Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The association of metabolic disorders with liver disease is receiving increasing attention in the gastroenterological community. Cohort studies have shown that advanced liver disease may stem from metabolic disorders, via fatty liver, non-alcoholic steatohepatitis, cryptogenic cirrhosis, and eventually hepatocellular carcinoma. In both obesity and diabetes, deaths from cirrhosis are higher than expected, mainly in subjects with no or moderate alcohol consumption, but high rates of fatty liver disease have been associated with all features of the metabolic syndrome. Also the risk of hepatocellular carcinoma is higher than normal, being dependent on body mass index (BMI) in obesity, and independent of age, BMI, gender and race in diabetes. Finally, metabolic liver disease may interact with hepatitis C virus infection, increasing the risk of steatosis and liver disease progression, as well as reducing the chances of an effective antiviral treatment. There is evidence that treatments aimed at reducing insulin resistance are also effective in improving liver histology. Although cardiovascular disease remains the major cause of increased morbidity and excess mortality in metabolic disorders, the risk of progressive liver disease should no longer be underestimated, being a threat to millions of people at risk in the present epidemics of obesity and diabetes, and therapeutic strategies need to be tested.
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PMID:Is liver disease a threat to patients with metabolic disorders? 1617 69

Nuclear factor (NF)-kappaB is a family of seven structurally related transcription factors that play a central role in cardiovascular growth, stress response, and inflammation by controlling gene network expression. Although the NF- kappaB subunits are ubiquitously expressed, their actions are regulated in a celltype and stimulus-specific manner, allowing for a diverse spectrum of effects. For example, NF-kappalB is activated by cytokines, reactive oxygen species, bacterial cell wall products, vasopressors, viral infection, and DNA damage. Recent molecular dissection of its mechanisms for activation has shown that NF-kappalB can be induced by the so-called "canonical" and "noncanonical" pathways, leading to distinct patterns in the individual subunits activated and downstream genetic responses produced. The canonical pathway involves activating the IkappalB kinase (IKK) with subsequent phosphorylation-induced proteolysis of the IkappaBalpha inhibitors and consequent nuclear translocation of the Rel A transcriptional activator. Recent work using high-density oligonucleotide arrays have begun to systematically dissect the scope of the gene network under canonical NF-kappaB control and have yielded important insights into biological pathways controlled by it. This pathway controls expression of noncontiguous, functionally discrete groups of genes ("regulons"), whose temporal expression occurs in waves. Moreover, its mode of activation (oscillatory or monophasic) plays an important role in determining the spectrum of target genes expressed. By contrast, the noncanonical NF-kappaB activation pathway involves activating the NF-kappaB inducing kinase (NIK) to stimulate IKKalpha-induced phosphorylation and proteolytic processing of the 100-kDa cytoplasmic NF-kappaB2 precursor. Activated NF-kappaB2 then forms a complex with Rel B and NIK to translocate into the nucleus thereby activating a distinct set of genes. Although the noncanonical pathway has been most clearly linked to control of adaptive immunity, recent intriguing studies have implicated this pathway in viral induced stress response and in the metabolic syndrome. In this way, a single family of transcription factors can respond to diverse stimuli to regulate cardiovascular homeostasis.
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PMID:The NF-kappaB regulatory network. 1730 19

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries and is considered the hepatic manifestation of metabolic syndrome. The hallmark of NAFLD is hepatic neutral lipid accumulation, mainly triacylglycerol, in the absence of significant ethanol consumption, viral infection or other specific etiologies. Hepatic lipid accumulation results from an imbalance between lipid availability (from circulating lipid uptake or de novo lipogenesis) and lipid disposal (via free fatty acid oxidation or triglyceride-rich lipoprotein secretion) and eventually triggers lipoperoxidative stress and hepatic injury. Each of these steps is altered in NAFLD, although to a different extent. Regulation of these pathways is complex and involves nuclear receptors, membrane transport proteins and cellular enzymes. We will review available data on different steps of hepatic lipid metabolism in NAFLD and recent advances in understanding molecular mechanisms underlying hepatic fat accumulation in these subjects.
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PMID:Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). 1882 34

