhotics (P < 0.001) and decreased with worsening of the clinical stage of liver disease. Hepatic visfatin secretion decreased with clinical stage (P < 0.05) and reduced liver function (P = 0.01). Consistent with these data, hepatic visfatin mRNA expression was significantly lower in cirrhotic livers (P < 0.05). Circulating visfatin in cirrhosis was correlated with body cell mass (r = 0.72, P < 0.01) as well as with body fat mass (r = 0.53, P < 0.05) but not with plasma glucose, insulin, the degree of insulin resistance, or whole body glucose oxidation rates. Higher visfatin levels were associated with higher hepatic glucose production (r = 0.53, P < 0.05) and also with a higher arterial ketone body ratio (KBR) (r = 0.48, P < 0.05), an indicator of increased hepatic NAD generation. In conclusion, circulating visfatin levels are significantly decreased in liver cirrhosis, presumably attributable to decreased hepatic expression and production. Plasma visfatin in cirrhosis is not associated with insulin resistance but correlates with hepatic glucose production and the arterial KBR, indicating a potential link between the NAD-generating properties of visfatin and metabolism.
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PMID:Plasma levels of PBEF/Nampt/visfatin are decreased in patients with liver cirrhosis. 1907 45

Alcoholic cirrhosis represents the terminal stage of alcoholic liver disease (ALD) and one of the main causes of death among alcohol abusers. The aim of this review was to provide an update on alcoholic cirrhosis, with an emphasis on recent findings. Increased alcohol consumption in developing countries is expected to increase cirrhosis mortality. There is a need, therefore, to develop new approaches to the prevention of ALD, including more attention to co-factors that may increase risk of ALD (i.e., obesity and diabetes, chronic HCV infection, and smoking). Furthermore, a better understanding of the pathological mechanisms on the basis of alcohol cirrhosis represents a cornerstone in order to develop new pharmacological treatments. Inflammatory and immune responses along with oxidative stress and alterations in adipokine secretion might contribute in different ways to the evolution of alcohol-induced fibrosis/cirrhosis. As of this date, patients with severe alcoholic hepatitis with a Maddrey Discriminant Factor (MDF) 32 should be offered pentoxifylline and/or corticosteroids unless contraindications exist. For ambulatory patients, S-adenosylmethionine (SAMe) may be considered in a motivated patient with nutritional support. Current studies do not support use of anti-tumor necrosis factor (TNF)-alpha antibody. Finally, achieving total alcohol abstinence should represent the main aim in the management of patients affected by any stage of cirrhosis. In the last decades, several drugs able to increase abstinence and prevent alcohol relapse have been evaluated and some of them have obtained approval for alcohol dependence. Patients with alcoholic cirrhosis; however, are usually excluded from such treatments. A recent study demonstrated the efficacy and safety of baclofen in inducing and maintaining alcohol abstinence in cirrhotic alcohol-dependent patients with cirrhosis. All together the information available suggests the need of a multimodal approach in the clinical management of these patients.
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PMID:Understanding and treating patients with alcoholic cirrhosis: an update. 1938 82

Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disorder of our times. Simple steatosis, a seemingly innocent manifestation of NAFLD, may progress into steatohepatitis and cirrhosis, but this process is not well understood. Since NAFLD is associated with obesity and insulin resistance, mechanisms that link lipid metabolism to inflammation offer insights into the pathogenesis. An important parallel between obesity-related pathology of adipose tissue and liver pertains to the emerging role of macrophages and evidence is growing that Kupffer cells critically contribute to progression of NAFLD. Toll-like receptors, in particular TLR4, represent a major conduit for danger recognition linked to Kupffer cell activation and this process may be perturbed at multiple steps in NAFLD. Steatosis may interfere with sinusoid microcirculation and hepatocellular clearance of microbial and host-derived danger signals, enhancing responsiveness of Kupffer cells. Altered lipid homeostasis in NAFLD may unfavourably affect TLR4 receptor complex assembly and sorting, interfere with signalling flux redistribution, promote amplification loops, and impair negative regulation including alternative activation of Kupffer cells. These events are further promoted by altered adipokine secretion and reactive oxygen species production. Specific targeting of these interactions may provide more effective strategies in the treatment of NAFLD.
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PMID:Kupffer cells in non-alcoholic fatty liver disease: the emerging view. 1944 17

