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)

Alcohol promotes accumulation of fat in the liver mainly by substitution of ethanol for fatty acids as the major hepatic fuel. The degree of lipid accumulation depends on the supply of dietary fat. Progressive alteration of the mitochondria, which occurs during chronic alcohol consumption, decreases fatty acid oxidation by interfering with citric acid cycle activity. This block is partially compensated for by increased ketone body production, which results in ketonemia. Thus, mitochondrial damage perpetuates fatty acid accumulation even in the absence of ethanol oxidation. Alcohol facilitates esterification of the accumulated fatty acids to triglycerides, phospholipids, and cholesterol esters, all of which accumulate in the liver. The accumulated lipids are disposed of in part as serum lipoprotein, resulting in moderate hyperlipemia. In some individuals with pre-existing alterations of lipid metabolism, small ethanol dose may provoke marked hyperlipemia which responds to alcohol withdrawal. Inhibition of the catabolism of cholesterol to bile salt may contribute to the hepatic accumulation and hypercholesterolemia. The capacity of lipoprotein production and hyperlipemia development increases during chronic alcohol consumption, probably as a result of the concomitant hypertrophy of the endoplasmic reticulum and Golgi apparatus. However, this compensation is relatively inefficient in ridding the liver of fat. This inefficiency may be linked to alterations of hepatic microtubules induced by ethanol or its metabolites, which interfere with the export of protein from liver to serum, promoting hepatic accumulation of proteins as well as fat. As liver injury aggravates, hyperlipemia wanes and liver steatosis is exaggerated. Derangements of serum lipids similar to those found in other types of liver disease also become apparent. The changes in serum lipids may be a sensitive indicator of the progression of liver damage in the alcoholic.
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PMID:Effects of ethanol on lipid metabolism. 8 83

Hepatic fine structural alterations induced by shortterm administration of the hypolipidemic drug oxandrolone were evaluated using morphometric techniques. These changes are described in the livers of normolipidemic young adult and hyperlipidemic retired breeder male rats. Retired breeder rats, characterized by hyperlipidemia and a high incidence of arteriosclerosis, are thought to undergo premature aging. A previous morphometric study has shown that the hepatocytes of retired breeder rats are larger, contain a greater volume fraction of lysosomes, and have significantly less smooth-surfaced endoplasmic reticulum than those of young adult rats. However, after oxandrolone administration, the livers of these two animal groups were no longer distinguishable on the basis of these morphometric parameters. Unlike a number of other hypolipidemic drugs, oxandrolone does not induce a marked proliferation of hepatic microbodies. The effect of oxandrolone on the livers of prematurely aging rats suggests that the age-related fine structural changes are not the result of irreversible alterations in the genome or translation-transcription apparatus but may actually represent secondary reactions to extrahepatic and/or endocrine metabolic changes. The relationship between (1) aging and hyperlipidemia and (2) aging and the reduced hepatic capacity to metabolize drugs suggest a need to evaluate the effects of lipid-lowering drugs on the livers of old as well as young animal models.
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PMID:Hepatic fine structure in young and aging rats treated with oxandrolone: a morphometric study. 112 54

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

In this study the influence of fasting on the structures in the human gastric mucosa was followed using selective histoenzymological and electronmicroscopic method. The gastrobioptical material of 7 healthy volunteers was examined after 24 to 240 hour fasting. During fasting an increased acid phosphatase activity in the chief cells of the human fundal mucosa was observed. The activity of the nonspecific esterase (naphtyl esterase) in the chief cells decreased mainly after 240 hour fasting. In the electronmicroscopic examination of the chief cells during fasting a multiplication of lysosomes and narrowing of the granular endoplasmic reticulum was observed. In some chief cells during fasting an agglomeration of zymogen granules was seen while in others only a few granules were observed. In the parietal and other cells of the human gastric glands a steatosis, which attained excessive values, was seen after 72 and 240 hours of fasting. We believe that this steatosis occurred mainly on the strength fasting lipemia with the possible participation of other factors. The changes in the mitochondrial structure of the parietal and other cells of the human gastric mucosa were only slightly pronounced. "The decreased" activity of dehydrogenase in the steatotic parietal cells under a histochemical examination may represent only findings caused by the agglomeration of a large amount of lipid drops in the steatotic cells. After 72 and 240 hours of fasting the parietal cells contained collapsed, underdeveloped intracellular canaliculi and narrowed tubulovesicular profiles probably related to the decreased HCl production. Generally it can be said that the observed morphological changes are the consequences of the decreased function of human gastric mucosa cells during fasting and that these regressive changes are reversible and they are caused by an insufficiency of nutrition.
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PMID:Histoenzymatic and ultrastructural findings in the human gastric mucosa during fasting. 123 3

