Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Viral hepatitis, obesity, and alcoholism all represent major risk factors for hepatocellular carcinoma (HCC). Although these conditions also lead to integrated stress response (ISR) or unfolded protein response (UPR) activation, the extent to which these stress pathways influence the pathogenesis of HCC has not been tested. Here we provide multiple lines of evidence demonstrating that the ISR-regulated transcription factor CHOP promotes liver cancer. We show that CHOP expression is up-regulated in liver tumors in human HCC and two mouse models thereof. Chop-null mice are resistant to chemical hepatocarcinogenesis, and these mice exhibit attenuation of both apoptosis and cellular proliferation. Chop-null mice are also resistant to fibrosis, which is a key risk factor for HCC. Global gene expression profiling suggests that deletion of CHOP reduces the levels of basal inflammatory signaling in the liver. Our results are consistent with a model whereby CHOP contributes to hepatic carcinogenesis by promoting inflammation, fibrosis, cell death, and compensatory proliferation. They implicate CHOP as a common contributing factor in the development of HCC in a variety of chronic liver diseases.
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PMID:The stress-regulated transcription factor CHOP promotes hepatic inflammatory gene expression, fibrosis, and oncogenesis. 2436 69

Hepatocellular carcinoma is the fifth most common human cancer worldwide, with an overall 5-year survival in the range of 10%. In addition to the very substantial role of chronic viral hepatitis in causing hepatocellular carcinoma, nutritional status and specific nutritional factors appear to influence disease risk. This is apparent in the increased risk associated with non-alcoholic hepatic cirrhosis occurring in the context of obesity, the metabolic syndrome, and type 2 diabetes. Specific nutrients and ingested toxins, including ethanol, aflatoxin, microcystins, iron, and possibly components of red meat, also are associated with increased hepatocellular carcinoma risk. Other dietary components, including omega-3 fatty acids and branched chain amino acids, may have protective effects. Recent data further suggest that several metabolic regulatory drugs, including metformin, pioglitazone, and statins, may have the potential to decrease the risk of hepatocellular carcinoma. The available data on these nutritional and metabolic factors in causing hepatocellular carcinoma are reviewed with the goal of identifying the strength of current knowledge and directions for future investigation.
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PMID:Nutrition and metabolism in hepatocellular carcinoma. 2457 Sep 22

Measurement of serum alanine aminotransferase (ALT) is a common, readily available, and inexpensive laboratory assay in clinical practice. ALT activity is not only measured to detect liver disease, but also to monitor overall health. ALT activity is influenced by various factors, including viral hepatitis, alcohol consumption, and medication. Recently, the impact of metabolic abnormalities on ALT variation has raised concern due to the worldwide obesity epidemic. The normal ranges for ALT have been updated and validated considering the metabolic covariates in the various ethnic districts. The interaction between metabolic and demographic factors on ALT variation has also been discussed in previous studies. In addition, an extremely low ALT value might reflect the process of aging, and frailty in older adults has been raised as another clinically significant feature of this enzyme, to be followed with additional epidemiologic investigation. Timely updated, comprehensive, and systematic introduction of ALT activity is necessary to aid clinicians make better use of this enzyme.
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PMID:Alanine aminotransferase-old biomarker and new concept: a review. 2501 73

Inflammation plays a critical role in the development and progression of cancer, evident in multiple patient populations manifesting increased, non-resolving inflammation, such as inflammatory bowel disease, viral hepatitis and obesity. Given the complexity of both the inflammatory response and the process of oncogenesis, we utilize principles from the field of Translational Systems Biology to bridge the gap between basic mechanistic knowledge and clinical/epidemiologic data by integrating inflammation and oncogenesis within an agent-based model, the Inflammation and Cancer Agent-based Model (ICABM). The ICABM utilizes two previously published and clinically/epidemiologically validated mechanistic models to demonstrate the role of an increased inflammatory milieu on oncogenesis. Development of the ICABM required the creation of a generative hierarchy of the basic hallmarks of cancer to provide a foundation to ground the plethora of molecular and pathway components currently being studied. The ordering schema emphasizes the essential role of a fitness/selection frame shift to sub-organismal evolution as a basic property of cancer, where the generation of genetic instability as a negative effect for multicellular eukaryotic organisms represents the restoration of genetic plasticity used as an adaptive strategy by colonies of prokaryotic unicellular organisms. Simulations with the ICABM demonstrate that inflammation provides a functional environmental context that drives the shift to sub-organismal evolution, where increasingly inflammatory environments led to increasingly damaged genomes in microtumors (tumors below clinical detection size) and cancers. The flexibility of this platform readily facilitates tailoring the ICABM to specific cancers, their associated mechanisms and available epidemiological data. One clinical example of an epidemiological finding that could be investigated with this platform is the increased incidence of triple negative breast cancers in the premenopausal African-American population, which has been identified as having up-regulated of markers of inflammation. The fundamental nature of the ICABM suggests its usefulness as a base platform upon which additional molecular detail could be added as needed.
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PMID:An agent-based modeling framework linking inflammation and cancer using evolutionary principles: description of a generative hierarchy for the hallmarks of cancer and developing a bridge between mechanism and epidemiological data. 2508 60

Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of viral hepatitis, insulin resistance, hepatosteatosis, and nonalcoholic steatohepatitis (NASH), disorders that increase risk of hepatocellular carcinoma (HCC). To determine whether and how ER stress contributes to obesity-driven hepatic tumorigenesis we fed wild-type (WT) and MUP-uPA mice, in which hepatocyte ER stress is induced by plasminogen activator expression, with high-fat diet. Although both strains were equally insulin resistant, the MUP-uPA mice exhibited more liver damage, more immune infiltration, and increased lipogenesis and, as a result, displayed classical NASH signs and developed typical steatohepatitic HCC. Both NASH and HCC development were dependent on TNF produced by inflammatory macrophages that accumulate in the MUP-uPA liver in response to hepatocyte ER stress.
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PMID:ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. 2520 16

