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)

Treatment of normolipidemic rats by alkylthiopropionic acid (CETTD), resulted in a dose- and time-dependent increase in total dihydroxyacetone phosphate acyltransferase (DHAPAT) activity, in extent comparable to that of 3-thiadicarboxylic acid (BCMTD) and alkylthioacetic acid (CMTTD). Thus, in CETTD- and CMTTD-treated rats, the specific DHAPAT activity increased in the microsomal, peroxisomal and mitochondrial fractions. In contrast, repeated administration of the peroxisome proliferator, BCMTD, decreased the specific DHAPAT activity both in the peroxisomal fraction and in purified peroxisomes. A three-fold increase in specific activity was, however, revealed in the mitochondrial fraction. Whether the variation of the DHAPAT activity in the mitochondrial and microsomal fractions among the feeding groups can be explained by increased number of enlarged and small peroxisomes sedimenting in the fractions, are to be considered. Subcellular fractionation studies confirmed previous findings that rat liver glycerophosphate acyltransferase (GPAT) was located both in mitochondria and the microsomal fraction. BCMTD was considerably more potent than CMTTD in stimulating the microsomal and mitochondrial GPAT activities. Administration of CETTD marginally affected the isoenzymes of GPAT. Diacylglycerol acyltransferase (DGAT) activity was increased by 35% in BCMTD and CMTTD treated rats, but by administration of CETTD the enzyme activity was decreased by more than 80%. The acyl-CoA cholesterol acyltransferase (ACAT) activity was marginally affected in animals treated with BCMTD, CMTTD and CETTD. Thus, the results indicate that the initial steps in the synthesis of triacylglycerols and ether glycerolipids as well as the last step in triacylglycerol synthesis could not be identified as mediating the fat accumulation or the lowering of triacylglycerol content in liver of CETTD, or BCMTD and CMTTD treated rats. On the other hand, CMTTD increased the palmitoyl-CoA oxidation in mitochondria, and CETTD considerably inhibited the activity. Therefore, it is conceivable that the development of fatty liver with CETTD is mostly due to inhibition of mitochondrial beta-oxidation.
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PMID:Effect of 3- and 4-thia-substituted fatty acids on glycerolipid metabolism and mitochondrial beta-oxidation in rat liver. 224 30

A high cholesterol diet induced a fatty liver and an increase in cholesterol oleate in spontaneously hypertensive rats. The activity of microsomal glycerophosphate acyltransferase in liver increased 2-3-fold to meet the increased supply of oleate, the synthesis of which was stimulated by a 10-fold increase in microsomal delta 9-desaturase activity. Hepatic fatty acid synthetase and diacylglycerol acyltransferase activities were decreased somewhat. These results, together with the fact that the large increases in hepatic cholesterol ester and triacylglycerol were not correspondingly reflected in plasma, indicated that the fatty liver resulted from decreased secretion of lipoprotein rather than increased lipogenesis. Endogenous cholesterol in liver microsomes increased 2-fold and hepatic acyl-CoA:cholesterol acyltransferase activity increased 3-fold, whereas plasma lecithin:cholesterol acyltransferase activity was unchanged. Thus, the increase in cholesterol oleate seen in spontaneously hypertensive rats fed a high cholesterol diet is due mainly to increases in acyl-CoA:cholesterol acyltransferase and delta 9-desaturase activities.
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PMID:Effect of a high cholesterol diet on lipid metabolizing enzymes in spontaneously hypertensive rats. 405 45

