Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A model has been developed for the administration to rats and baboons of ethanol as part of a nutritionally adequate liquid diet. With this regimen, ethanol intake was much higher than with conventional procedures. All animals gained or maintained their body weight, and liver morphology was normal in the controls. Isocaloric substitution of carbohydrate by ethanol (36% of total calories in rats and 50% in baboons) resulted in the production of fatty liver in all animals, while the baboons also developed alcoholic hepatitis and cirrhosis with increased activities of serum glutamic oxaloacetic transaminase. Inebriation and manifestation of dependence on withdrawal of the diet were observed in baboons and quantitated in the rat. Chemical alterations produced by ethanol at the fatty liver stage were characterized by hyperlipemia, striking triglyceride accumulation in the liver, and enhanced activities of microsomal drug metabolizing enzymes, including the microsomal ethanol oxidizing system (MEOS). In showing that all aspects of liver injury observed in alcoholics can be reproduced in animals by the feeding of pure ethanol with an adequate diet, this study incriminates ethanol itself as a cause for the hepatic complications. This new experimental model is proposed as a tool for the study of the pathogenesis and treatment of alcoholic liver injury and dependence.
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PMID:Animal models of ethanol dependence and liver injury in rats and baboons. 94 46

Malnutrition is common among alcoholics because alcohol displaces protein-, vitamin-, and mineral-containing foods in the diet, and chronic alcohol consumption results in maldigestion and malabsorption of essential nutrients. In addition, alcohol exerts direct toxic effects on both the liver and gut, resulting in structural alterations in the intestine and the development of fatty liver, alcoholic hepatitis, and cirrhosis. Liver injury is preceded by an adaptive phase characterized by accelerated metabolism of drugs (including ethanol), and hyperlipemia, secondary to hypertrophy and hyperactivity of the smooth endoplasmic reticulum. Side effects include enhanced hepatotoxicity of CCI4 and possibly energy wastage. Alcoholics should not be led to beleive that correction or prevention of nutritional deficiency will prevent liver damage in the face of continued alcohol abuse.
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PMID:Alcohol and malnutrition in the pathogenesis of liver disease.. 117 54

A model has been developed for the administration to rats and baboons of ethanol as part of a nutritionally adequate liquid diet. With this regimen, ethanol intake was much higher than with conventional procedures. All animals gained or maintained their body weight, and liver morphology was normal in the controls. Isocaloric substitution of carbohydrate by ethanol (36% of total calories in rats and 50% in baboons) resulted in the production of fatty liver in all animals, while the baboons also developed alcoholic hepatitis and cirrhosis with increased activities of serum glutamic oxaloacetic transaminase. Inebriation and manifestation of dependence upon withdrawal of the diet were observed in baboons and quantitated in the rat. Chemical alterations produced by ethanol at the fatty liver stage were characterized by hyperlipemia, striking triglyceride accumulation in the liver and enhanced activities of microsomal drug metabolizing enzymes, including the microsomal ethanol oxidizing system (MEOS). Ultrastructural changes of the mitochondria and the endoplasmic reticulum were already present at the fatty liver stage and persisted throughout the hepatitis and cirrhosis. The lesions were similar to those observed in alcoholics (including the inflammation and the central sclerosis), and differed strikingly from the alterations produced by other models of liver injury. In showing that all aspects of liver injury observed in alcoholics can be reproduced in animals by the feeding of pure ethanol with an adequate diet, this study incriminates ethanol itself as a cause for the hepatic complications. This new experimental model is proposed as a tool for the study of the pathogenesis and treatment of alcoholic liver injury and dependence.
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PMID:Alcoholic liver injury: experimental models in rats and baboons. 123 25

Obesity is associated either with hepatic steatosis, a well known and innocuous entity or with non alcoholic steatohepatitis. This latter lesion has been recently individualized. It affects mainly middle-aged, obese women, with diabetes and/or hyperlipidaemia. It is morphologically very similar to alcoholic hepatitis. We review the literature considering 1) histologic hepatic lesions of the obese, 2) epidemiologic, clinical and biological characteristics of the non alcoholic steatohepatitis, 3) evolution and treatment of the non alcoholic steatohepatitis and 4) present physiopathological considerations. We conclude by considering the clinician's attitude in front of an obese potentially afflicted by a non alcoholic steatohepatitis.
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PMID:[Obesity: danger for the hepatocytes?]. 133 21

