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)

For the first time in history, populations in affluent countries may concomitantly indulge in rich food and physical idleness. Various combinations of obesity, diabetes, and hypertriglyceridemia, with insulin resistance as the common feature, cause hepatic steatosis, which can trigger necroinflammation and fibrosis. Patients with "primary" steatohepatitis exhibit ultrastructural mitochondrial lesions, decreased activity of respiratory chain complexes, and have impaired ability to resynthesize ATP after a fructose challenge. Mitochondria play a major role in fat oxidation and energy production but also leak reactive oxygen species (ROS) and are the main cellular source of ROS. In patients with steatosis, mitochondrial ROS may oxidize hepatic fat deposits, as suggested in animal models. Lipid peroxidation products impair the flow of electrons along the respiratory chain, which may cause overreduction of respiratory chain components, further increasing mitochondrial ROS formation and lipid peroxidation. Another vicious circle could involve ROS-induced depletion of antioxidants, impairing ROS inactivation. Blood vitamin E is decreased in some obese children with steatohepatitis, and serum transaminases improve after vitamin E supplementation. Steatohepatitis is also caused by alcohol abuse, drugs, and other causes. In "secondary" steatohepatitis, mitochondrial ROS formation is further increased as the causative disease itself directly increases ROS or first impairs respiration, which secondarily increases mitochondrial ROS formation. This "second hit" could cause more lipid peroxidation, cytokine induction, Fas ligand induction, and fibrogenesis than in primary steatohepatitis.
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PMID:Mitochondria in steatohepatitis. 1129 97

Rich diet and lack of exercise are causing a surge in the prevalence of obesity and hepatic steatosis, which causes "primary" steatohepatitis in some patients. Ultrastructural mitochondrial lesions, decreased activity of respiratory chain complexes, and impaired ability to synthesize ATP are observed in these patients. Reactive oxygen species (ROS) may increase tumor necrosis factor-alpha (TNF-alpha) production and also oxidize fat deposits. TNF-alpha and lipid peroxidation products impair the flow of electrons along the respiratory chain, causing overreduction of respiratory chain components and enhanced mitochondrial ROS formation. Steatohepatitis can also be due to alcohol, drugs, or other causes that either directly increase ROS formation or first impair respiration, which secondarily increases ROS formation. Higher ROS formation in secondary steatohepatitis could cause more lipid peroxidation, cytokine induction, and fibrogenesis than in primary steatohepatitis.
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PMID:Nonalcoholic steatosis and steatohepatitis. V. Mitochondrial dysfunction in steatohepatitis. 1180 39

The most common cause of hepatic fibrosis is currently chronic HCV infection, the characteristic feature of which 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 regarded as the primary target cells for inflammatory stimuli, and produce extracellular matrix components. It should be noted that transforming growth factor beta (TGF-beta) is a potent fibrogenic cytokine produced by Kupffer cells and HSCs. There are several approaches to inhibit TGF-beta; use of decorin, soluble receptors, and gene therapy approaches. Hepatocyte growth factor (HGF) is a hepatotrophic factor for liver regeneration and seems to suppress hepatic fibrogenesis in animals. HOE 77, Safironil, and S 4682 are inhibitors of prolyl 4-hydroxylase, which is essential for thecollagen formation. Although HOE 77, Safironil, and S 4682 seem to work by inhibiting HSC activation, further studies will be required before their clinical application. alpha-Tocopherol, retinyl palmitate, and silybinin reduce lipid peroxidation and attenuate HSC activation in experimental models. Retinyl palmitate is the main storage type for retinoids in HSCs. Silymarin is extracted from milk thistle, the principle component of which is the silybinin. Unfortunately, they have had mixed effects in human liver diseases. A Japanese herbal medicine Sho-saiko-to functions as a potent antifibrosuppressant via the inhibition of oxidative stress in hepatocytes and HSCs. Its active components are baicalin and baicalein of flavonoids with chemical structures very similar to silybinin. Understanding the basic mechanisms underlying the HCV-mediated fibrogenesis provides valuable information on the search for effective antifibrogenic therapies.
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PMID:Antifibrogenic therapies in chronic HCV infection. 1245 17