Cirrhosis is a condition that arises as a result of chronic liver damage, typically over many years. It is characterised by fibrosis and nodularity of the liver parenchyma. Cirrhosis interferes with the normal functions of the liver, reducing its ability to produce proteins, which can lead to coagulopathy, low serum albumin and raised bilirubin. The incidence of cirrhosis is rising in the UK, this can primarily be attributed to increasing levels of alcohol consumption and obesity. Mortality from cirrhosis is also rising. Common causes of chronic liver disease include alcohol, non-alcoholic fatty liver disease and chronic viral hepatitis. Nearly half of patients with cirrhosis are asymptomatic. As a result the condition may only be discovered incidentally as a result of abnormalities in liver function tests or imaging of the abdomen performed for other reasons. Alternatively patients may present with signs and symptoms of the complications of cirrhosis e.g. jaundice, ascites, variceal bleeding, hepatic encephalopathy or hepatocellular carcinoma. Detecting patients with cirrhosis in primary care usually relies on identifying common risk factors. Currently, there are no standard criteria for the investigation of patients with suspected cirrhosis. If a patient is suspected of having cirrhosis, most GPs will arrange for blood tests and an ultrasound of the liver to be performed. The gold standard test for the diagnosis of cirrhosis remains a liver biopsy. Staging of liver fibrosis is an important predictor of prognosis and is necessary to guide management.
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PMID:Detecting patients with cirrhosis in primary care. 2521 89

Hepatocellular carcinoma (HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoholic fatty liver disease (NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger, especially in developed countries. Older age, severity of insulin resistance and diabetes, and iron overload have been reported to predispose to HCC in this context. Remarkably, HCCs have been reported in non-cirrhotic livers in a higher proportion of cases in NAFLD patients than in other etiologies. Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seems magnified in fatty liver, where only a minority of affected subjects progresses to cancer. In particular, the common I148M variant of the PNPLA3 gene influencing hepatic lipid metabolism influences HCC risk independently of its effect on the progression of liver fibrosis. Recently, rare loss-of-function mutations in Apolipoprotein B resulting in very low density lipoproteins hepatic retention and in Telomerase reverse transcriptase influencing cellular senescence have also been linked to HCC in NAFLD. Indeed, hepatic stellate cells senescence has been suggested to bridge tissue aging with alterations of the intestinal microbiota in the pathogenesis of obesity-related HCC. A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance, and the identification of its genetic determinants will hopefully provide new diagnostic and therapeutic tools.
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PMID:Hepatocellular carcinoma in nonalcoholic fatty liver: role of environmental and genetic factors. 2527 90

Glucagon-like peptide1 (GLP-1) is secreted from Langerhans cells in response to oral nutrient intake. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a new class of incretin-based anti-diabetic drugs. They function to stimulate insulin secretion while suppressing glucagon secretion. GLP-1-based therapies are now well established in the management of type 2 diabetes mellitus (T2DM), and recent literature has suggested potential applications of these drugs in the treatment of obesity and for protection against cardiovascular and neurological diseases. As we know, along with change in lifestyles, the prevalence of non-alcoholic fatty liver disease (NAFLD) in China is rising more than that of viral hepatitis and alcoholic fatty liver disease, and NAFLD has become the most common chronic liver disease in recent years. Recent studies further suggest that GLP-1RAs can reduce transaminase levels to improve NAFLD by improving blood lipid levels, cutting down the fat content to promote fat redistribution, directly decreasing fatty degeneration of the liver, reducing the degree of liver fibrosis and improving inflammation. This review shows the NAFLD-associated effects of GLP-1RAs in animal models and in patients with T2DM or obesity who are participants in clinical trials.
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PMID:Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation. 2535 42

Following chronic liver injury, hepatocytes undergo apoptosis leading to activation of hepatic stellate cells (HSC). Consequently, activated HSC proliferate and produce excessive extracellular matrix, responsible for the scar formation. The pandemic trend of obesity, combined with the high incidence of alcohol intake and viral hepatitis infections, highlights the urgent need to find accessible antifibrotic therapies. Treatment strategies should take into account the versatility of its pathogenesis and act on all the cell lines involved to reduce liver fibrosis. Medicinal plants are achieving popularity as antifibrotic agents, supported by their safety, cost-effectiveness, and versatility. This review will describe the role of hepatocytes and HSC in the pathogenesis of liver fibrosis and detail the mechanisms of modulation of apoptosis of both cell lines by twelve known hepatoprotective plants in order to reduce liver fibrosis.
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PMID:Liver fibrosis and protection mechanisms action of medicinal plants targeting apoptosis of hepatocytes and hepatic stellate cells. 2550 5

Hepatocellular carcinoma (HCC) is a common cancer worldwide, with significant increase in the incidence observed in the past two decades in the United States. Majority of cases of HCC are due to chronic viral hepatitis B and C infections; however non-alcoholic fatty liver disease, associated with obesity and diabetes emerges as an important risk factor for HCC, in particular in the developed countries. Here we will review viral characteristics associated with increased risk for development of HCC and role of antiviral therapy in decreasing risk of HCC in those with viral hepatitis and cirrhosis. Association of alcoholic cirrhosis and non-alcoholic fatty liver disease with liver cancer will be reviewed as well as possible measures to decrease the risk of HCC in these highly prevalent populations.
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PMID:Viral hepatitis, non-alcoholic fatty liver disease and alcohol as risk factors for hepatocellular carcinoma. 2584 11


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