Ther are several main mechanisms that allow us to understand a number of the hepatic and metabolic effects of ethanol. Ethanol is oxidized in the liver to two products (hydrogen and acetaldehyde), to which many of the effects of ethanol can be attributed. The hydrogen generated alters the redox state, and though this effect is attenuated after chronic ethanol consumption, it may still be sufficient to explain alterations in lipid metabolism, possibly increased collagen deposition, and, under special circumstances, depression of protein synthesis. Acetaldehyde impairs microtubules, decreases protein secretion, and causes protein retention and ballooning of the hepatocyte. Acetaldehyde exerts toxicity also with regard to other key cellular functions, particularly in the mitochondria, and it may promote peroxidation of the cellular membranes. It is noteworthy that after chronic consumption of ethanol, there is increased acetaldehyde, in part because of decreased disposition in the mitochondria and partly because of induction of an alternative pathway of ethanol metabolism, namely the microsomal ethanol-oxidizing system. Indeed, this MEOS increases in activity after chronic ethanol consumption, with cross induction and acceleration of the metabolism of other drugs and increased lipoprotein production with hyperlipemia. There is also increased microsomal activation of hepatotoxic compounds (including drugs and possibly vitamin A). Fibrosis and cirrhosis can develop despite an associated adequate diet and even in the absence of alcoholic hepatitis. They are preceded by myofibroblasts and fibroblast proliferation. What eventually causes the increased number of myofibroblasts and promotes fibrosis is unclear, nor do we know the relative role of hepatocytes or mesenchymal cells in the process of fibroplasis. Possibly selective roles in this process of specific nutritional factors remain to be elucidated.
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PMID:Alcohol, protein nutrition, and liver injury. 634 74

Administration of ethanol to healthy subjects as well as those with alcoholic fatty livers has been noted to cause mild elevation of serum enzyme activities and alcoholic hyperlipemia. To see whether this effect is also manifested in alcoholics with advanced liver damage, the serum enzyme activities and lipid content after administration of i.v. ethanol (1.2 g/kg of body wt) over 90 min were compared in 5 alcoholics with hepatic fibrosis and/or alcoholic fatty liver and in 9 patients with alcoholic hepatitis with or without cirrhosis. Disappearance rate of ethanol from the serum was nearly the same in both groups. Serum activities of asparate aminotransferase, mitochondrial isoenzyme of asparate aminotransferase, and ornithine carbamyl transferase, measured at 9 and 12 hr after termination of the i.v. ethanol, were significantly elevated in alcoholics with alcoholic hepatitis (P less than 0.05). They were not elevated in alcoholics with fatty liver. By contrast, hyperlipemic responses, measured as the serum content of triacylglycerol 3 hr after ethanol were significantly greater in alcoholics with fatty liver than in alcoholics with alcoholic hepatitis (P less than 0.05). The observed difference in responses of serum enzyme activities and lipid content after ethanol represents an enhanced susceptibility of patients with alcoholic hepatitis and cirrhosis towards alcohol-induced injury.
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PMID:Effect of an intravenous infusion of ethanol on serum enzymes and lipids in patients with alcoholic liver disease. 735 55

Nonalcoholic steatohepatitis (NASH) is a liver disease that, until recently, has been underrecognized as a common cause of elevated liver enzymes. This distinct clinical entity is characterized by liver biopsy findings similar to those seen in alcoholic hepatitis but in the absence of alcohol consumption sufficient to cause such changes. Patients with NASH are often middle-aged and obese, with coexisting diabetes or hyperlipidemia, but NASH also occurs in younger lean, otherwise healthy individuals and even in children. Although NASH is generally a benign disorder, it may be progressive, leading to cirrhosis and complications of portal hypertension. Liver biopsy remains the gold standard for diagnosis. Therapy for NASH remains poorly defined, although weight reduction and ursodeoxycholic acid may have a beneficial effect.
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PMID:Nonalcoholic steatohepatitis. 1090 90

Increased concentrations and activity of plasma cytokines produced by monocytes, macrophages, and hepatocytes in patients with alcoholic liver diseases, correlate with the clinical course of liver diseases and are of prognostic value. Especially, high levels of circulating tumor necrosis factor (TNF)-alpha have been found to correlate with increased mortality in alcoholic hepatitis. Moreover, hepatic RANTES was increased in patients with alcoholic hepatitis. Thus, TNF-alpha-induced RANTES expression may have a critical role in cell-mediated liver injury associated with alcoholic hepatitis. Fibrates are widely used in the treatment of hyperlipidemia and lower triglyceride levels in patients with hyperlipidemia. Recently, several groups reported that bezafibrate, one of fibrates, is effective in primary biliary cirrhosis treatment. Additionally, it is reported that bezafibrate is effective in the treatment not only of primary biliary cirrhosis but also of chronic hepatitis C and tamoxifen-induced non-alcoholic steatohepatitis. We, here, presented that bezafibrate and fenofibrate repressed TNF-alpha-induced protein production and mRNA expression of RANTES in human hepatocyte-derived cells. Luciferase assay showed that bezafibrate and fenofibrate inhibited RANTES gene expression in response to TNF-alpha. Moreover, bezafibrate repressed TNF-alpha-induced DNA-binding activity of NF-kappaB. Thus, fibrates reduced TNF-alpha-induced NF-kappaB activation and RANTES expression, possibly suggesting that fibrates might be inhibitory agents of migration of inflammatory cells by RANTES to the liver in patients with alcoholic liver diseases. In line of these results, it might be possible that fibrates are therapeutic agents in alcoholic liver diseases.
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PMID:Inhibition of TNF-alpha-induced RANTES expression in human hepatocyte-derived cells by fibrates, the hypolipidemic drugs. 1258 3