After more than two decades of AIDS epidemic, the spectrum of HIV-associated vascular diseases has mainly evolved from infectious and inflammatory vasculitides to premature atherosclerosis, its related contributing conditions (metabolic syndrome, dyslipidemia, insulin resistance syndrome) and complications (acute coronary and cerebrovascular syndromes). Today, as the AIDS epidemic further progresses worldwide and as the life expectancy of HIV-infected patients treated with effective antiviral regimens has dramatically increased, more than 10% of patients experience cardiovascular manifestations. The complex interplay between viral infection, inflammatory and cytokines pathways, protease inhibitors-induced hyperlipidemia and direct effects on endothelial cells has not, by far, been integrated in a single comprehensive pathogenesis network. However, recognition of its main components has resulted in a broader appreciation of cardiovascular risk and risk factors in HIV-infected/treated patients. Cardiovascular prevention is required in more than one half of HIV-infected/treated patients to achieve a reliable effectiveness of modern antiretroviral therapy. As the prognosis of HIV patients improves continuously, this rate is also likely to increase in the future.
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PMID:HIV-associated vascular diseases: structural and functional changes, clinical implications. 1913 Nov 30

The natural history of chronic hepatitis C has been defined in several retrospective and prospective studies conducted in the last 20 years. These studies have clearly demonstrated that the outcome of chronic hepatitis C virus infection is profoundly influenced by a variety of cofactors and comorbidities. Many of the cofactors that affect the course of liver disease in hepatitis C also have a significant influence on the result of antiviral therapy. Unfortunately, comorbidities that have been shown to negatively influence the course and outcome of liver disease often reduce the chance of achieving a sustained virological response with pegylated interferon (PEG-IFN) and ribavirin treatment. The most important and frequent comorbidity influencing the course of chronic hepatitis C and the response to antiviral therapy is represented by the metabolic syndrome, and by the associated state of insulin resistance. Other comorbidities that have a negative influence on the progression of hepatitis C and on the response to antiviral therapy include excess alcohol intake, human immunodeficiency virus and hepatitis B virus co-infection and a number of conditions that reduce the benefit of therapy by affecting negatively compliance and/or adherence to adequate PEG-IFN or ribavirin doses.
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PMID:What are the comorbidities influencing the management of patients and the response to therapy in chronic hepatitis C? 1920 61

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation in the absence of significant ethanol consumption, viral infection, or other specific causes of liver disease. Currently the most common chronic liver disease, affecting 30% of the Western world, NAFLD may progress to cirrhosis and end-stage liver disease and may increase the risk of developing diabetes and cardiovascular disease. Although its pathogenesis is unclear, NAFLD is tightly associated with insulin resistance and the metabolic syndrome. No established treatment exists, and current research is targeting new molecular mechanisms that underlie NAFLD and associated cardiometabolic disorders. This review discusses some of these emerging molecular mechanisms and their therapeutic implications for the treatment of NAFLD: microRNAs, incretin analogs/antagonists, liver-specific thyromimetics, AMP-activated protein kinase activators, and nuclear receptors farnesoid X receptor and pregane X receptor.
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PMID:Emerging molecular targets for the treatment of nonalcoholic fatty liver disease. 2005 44

The incidence of hepatocellular carcinoma is rising due to alcohol drinking, hepatitis C viral infection and metabolic syndrome. Differential expression of CYP2E1 may play a pleiotropic role in the multistep process of liver carcinogenesis. Considerable attention has focused on the antitumor effect of trichostatin A (TSA) as well as CYP2E1 expression-induced apoptosis of cancer cells. However, very few studies have examined the mechanisms by which TSA has an antitumor effect and its association to CYP2E1 expression. The current study examined the action of TSA on CYP2E1 expression and the role of CYP2E1 in inducing apoptosis of HepG2 cells. Our data showed that TSA selectively induced CYP2E1 in four studied human hepatocellular carcinoma (HCC) cell lines (Huh7, PLC/PRF/5, Hep3B and HepG2), but not in normal primary human hepatocytes. TSA-mediated up-regulation of CYP2E1 expression was associated with histone H3 acetylation and the recruitment of HNF-1 and HNF-3beta to the CYP2E1 promoter in HepG2 cells. siRNA-mediated knockdown experiments showed that TSA-induced caspase-3 cleavage was decreased due to reduced expression of CYP2E1 in HepG2 cells. Moreover, down-regulation of CYP2E1 was accompanied by decreased production of mitochondrial reactive oxygen species. These results suggest that histone modification is involved in CYP2E1 gene expression and that CYP2E1-dependent mitochondrial oxidative stress plays a role in TSA-induced apoptosis.
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PMID:Histone modification-mediated CYP2E1 gene expression and apoptosis of HepG2 cells. 2040 16