Type 2 diabetes is strongly associated with nonalcoholic fatty liver disease (NAFLD), a spectrum of liver damage that ranges from relatively benign hepatic steatosis to potentially fatal cirrhosis. The severities of insulin resistance and liver damage parallel each other, with the greatest prevalence of cirrhosis occurring in cirrhotics. However, it is unknown whether one of these conditions causes the other, or if both are consequences of another process. Experimental evidence suggests that both insulin resistance and NAFLD result from a chronic inflammatory state. The mechanisms driving this chronic inflammation are unknown but might include the egress of products from intestinal bacteria into the portal blood, liver, and systemic circulation to trigger a sustained inflammatory cytokine response in genetically susceptible individuals. More research is needed to evaluate this hypothesis and to determine the benefits of treatments that interrupt this pathogenic cascade.
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PMID:Hepatic steatosis and type 2 diabetes mellitus. 1264 75

Adiponectin has recently been shown to be a promising candidate for the treatment of obesity-associated metabolic syndromes. Replenishment of recombinant adiponectin in mice can decrease hyperglycemia, reverse insulin resistance, and cause sustained weight loss without affecting food intake. Here we report its potential roles in alcoholic and nonalcoholic fatty liver diseases in mice. Circulating concentrations of adiponectin decreased significantly following chronic consumption of high-fat ethanol-containing food. Delivery of recombinant adiponectin into these mice dramatically alleviated hepatomegaly and steatosis (fatty liver) and also significantly attenuated inflammation and the elevated levels of serum alanine aminotransferase. These therapeutic effects resulted partly from the ability of adiponectin to increase carnitine palmitoyltransferase I activity and enhance hepatic fatty acid oxidation, while it decreased the activities of two key enzymes involved in fatty acid synthesis, including acetyl-CoA carboxylase and fatty acid synthase. Furthermore, adiponectin treatment could suppress the hepatic production of TNF-alpha and plasma concentrations of this proinflammatory cytokine. Adiponectin was also effective in ameliorating hepatomegaly, steatosis, and alanine aminotransferase abnormality associated with nonalcoholic obese, ob/ob mice. These results demonstrate a novel mechanism of adiponectin action and suggest a potential clinical application of adiponectin and its agonists in the treatment of liver diseases.
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PMID:The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. 1284 63

Fatty livers are vulnerable to ischemia/reperfusion (I/R) injury. We investigated the role of hepatic macrophages in the I/R injury in the fatty liver. Rats with alcoholic or nonalcoholic fatty liver were subjected to hepatic warm ischemia for 30 min. A bolus of gadolinium chloride (GdCl(3)) was injected intravenously twice before I/R to block hepatic macrophage activity. Alcoholic fatty liver developed more extensive hepatic necrosis with neutrophil infiltration in association with a higher production of cytokine-induced neutrophil chemoattractant (CINC)-1, a potent neutrophil chemokine in rat, after I/R than the nonalcoholic fatty liver or control liver without steatosis. Hepatic apoptosis after I/R increased to a similar degree (3-fold) in each of the two fatty liver models, compared with the control liver. Alcoholic fatty liver exposed to I/R showed a rapid increase in nuclear factor-kappa B (NF-kappaB) binding activity. The GdCl(3) pretreatment significantly reduced NF-kappaB binding activity, CINC-1 level and necrosis in alcoholic fatty liver, despite no significant decrease in the extent of apoptosis. Our results suggest that the activation of hepatic macrophages in alcoholic fatty liver may contribute to hepatic necrosis after I/R, and that the apoptosis might be less dependent on the macrophage activity.
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PMID:Activation of hepatic macrophage contributes to hepatic necrosis after post-ischemic reperfusion in alcoholic fatty liver. 1285 Jun 93