Lipids of HDL (high density lipoproteins) and their subfractions (HDL2 and HDL3), and LCAT activity (lecithin: cholesterol acyltransferase) were determined in hepatobiliary diseases without severe hyperbilirubinemia (less than 10 mg/dl). The decrease in major lipid constituents (cholesterol and phospholipids) of HDL was mainly attributable to the decrease in those of HDL3, except in some liver diseases of acute or severe stage (acute hepatitis in an acute stage and hepatoma) which were accompanied with a simultaneous moderate decrease in those of HDL2 and in fatty liver which showed a preferential decrease in those of HDL2. The LCAT activity also decreased in several diseases. Some of the hepatobiliary diseases, on the contrary, showed an increase in HDL-triglycerides (mostly in HDL3 and in some diseases also in HDL2) which might participate to some extent in secondary hyperlipidemia in the liver parenchymal diseases, although they were the minor lipid constituents of HDL. From results that HDL3- but not HDL2-cholesterol levels significantly correlated with serum total protein, albumin and choline esterase, it was suggested that the decrease in large constituents of HDL, particularly of HDL3, is caused by hepatocellular dysfunction which causes inhibition of protein and lipid syntheses in the liver in most of the hepatobiliary diseases except for fatty liver which has a preferential decrease in HDL2 lipids.
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PMID:Changes in high density lipoproteins in patients with hepatobiliary diseases. Levels and lipid composition of HDL2 and HDL3 and LCAT reaction. 685 43

We have previously shown that fatty liver was easily induced in suncus by starvation and that the plasma level of apolipoprotein B (apoB) was very low. We also previously reported that a defect in the assembling process of apo B-containing lipoprotein (very low density lipoprotein, VLDL) may be one of the reasons for the low level of plasma apo B and for induction of fatty liver by starvation in suncus. We also found that hepatic acyl coenzyme A cholesterol acyltransferase (ACAT) activity is very low in the animals, resulting in decreased cholesteryl ester contents in the liver. A deficiency of cholesteryl ester in suncus liver may be one of the reasons for the defect in the assembling process of VLDL. In this study, we investigated the effect of cholesterol-feeding, which induces an increase in triglyceride and cholesteryl ester of the liver as a consequence of the induction of both intestinal and hepatic ACAT activities, on the secretion of VLDL. Although the basal ACAT activity of intestinal mucosa was high, cholesterol-feeding did not induce either an increase in plasma lipid or an increase in intestinal ACAT activities in suncus. The hepatic secretion rate of VLDL was estimated by treatment with Triton WR1339, which is well known to inhibit the catabolism of VLDL. Cholesterol-feeding caused a slight increase in hepatic triglyceride and cholesteryl ester but no increase either in the secretion rate of VLDL or in hepatic ACAT activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of acyl coenzyme A cholesterol acyltransferase in intrahepatic processing of apo B-lipoprotein in suncus. 854 56

Lecithin:cholesterol acyltransferase (LCAT) activity in serum was evaluated in spontaneous cases of fatty liver in cows. The enzyme activity of 631 +/- 62 U (mean +/- SEM, decrease in nmol of free cholesterol per h per ml of serum) in cows with fatty liver (n = 16) was significantly (p < 0.01) lower than that in cows without fatty liver (979 +/- 22 U; n = 16). In addition to the decrease in LCAT activity, the concentrations of phosphatidylcholine (a fatty aryl donor for esterification of free cholesterol) and of cholesteryl esters (products of the LCAT reaction) were reduced in the high-density lipoprotein fractions from cows with fatty livers. The concentrations in the serum of apolipoprotein A-I, an activator of LCAT, was also reduced in cows with fatty livers. These results suggest that the decreased LCAT activity, which may be attributable to impaired hepatic secretion or to the suppression of the activity in the plasma by reduced concentrations of phosphatidylcholine and apolipoprotein A-I, resulted in the lower concentrations of cholesteryl esters. Because cholesteryl esters are utilized in steroidogenic tissues for the synthesis of steroid hormones such as progesterone and glucocorticoids, and insufficient supply of the cholesterols may be of relevance to the reduced fertility and immune competence observed in cows with fatty livers.
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PMID:Decreased serum lecithin:cholesterol acyltransferase activity in spontaneous cases of fatty liver in cows. 906 Jan 37