The tumor suppressor PTEN is a protein/phosphoinositide phosphatase regulating the PI3K/Akt signaling pathway and is mutated or deleted in a variety of human cancers, including hepatocellular carcinoma (HCC). Accumulating evidence indicates that alterations of PTEN expression and activity in hepatocytes are common and recurrent molecular events associated with liver disorders of various etiologies including obesity, the metabolic syndrome, hepatitis B virus/hepatitis C virus infection and abusive alcohol consumption. Genetic and molecular studies, particularly in the context of non-alcoholic fatty liver disease (NAFLD), support a critical role for PTEN in hepatic insulin sensitivity and the development of steatosis, steatohepatitis and fibrosis. PTEN mutations/deletion or low PTEN expression are also associated with diverse liver malignancies, suggesting a critical role for PTEN in hepatic cancers. This review provides an overview of the current knowledge on pathological dysregulations of PTEN expression/activity in the liver with obesity and the metabolic syndrome, and the role of this enzyme in the development of non-alcoholic fatty liver disease and hepatocellular carcinoma.
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PMID:PTEN in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and cancer. 2046 Sep 18

The metabolic syndrome refers to a well defined group of risk factors, including central obesity and inflammation, for the development of diabetes and cardiovascular disease. Interestingly, many studies have recently led to the emergence of somewhat unexpected relationships between several infectious diseases and various aspects of the metabolic syndrome. Our understanding of the mechanisms underlying these interactions is also rapidly developing and some of these are summarized in this article. We will focus first on bacterial infection, and most notably the role of gut microbiota in regulaton of both obesity and inflammation. In particular, we focus on the role of inflammasomes and propose that understanding the role of Toll-like receptors and Nod-like receptors in the pathogenesis of inflammatory disorders with or without infection may provide novel targets for prevention and/or treatment of associated diseases. Secondly, chronic bacterial or viral infection and emerging links with metabolism will be reviewed. Finally, consideratons of biomarkers for metabolic syndrome, in particular lipocalin-2, and their link with infection will be discussed.
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PMID:Functional and mechanistic integration of infection and the metabolic syndrome. 2054 37

Non-alcoholic fatty liver disease (NAFLD), an important consequence of the global epidemic of obesity, is a common indication of orthotopic liver transplantation in the western world. Currently, NAFLD is the fourth most common indication of liver transplantation in the United Stated with prediction for increase demand of liver transplantation for NAFLD cirrhosis in the next two decades to exceed that of liver transplantation for chronic hepatitis C virus infection. Given the advances in the efficacy and tolerability of immunosuppressive agents which have reduced the incidence of chronic rejection, long-term survival rates after liver transplantation have remarkably improved. Today, long-term graft loss and death after liver transplantation are commonly related to age-related complications, such as cardiovascular disease. Features of metabolic syndrome including obesity, hypertension, hyperglycemia and dyslipidemia are very prevalent and almost universal after liver transplantation. These metabolic derangements are intricately associated with cardiovascular events and have emerged as the leading cause of morbidity and mortality after liver transplantation. In addition, the international epidemic of obesity has negatively impacted the liver transplant candidacy. Because obesity is associated with poor postoperative outcome, many transplant centers decline liver transplantation for morbidly obese individuals above certain level of body mass index.
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PMID:Metabolic syndrome and liver transplantation. 2103 47


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