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

We tested whether apoprotein B is present in fasting and postprandial human duodenojejunal mucosa because lipoprotein-like particles are visualized by electron microscopy within the smooth endoplasmic reticulum and the Golgi cisternae of these absorptive cells. Duodenojejunal biopsies from normal volunteers were incubated in citrate buffer and were shaken in 1% EDTA so that absorptive cells could be freed from underlying tissue. Apoprotein B was determined by double-antibody radioimmunoassay in homogenates of absorptive cells. The preparations of absorptive cells were shown to be uncontaminated by plasma lipoproteins; they did not contain any albumin by immunodiffusion able to detect 2 mug/ml. They adsorbed less than 0.1% of 125I-low density lipoprotein which was added to the citrate buffer. Cell preparations from suction biopsies of human rectum contained no detectable apoprotein B. Duodenojejunal absorptive cells from 22 fasting subjects contained 3.2 +/- 0.5 mug of apoprotein B per 100 mg (wet wt) of biopsies or 1.3 mug of apoprotein B per mg of total cell protein. The amount of apoprotein B per milligram of cell protein fell to 0.3 mug in 14 of these individuals whose mucosa was also sampled 45 min after instilling fat intraduodenally. These experiments provide immunochemical evidence that human duodenojejunal absorptive cells contain apoprotein B. This technique should be valuable for studying the physiology of intestinal lipoproteins in absorption and in patients with hyperlipidemia.
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PMID:Apoprotein B in fasting and postprandial human jejunal mucosa. 125 33

The hypolipidemic activity of tiadenol-disulfoxide, the major metabolite of 1,10-bis(hydroxyethylthio)decane (tiadenol, Eulip) in man and in the rat was assessed in various experimental models versus the corresponding activity of tiadenol. Tiadenol-disulfoxide in the normolipidemic rats lowers total serum cholesterol and serum and liver triglycerides in an extent comparable to that of the reference compound. Likewise, it is equally effective as tiadenol in preventing Triton-induced hyperlipidemia and Nath diet induced hypercholesterolemia; in addition tiadenol-disulfoxide is slightly more effective than tiadenol in increasing HDL-cholesterol in hypercholesterolemic rats. At hypolipidemic doses the compound causes no hepatomegaly, no induction of peroxisomal catalase and palmitoyl-CoA oxidase activities, no smooth endoplasmic reticulum proliferation and no induction of microsomal cytochrome P-450 and of cytochrome P-450 dependent enzyme activities: aminopyrine (aminophenazone) N-demethylase, aniline hydroxylase, zoxazolamine hydroxylase and hexobarbital oxidase. At the suprapharmacological dose of 300 mg/kg tiadenol-disulfoxide, if compared to the reference compound, shows a generally lower order of toxicity on these hepatic parameters. Orally administered tiadenol-disulfoxide is well absorbed by the gastrointestinal tract and is eliminated in urine at 45% of the dose in unchanged form, and the remaining being: glucuron-conjugated tiadenol-disulfoxide (10%), S-oxidized metabolites (15%) and sulfoxidized carboxylic metabolites (15%). The compound is well tolerated both in mice and rats. The results of this comparative study demonstrate that: 1. tiadenol-disulfoxide is a substance with promising hypolipidemic properties; 2. tiadenol-disulfoxide is largely responsible for the hypolipidemic activity of tiadenol; 3. hepatomegaly consequent to tiadenol administration is the consequence of the response of the liver cell to the increased functional demand of the mixed function oxidase (MFO) system involved in the metabolism of the drug; 4. peroxisomal enzyme activities induction observed with both drugs at non-pharmacological doses does not play any role in their hypolipidemic action and is not associated with hepatomegaly.
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PMID:Experimental studies on pharmacology, metabolism and toxicology with tiadenol-disulfoxide. Dissociation of lipid lowering effects and the induction of peroxisomal and microsomal drug-metabolizing enzymes. 366 66