Chronic alcohol abuse is an important cause of morbidity and mortality throughout the world. Liver damage due to chronic alcohol intoxication initially leads to accumulation of lipids within the liver and with ongoing exposure this condition of steatosis may first progress to an inflammatory stage which leads the way for fibrogenesis and finally cirrhosis of the liver. While the earlier stages of the disease are considered reversible, cirrhotic destruction of the liver architecture beyond certain limits causes irreversible damage of the organ and often represents the basis for cancer development. This review will summarize current knowledge about the molecular mechanisms underlying the different stages of alcoholic liver disease (ALD). Recent observations have led to the identification of new molecular mechanisms and mediators of ALD. For example, plasminogen activator inhibitor 1 was shown to play a central role for steatosis, the anti-inflammatory adipokine, adiponectin profoundly regulates liver macrophage function and excessive hepatic deposition of iron is caused by chronic ethanol intoxication and increases the risk of hepatocellular carcinoma development.
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PMID:Current experimental perspectives on the clinical progression of alcoholic liver disease. 1964 34

No detailed data are available on hepatic clearance, postprandial release, and distribution profile of metabolically active adipokines in splanchnic blood compartments such as portal and hepatic veins. This would be a prerequisite for understanding the role of visceral adipose tissue-derived adipokines in metabolism. Adiponectin, resistin, leptin, and visfatin concentrations were measured by enzyme-linked immunosorbent assay in peripheral veins, arterial blood, hepatic veins, and portal veins in 50 patients with liver cirrhosis undergoing transjugular intrahepatic portosystemic shunt implantation, in 6 patients with normal liver function, and in fasted and fed rats. Adiponectin, leptin, resistin, and visfatin did not differ among blood compartments in normal-weight probands in the fasted state. Adiponectin and leptin levels were similar in patients with and without liver cirrhosis. Systemic visfatin levels were decreased and resistin levels were increased in liver cirrhosis. Visfatin secretion was higher from visceral than from peripheral subcutaneous adipose tissue in liver cirrhosis. There was no hepatic clearance of visfatin. Leptin secretion was higher from peripheral than from visceral adipose tissue. Leptin did not undergo hepatic clearance. Resistin and adiponectin did not differ between blood compartments in liver cirrhosis. Resistin concentrations increased upon feeding in rats, and there was an increase in the postprandial clearance of adiponectin by the liver. A postprandial increase of leptin concentrations was restricted to peripheral adipose tissue in rats. The results give insight into the dynamics of splanchnic adipokine concentrations and help critically interpret data derived from messenger RNA expression studies.
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PMID:Splanchnic concentrations and postprandial release of visceral adipokines. 1991 46

Adipose tissue dysfunction, featured by insulin resistance and/or dysregulated adipokine production, plays a central role not only in disease initiation but also in the progression to nonalcoholic steatohepatitis and cirrhosis. Promising beneficial effects of betaine supplementation on nonalcoholic fatty liver disease (NAFLD) have been reported in both clinical investigations and experimental studies; however, data related to betaine therapy in NAFLD are still limited. In this study, we examined the effects of betaine supplementation on hepatic fat accumulation and injury in mice fed a high-fat diet and evaluated mechanisms underlying its hepatoprotective effects. Male C57BL/6 mice weighing 25 +/- 0.5 (SE) g were divided into four groups (8 mice/group) and started on one of four treatments: control diet, control diet supplemented with betaine, high-fat diet, and high-fat diet supplemented with betaine. Betaine was supplemented in the drinking water at a concentration of 1% (wt/vol) (anhydrous). Our results showed that long-term high-fat feeding caused NAFLD in mice, which was manifested by excessive neutral fat accumulation in the liver and elevated plasma alanine aminotransferase levels. Betaine supplementation alleviated hepatic pathological changes, which were concomitant with attenuated insulin resistance as shown by improved homeostasis model assessment of basal insulin resistance values and glucose tolerance test, and corrected abnormal adipokine (adiponectin, resistin, and leptin) productions. Specifically, betaine supplementation enhanced insulin sensitivity in adipose tissue as shown by improved extracellular signal-regulated kinases 1/2 and protein kinase B activations. In adipocytes freshly isolated from mice fed a high-fat diet, pretreatment of betaine enhanced the insulin signaling pathway and improved adipokine productions. Further investigation using whole liver tissues revealed that betaine supplementation alleviated the high-fat diet-induced endoplasmic reticulum stress response in adipose tissue as shown by attenuated glucose-regulated protein 78/C/EBP homologous protein (CHOP) protein abundance and c-Jun NH(2)-terminal kinase activation. Our findings suggest that betaine might serve as a safe and efficacious therapeutic tool for NAFLD by improving adipose tissue function.
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PMID:Betaine improved adipose tissue function in mice fed a high-fat diet: a mechanism for hepatoprotective effect of betaine in nonalcoholic fatty liver disease. 2020 61


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