Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0015695 (fatty liver)
13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipid peroxidation and secondary cellular injury are the dominant mechanism in the transition from relatively stable hepatic steatosis to potentially progressive steatohepatitis in nonalcoholic fatty liver disease (NAFLD). Oxidation of excessive fatty acids generates free radicals (reactive oxygen species) that damage organelles and stimulate signaling pathways leading to fibrosis and cellular injury. Both antioxidant agents (by breaking the chain reaction of lipid peroxidation) and cytoprotective agents (by stabilizing cellular and organelle phospholipid membranes) may be effective agents in treating an active steatohepatitis through amelioration of the driving force and attenuation of the secondary effects. Here we have reviewed the existing studies on such therapies, including vitamin E, S-adenosylmethionine (SAMe), betaine, and ursodeoxycholic acid. Small trials suggest possible improvement in liver enzymes with the use of these agents in NAFLD. However, controlled studies have not uniformly demonstrated benefit from these agents when compared with control groups treated with diet and weight loss alone, and measurement of reliable histologic endpoints is limited. These agents may show benefit in NAFLD through future larger controlled studies. Particular promise may exist in the use of these agents in combination therapy with ones that target other aspects in the pathogenesis of NAFLD, such as insulin-sensitizing agents.
...
PMID:Therapy of NAFLD: antioxidants and cytoprotective agents. 1654 Jul 69

Oxidative stress plays an important role in the pathogenesis of non-alcoholic steatohepatitis (NASH). Reactive oxygen species (ROS) would derive from mitochondria, cytochrome P-450 2E1, peroxisome, and iron overload in the liver with steatosis. These excessive ROS is considered to cause simple steatosis to progress to NASH. On the other hand, oxidative stress exacerbates insulin sensitivity in hepatocytes, while hepatic steatosis causes oxidative stress. Thus, oxidative stress and insulin resistance might be interactive in NASH. Actually, we have found that the grade of steatosis correlates with serum thioredoxin level, a marker of oxidative stress, in NASH patients. Therefore, we propose that the feedback loop of oxidative stress, insulin resistance, and steatosis would play a significant role in the development of NASH.
...
PMID:[Role of oxidative stress in non-alcoholic steatohepatitis]. 1676 12

Steatohepatitis represents an advanced stage of fatty liver disease that encompasses alcoholic (ASH) and non-alcoholic steatohepatitis (NASH). The progression from steatosis to steatohepatitis is poorly understood. One of the clues to this progression is the sensitization of hepatocytes to oxidative stress and cytokine-induced cell death. Mitochondrial glutathione (mGSH), which plays a central role in the control of mitochondrial reactive oxygen species (ROS) generation, modulates the sensitivity to cell death pathways. Mitochondrial GSH depletion due to alcohol-mediated alteration in mitochondrial membrane dynamics underlies the susceptibility of hepatocytes from alcohol-fed models to tumor necrosis factor (TNF), and in nutritional and genetic models of hepatic steatosis, mGSH depletion occurs due to the enrichment of mitochondria in free cholesterol, resulting in decreased mitochondrial membrane fluidity. The signaling of TNF through its membrane receptor TNFR1 from complex I to complex II is similar in hepatocytes depleted or not depleted in mGSH, yet hepatocellular susceptibility to TNF occurs if mGSH is depleted. Thus, mGSH is a critical factor in the development of steatohepatitis through sensitization of hepatocytes to inflammatory cytokines, and understanding the homeostasis of cholesterol and its trafficking to mitochondria may be of relevance in the pathophysiology of ASH and NASH.
...
PMID:Mitochondrial glutathione: hepatocellular survival-death switch. 1695 67

Adiponectin protects the liver from steatosis caused by obesity or alcohol and therefore the influence of adiponectin on human hepatocytes was analyzed. GeneChip experiments indicated that recombinant adiponectin downregulates aldehyde oxidase 1 (AOX1) expression and this was confirmed by real-time RT-PCR and immunoblot. AOX1 is a xenobiotic metabolizing protein and produces reactive oxygen species (ROS), that promote cell damage and fibrogenesis. Adiponectin and fenofibric acid activate peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and both suppress AOX1 protein and this is blocked by the PPAR-alpha antagonist RU486. Obesity is associated with low adiponectin, reduced hepatic PPAR-alpha activity and fatty liver, and AOX1 was found induced in the liver of rats on a high-fat diet when compared to controls. Free fatty acids and leptin, that are elevated in obesity, failed to upregulate AOX1 in vitro. The current data indicate that adiponectin reduces AOX1 by activating PPAR-alpha whereas fatty liver disease is associated with elevated hepatic AOX1. High AOX1 may be associated with higher ROS well described to induce fibrogenesis in liver tissue but may also influence drug metabolism and activity.
...
PMID:Aldehyde oxidase 1 is highly abundant in hepatic steatosis and is downregulated by adiponectin and fenofibric acid in hepatocytes in vitro. 1702 44