Ethanol toxicity on liver is a function of duration of alcoholism, amount of daily intake of alcohol and patient's nutrition. The threshold of alcohol toxicity on the liver is about 40 g of ethanol daily in men and 20-30 g in women, however liver cirrhosis develops in no more than 8-20% of patients exceeding this values. Ethanol is oxidized in the liver to acetaldehyde--a compound considerably more toxic than ethanol itself. Despite small amount of alcohol dehydrogenase (ADH) found in gastric mucosa, the metabolism of ethanol in this site may have an important hepatoprotective effect. The oxidation of ethanol is associated with a change of hepatocyte redox homeostasis, which leads to a number of metabolic disorders such as lactic acidosis, hyperlipidaemia and hyperuricaemia. Chronic ethanol consumption does not influence ADH activity, but has a profound stimulatory effect on microsomal enzymes, in particular cytochrome CYP2E1. This fact is responsible for development in alcoholic liver associated with rise of oxygen consumption, excessive production of free radicals and increased metabolism of ethanol, vitamin A and testosterone. Ethanol and acetaldehyde have a deleterious effect, both the direct and indirect, on hepatocytes e.g., generating radical oxygen species and damaging intestinal mucosal barrier. Cellular oxidative stress that is caused by both an excess of free radicals and the antioxidatives' deficiency (glutathion, vitamin E, phosphatidylcholine), may be the principal factor responsible for progression of alcoholic liver disease. Among other factors accelerating alcohol-related liver lesion there are certain drugs, high fat diet, infection with HCV and genetic factors (female sex, enzymatic polymorphic forms of ADH and ALDH, hemochromatosis). Great importance in pathogenesis of necrotic and inflammatory hepatic events is being attributed to portal endotoxaemia and cytokines induced within the liver, in particular TNF-alpha and interleukin 8. These cytokines play a key role in development of alcoholic hepatitis, which clinical severity ranges from subclinical to fatal forms. Apart from abstinence, the treatment of alcohol liver disease is based on hyperalimentation, since alcoholism is generally associated with protein malnutrition. In severe forms of alcohol hepatitis corticosteroids are recommended.
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PMID:[Alcoholic liver disease]. 1290 Dec 71

In 1980, the term non-alcoholic steatohepatitis was coined to describe a new syndrome occurring in patients who usually were obese (often diabetic) females who had a liver biopsy picture consistent with alcoholic hepatitis, but who denied alcohol use. The causes of this syndrome were unknown, and there was no defined therapy. More than two decades later, this clinical syndrome is only somewhat better understood, and still there is no Food and Drug Administration-approved or even generally accepted drug therapy. Patients with primary non-alcoholic steatohepatitis typically have the insulin resistance syndrome (synonymous with the metabolic syndrome, syndrome X, and so forth), which is characterized by obesity, diabetes, hyperlipidemia, hypertension, and, in some instances, other metabolic abnormalities such as polycystic ovary disease. Secondary non-alcoholic steatohepatitis may be caused by drugs such as tamoxifen, certain industrial toxins, rapid weight loss, and so forth. The cause of non-alcoholic steatohepatitis remains elusive, but most investigators agree that a baseline of steatosis requires a second hit capable of inducing inflammation, fibrosis, or necrosis for non-alcoholic steatohepatitis to develop. Our research group has focused its efforts on the interactions of nutritional abnormalities, cytokines, oxidative stress with lipid peroxidation, and mitochondrial dysfunction in the induction of steatohepatitis, both alcoholic and non-alcoholic in origin. Research findings from other laboratories also support the role of increased cytokine activity, oxidative stress, and mitochondrial dysfunction in the pathogenesis of non-alcoholic steatohepatitis. The objectives of this article are to review the (1) definition and clinical features of non-alcoholic steatohepatitis, (2) potential mechanisms of non-alcoholic steatohepatitis, and (3) potential therapeutic interventions in non-alcoholic steatohepatitis.
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PMID:Mechanisms of non-alcoholic steatohepatitis. 1567 Jun 68


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