Lipoprotein lipase and hepatic lipase activities are very low in tissues of mice born with genetic combined lipase deficiency (cld/cld). Consequently, if allowed to suckle, the mice develop severe hyperlipemia and die within 3 days. The ultrastructure of capillaries and parenchymal cells in tissues that normally contain lipoprotein lipase and hepatic lipase was studied in tissues from cld/cld and unaffected mice 6 to 24 hours of age. Capillaries in tissues from suckled cld/cld mice were packed with numerous abnormally shaped chylomicrons. There was close contact between surfaces of chylomicrons and the luminal plasma membrane of endothelium. Chylomicrons were sometimes found between endothelial cells and in the subendothelial space in heart, lung, and liver, and in the lumen of lung alveoli. In contrast, capillaries of suckled unaffected mice contained very few chylomicrons, and the subendothelial spaces and lung alveoli were free of chylomicrons. Myocytes of diaphragm and heart from suckled cld/cld mice did not contain lipid droplets, whereas brown adipocytes contained a few small droplets. Parenchymal cells in diaphragm, heart, brown adipose tissue, and lung from suckled unaffected mice contained numerous large lipid droplets. Hepatocytes of suckled cld/cld mice contained small irregularly shaped lipoprotein particles (100 A) in endoplasmic reticulum and Golgi, numerous large lysosomes containing small lipoprotein particles, lipid spheres and lamellar structures, and no intracellular lipid droplets, whereas hepatocytes of suckled unaffected mice contained larger lipoprotein particles (400 A), large lipid droplets, and very few lysosomes. Triacylglycerol of chylomicrons from cld/cld mice was readily hydrolyzed by bovine lipoprotein lipase in vitro, and this effect was not augmented by heat-inactivated serum, indicating that the chylomicrons contained adequate amounts of apoprotein C-II. Thus, the large amount of chylomicrons in capillaries and small amount of lipid droplets in cells of suckled cld/cld mice reflect the very low level of lipoprotein lipase activity in these animals. The findings in hepatocytes indicate that lipoprotein metabolism in liver is markedly disturbed in cld/cld mice.
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PMID:Effect of the combined lipase deficiency mutation (cld/cld) on ultrastructure of tissues in mice. Diaphragm, heart, brown adipose tissue, lung, and liver. 374 49

To study the mechanism of the increase in serum lipoproteins which occurs in rats fed alcohol chronically, and especially to assess the role of the intestine, the effects of acute and chronic ethanol administration on lymph and plasma lipids were compared in rats with and without intestinal lymph fistulae. In rats not previously given alcohol, the administration of one dose of a diet containing ethanol (3 g/kg) produced a significant increase in lymph flow, lipid output, and incorporation of dietary fat into lymph lipids when compared with the effects of a control diet containing isocaloric carbohydrate. However, no hyperlipemia developed after ethanol. By contrast, previous feeding of ethanol for several weeks modified the acute effects of ethanol on both lymph and serum lipids. Compared with control animals pair-fed with isocaloric carbohydrate-containing diets, rats which had been fed a diet with 36% of total calories as ethanol for 3-4 wk developed postprandial hyperlipemia when given a single dose of the ethanol-containing or even the ethanol-free diet. This was associated with an increased incorporation of labeled dietary fat and of intravenously injected [(3)H]lysine into plasma lipoproteins of d < 1.006. However, postprandial lymph flow and lipid output were not higher in rats fed alcohol chronically than in their pair-fed controls. Moreover, when rats with lymph fistulae were given intravenous (i.v.) infusions of lymph lipids (to substitute for the diverted intestinal lymph), the ethanol-fed animals still developed hyperlipemia. Incorporation of i.v. lysine into d < 1.006 plasma lipoproteins also remained significantly increased. Thus, under these conditions, alcoholic hyperlipemia does not result from changes in intestinal lymph lipids. Two main factors appear to be involved; the acute effects of ethanol on hepatic lipid metabolism and the development of an increased capacity for lipoprotein synthesis during chronic ethanol feeding. The latter most likely occurs in the liver and it is postulated that it is linked to the associated changes in the hepatic endoplasmic reticulum.
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PMID:Pathogenesis of postprandial hyperlipemia in rats fed ethanol-containing diets. 468 74

The interaction of ethanol with lipid metabolism is complex. When ethanol is present, it becomes a preferred fuel for the liver and displaces fat as a source of energy. This favors fat accumulation. In addition, the altered redox state secondary to the oxidation of ethanol promotes lipogenesis, for instance, through enhanced formation of acylglycerols. The depressed oxidative capacity of the mitochondria injured by chronic alcohol feeding also contributes to the development of the fatty liver. Accumulation of fat acts as a stimulus for the secretion of lipoproteins and the development of hyperlipemia. Hyperlipemia may also be facilitated by the proliferation of the endoplasmic reticulum after chronic ethanol consumption and the associated increase of enzymes involved in the production of triglycerides and lipoproteins. The propensity to enhance lipoprotein secretion is offset, at least in part, by a decrease in microtubules and an impairment of the secretory capacity of the liver. The level of blood lipids depends on the balance between these two opposite changes: At the early stage of alcohol abuse, when liver damage is still small, hyperlipemia will prevail, whereas the opposite occurs with severe liver injury. When hyperlipemia occurs, it involves all lipoprotein classes, including high density lipoprotein (HDL). The latter have been suggested to be responsible for the lower incidence of coronary complications of moderate drinkers compared to teetotalers, but in fact, the subtype of HDL involved (HDL3) differs from the HDL2 subtype associated with protection.
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PMID:Ethanol and lipids. 638 65


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