Liver grafts are frequently discarded due to steatosis. Steatotic livers can be classified as suboptimal and deteriorate rapidly during hypothermic static preservation, often resulting in graft nonfunction. Hypothermic machine perfusion (MP) has been introduced for preservation of donor livers instead of cold storage (CS), resulting in superior preservation outcomes. The aim of this study was to compare CS and MP for preservation of the steatotic donor rat liver. Liver steatosis was induced in male Wistar rats by a choline-methionine-deficient diet. After 24 hours hypothermic CS using the University of Wisconsin solution (UW) or MP using UW-Gluconate (UW-G), liver damage (liver enzymes, perfusate flow, and hyaluronic acid clearance) and liver function (bile production, ammonia clearance, urea production, oxygen consumption, adenosine triphosphate [ATP] levels) were assessed in an isolated perfused rat liver model. Furthermore, liver biopsies were visualized by hematoxylin and eosin staining. Animals developed 30 to 60% steatosis. Livers preserved by CS sustained significantly more damage as compared to MP. Bile production, ammonia clearance, urea production, oxygen consumption, and ATP levels were significantly higher after MP as compared to CS. These results were confirmed by histology. In conclusion, MP improves preservation results of the steatotic rat liver, as compared to CS.
...
PMID:Preservation of steatotic livers: a comparison between cold storage and machine perfusion preservation. 1739 43

Hepatitis C virus infections are recognized as a major causative factor of chronic liver disease. A characteristic feature of chronic hepatitis C, alcoholic liver disease and non-alcoholic fatty liver disease is hepatic steatosis. Hepatic steatosis leads to an increase in lipid peroxidation in hepatocytes, which, in turn, activates hepatic stellate cells (HSCs). HSCs are also thought to be the primary target cells for inflammatory and oxidative stimuli, and to produce extracellular matrix components. Based on available clinical information, chronic hepatitis C appears to progress more rapidly in men than in women, and cirrhosis is predominately a disease of men and postmenopausal women. Estradiol is a potent endogenous antioxidant. Hepatic steatosis was reported to become evident in an aromatase-deficient mouse and was diminished in animals after treatment with estradiol. Our previous studies showed that estradiol suppressed hepatic fibrosis in animal models, and attenuated HSC activation by suppressing the generation of reactive oxygen species in primary cultures. Variant estrogen receptors were found to be expressed to a greater extent in male patients with chronic liver disease than in female subjects. A better understanding of the basic mechanisms underlying the gender-associated differences observed in the progression of chronic liver disease would provide valuable information relative to the search for effective antifibrogenic therapies.
...
PMID:Protection of estrogens against the progression of chronic liver disease. 1739 11

Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic disorder in western countries, and its incidence is increasing. This review outlines the significant health burden posed by NAFLD and discusses what is presently known about its pathogenesis, including the roles of the metabolic syndrome, obesity, insulin resistance, hepatic steatosis, reactive oxygen species, inflammatory cytokines and adipocytokines. The way in which NAFLD is clinically diagnosed is described, and areas of uncertainty surrounding its investigation are identified, before discussing the relative merits of the limited treatment options available and looking ahead to potential therapeutic strategies for the future.
...
PMID:A growing burden: the pathogenesis, investigation and management of non-alcoholic fatty liver disease. 1748 47