Non-alcoholic fatty liver disease is a new clinicopathological condition of emerging importance, now recognized as the most common cause of abnormal liver tests. It is characterized by a wide spectrum of liver damage: simple steatosis may progress to advanced fibrosis and to cryptogenic cirrhosis through steatohepatitis, and ultimately to hepatocellular carcinoma. Obesity is the most significant single risk factor for the development of fatty liver, both in children and in adults; obesity is also predictive of the presence of fibrosis, potentially progressing to advanced liver disease. From a pathogenic point of view, insulin resistance plays a central role in the accumulation of triglycerides within the hepatocytes and in the initiation of the inflammatory cascade. Chronic hepatocellular injury, necroinflammation, stellate cell activation, progressive fibrosis and ultimately, cirrhosis may be initiated by peroxidation of hepatic lipids and injury-related cytokine release. In the last few years, several pilot studies have shown that treatment with insulin-sensitizing agents, anti-oxidants or cytoprotective drugs may be useful, but there is no evidence-based support from randomized clinical trials. Modifications in lifestyle (e.g. diet and exercise) to reduce obesity remain the mainstay of prevention and treatment of a disease, which puts a large number of individuals at risk of advanced liver disease in the near future.
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PMID:Hepatic steatosis in obese patients: clinical aspects and prognostic significance. 1496 5

The pathogenesis of nonalcoholic steatohepatitis (NASH) is poorly defined. Feeding mice a diet deficient in methionine and choline (MCD diet) induces experimental NASH. Osteopontin (OPN) is a Th1 cytokine that plays an important role in several fibroinflammatory diseases. We examined the role of OPN in the development of experimental NASH. A/J mice were fed MCD or control diet for up to 12 wk, and serum alanine aminotransferase (ALT), liver histology, oxidative stress, and the expressions of OPN, TNF-alpha, and collagen I were assessed at various time points. MCD diet-fed mice developed hepatic steatosis starting after 1 wk and inflammation by 2 wk; serum ALT increased from day 3. Hepatic collagen I mRNA expression increased during 1-4 wk, and fibrosis appeared at 8 wk. OPN protein expression was markedly increased on day 1 of MCD diet and persisted up to 8 wk, whereas OPN mRNA expression was increased at week 4. TNF-alpha expression was increased from day 3 to 2 wk, and evidence of oxidative stress did not appear until 8 wk. Increased expression of OPN was predominantly localized in hepatocytes. Hepatocytes in culture also produced OPN, which was stimulated by transforming growth factor-beta and TNF-alpha. Moreover, MCD diet-induced increases in serum ALT levels, hepatic inflammation, and fibrosis were markedly reduced in OPN(-/-) mice when compared with OPN(+/+) mice. In conclusion, our results demonstrate an upregulation of OPN expression early in the development of steatohepatitis and suggest an important role for OPN in signaling the onset of liver injury and fibrosis in experimental NASH.
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PMID:Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model. 1504 74

Insulin resistance, obesity, diabetes, dyslipidemia, and nonalcoholic fatty liver are components of the metabolic syndrome, a disease complex that is increasing at epidemic rates in westernized countries. Although proinflammatory cytokines have been suggested to contribute to the development of these disorders, the molecular mechanism is poorly understood. Here we show that overexpression of suppressors of cytokine signaling (SOCS)-1 and SOCS-3 in liver causes insulin resistance and an increase in the key regulator of fatty acid synthesis in liver, sterol regulatory element-binding protein (SREBP)-1c. Conversely, inhibition of SOCS-1 and -3 in obese diabetic mice improves insulin sensitivity, normalizes the increased expression of SREBP-1c, and dramatically ameliorates hepatic steatosis and hypertriglyceridemia. In obese animals, increased SOCS proteins enhance SREBP-1c expression by antagonizing STAT3-mediated inhibition of SREBP-1c promoter activity. Thus, SOCS proteins play an important role in pathogenesis of the metabolic syndrome by concordantly modulating insulin signaling and cytokine signaling.
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PMID:Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. 1524 Aug 80

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of hepatic pathology that resembles alcohol-induced fatty liver disease(AFLD), but which develops in individuals who are not heavy drinkers. In people, NAFLD is associated strongly with obesity,insulin resistance, and dysmetabolic syndrome, but the exact mechanisms that promote liver disease in this clinical context remain poorly understood. The proinflammatory cytokine, funor necrosis factor alpha is known to be a key mediator of AFLD. This article discusses clinical and experimental evidence that tumor necrosis factor plays a role in the pathogenesis of insulin resistance syndromes, including nonalcoholic fatty syndromes, including nonalcoholic fatty liver disease.
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PMID:Tumor necrosis factor and its potential role in insulin resistance and nonalcoholic fatty liver disease. 1533 Oct 67


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