Abnormal dietary intake of macronutrients is implicated in the development of obesity and fatty liver disease. Steatosis develops in cultured hepatocytes exposed to medium containing either a high concentration of long chain free fatty acids (HFFA) or medium deficient in methionine and choline (MCD). This study examined the mitochondrial reactive oxygen species (ROS)-dependent regulation of the phosphoinositol (PI) 3-kinase pathway in steatosis induced by exposure of AML-12 mouse hepatocytes to MCD or HFFA medium. Exposure to either MCD or HFFA medium resulted in increased production of superoxide anions and H(2)O(2), transduction of the PI 3-kinase pathway and steatosis. Inhibition of PI 3-kinase with LY294002 prevented steatosis. Pharmacologically inhibiting electron transport chain complex III production of ROS prevented activation of PI 3-kinase during macronutrient perturbation, whereas pharmacologically promoting electron transport chain complex III ROS production activated PI 3-kinase independent of nutrient input. The data suggest that H(2)O(2) is the ROS species involved in signal transduction; promoting the rapid conversion of superoxide to H(2)O(2) does not inhibit PI 3-kinase pathway activation during nutrient perturbation, and exogenous H(2)O(2) activates it independent of nutrient input. In addition to transducing PI 3-kinase, the ROS-dependent signal cascade amplifies the PI 3-kinase signal by maintaining phosphatase and tensin homolog in its inactive phosphorylated state. Knockdown of phosphatase and tensin homolog by small interfering RNA independently activated the PI 3-kinase pathway. Our findings suggest a common path for response to altered nutrition involving mitochondrial ROS-dependent PI 3-kinase pathway regulation, leading to steatosis.
...
PMID:Mitochondrial reactive oxygen species signal hepatocyte steatosis by regulating the phosphatidylinositol 3-kinase cell survival pathway. 1754 Jul 68

Mitochondrial dysfunction is involved in the three stages of the transition from lack of exercise and excessive food intake to insulin resistance, diabetes and non-alcoholic steatohepatitis (NASH). In muscle, lack of exercise, a fat-rich diet, a polymorphism in peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1), and possibly age-related mitochondrial DNA (mtDNA) mutations may variously combine their effects to decrease PGC-1 expression, mitochondrial biogenesis and fat oxidation. Together with excessive food intake, insufficient fat oxidation causes fat accumulation and cellular stress in myocytes. The activation of Jun N-terminal kinase and protein kinase C-theta triggers the serine phosphorylation and inactivation of the insulin receptor substrate, and hampers the insulin-mediated translocation of glucose transporter-4 to the plasma membrane. Initially, the trend for increased blood glucose increases insulin secretion by pancreatic beta-cells. High plasma insulin levels compensate for insulin resistance in muscle and maintain normal blood glucose levels. Eventually, however, increased uncoupling protein-2 expression and possibly acquired mtDNA mutations in pancreatic beta-cells can blunt glucose-mediated adenosine triphosphate (ATP) formation and insulin secretion, to cause diabetes in some patients. High plasma glucose and/or insulin levels induce hepatic lipogenesis and cause hepatic steatosis. In fat-engorged hepatocytes, several vicious cycles involving tumor necrosis factor-alpha, reactive oxygen species (ROS), peroxynitrite, and lipid peroxidation products alter respiratory chain polypeptides and mtDNA, thus partially blocking the flow of electrons in the respiratory chain. The overreduction of upstream respiratory chain complexes increases mitochondrial ROS and peroxynitrite formation. Oxidative stress increases the release of lipid peroxidation products and cytokines, which together trigger the liver lesions of NASH.
...
PMID:Role of mitochondria in non-alcoholic fatty liver disease. 1756 59

Chronic ethanol feeding sensitizes Kupffer cells to activation by lipopolysaccharide (LPS), leading to increased production of tumor necrosis factor alpha (TNFalpha). The regulation of TNFalpha synthesis is controlled by both transcriptional and post-transcriptional mechanisms via the integration of complex signal transduction pathways activated in response to LPS exposure. Recent data has shown that increased LPS-stimulated phosphorylation of extracellular signal-regulated kinase pathway 1/2 (ERK1/2) is one of the important molecular targets of chronic ethanol in Kupffer cells. This increased activation of ERK1/2 after chronic ethanol is associated with increased expression of Egr-1, a transcription factor required for enhanced LPS-stimulated TNFalpha mRNA expression after chronic ethanol exposure. egr-1 null mice are protected from the development of fatty liver injury in response to chronic ethanol feeding, identifying an essential role for Egr-1 in the development of chronic ethanol-induced liver injury. Here we review recent studies aimed at understanding the mechanisms by which chronic ethanol enhances the LPS-->ERK1/2-->Egr-1-->TNFalpha pathway in Kupffer cells. These studies identify a critical role for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived reactive oxygen species in the activation of ERK1/2 and subsequent production of TNFalpha in Kupffer cells after chronic ethanol feeding.
...
PMID:Regulation of macrophage activation in alcoholic liver disease. 1756 66


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---