We have previously shown that fatty liver is easily induced in suncus by starvation and that the plasma level of apolipoprotein B (apo B) is very low. We also found that hepatic acyl coenzyme A cholesterol acyltransferase (ACAT) activity is almost absent in the animals, resulting in decreased cholesteryl ester contents in the liver. A deficiency of cholesteryl ester in suncus liver may be one of the reasons for the defect in the assembly process of apo B-containing lipoproteins, leading to a low level of plasma apo B. Another possible explanation for the induction of fatty liver in suncus is a defect in apo B-processing in the liver. In this study, we investigated the hepatic synthetic rate and intrahepatic degradation of apo B using primary cultured hepatocytes derived from suncus and rats. In order to estimate intrahepatic degradation of apo B, we added N-acetylleucyl-leucynorleucinal to the culture medium as an inhibitor of apo B degradation. The basal synthesis of apo B in suncus hepatocytes was 50% of that in rat. Intracellular degradation of apo B was not observed in suncus hepatocytes, while it was obvious in rat hepatocytes. This evidence suggests that the lower secretion rate of apo B lipoprotein is not due to the intrahepatic degradation of apo B, but may be due to the low synthetic rate of apo B.
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PMID:Defect in an intrahepatic degradation of apolipoprotein B in suncus: an animal model of hypobetalipoproteinemia. 950 5

Lecithin:cholesterol acyltransferase (LCAT) is the enzyme responsible for production of cholesteryl esters in plasma. The LCAT activity is reduced in cows with fatty liver developed during the nonlactating stage and those with the fatty liver-related postparturient diseases such as ketosis. The purpose of the present study was to examine whether reduced LCAT activity during the nonlactating stage could be detected before the occurrence of postparturient diseases. Sera from 24 cows were collected at approximately 10-day intervals from -48 to +14 days from parturition. Of the 24 cows, 14 were apparently healthy, whereas 7 had ketosis and 3 had milk fever at around parturition. Of the 14 healthy cows, 7 had unaltered LCAT activity during the observation period, whereas 7 showed reduced activity from -20 to +14 days. Ketosis and milk fever occurred at from -3 to +10 days, but reductions of LCAT activity in diseased cows had already been observed from days -20 to 0. These results suggest that LCAT activity is virtually unaffected during the peripartum period at least in some healthy cows and also that the reduction in LCAT activity can be detected before the occurrence of ketosis and milk fever.
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PMID:Reduction in serum lecithin:cholesterol acyltransferase activity prior to the occurrence of ketosis and milk fever in cows. 1119 41

The field of new lipid-lowering drug research is very active, with researchers, looking to make the currently available drugs more powerful and safer, and to develop new classes of drugs. Among the statins, development has gone the farthest for rosuvastatin and pitavastatin. Colesevelam is a new bile acid sequestrant with a better digestive tolerance. Among the new classes of drugs, the most promising molecules are the cholesterol absorption inhibitors--with ezetimibe as the first in line--and the PPAR-alpha and PPAR-gamma activators. Among the other classes, the acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, and ileal bile acid transporter inhibitors, have to be mentioned. In most of the cases, those new compounds are being developed mainly as a combined treatment with statins. However, these combination therapies differ depending on the lipid abnormalities of the patient. The statin-ezitimibe and the statin-bile acid sequestrant combinations have been the most studied treatments in pure hypercholesterolaemia. On another hand, the statin-PPAR-alpha and -gamma activator combination were the first to be developed for patients with combined hyperlipidaemia or type 2 diabetes mellitus. However, the clinical benefit of ACAT or CETP inhibitors remains to be determined and the development of MTP inhibitors has been restricted so far, because of problems of digestive intolerance and hepatic steatosis. Finally, the discovery of new specific lipoprotein receptors, such as the ABCA1 and SRB1 receptors, means that we can work towards developing new potential targets for pharmacological intervention.
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PMID:[New antilipemics: prospects]. 1282 7

The aromatase knockout (ArKO) mouse cannot synthesize endogenous estrogens due to disruption of the Cyp19 gene. We have shown previously, that ArKO mice present with age-progressive obesity and hepatic steatosis, and by 1 yr of age both male and female ArKO mice develop hypercholesterolemia. In this present study 10- to 12-wk-old ArKO mice were challenged for 90 d with high cholesterol diets. Our results show a sexually dimorphic response to estrogen deficiency in terms of cholesterol homeostasis in the liver. ArKO females presented with elevated serum cholesterol; conversely, ArKO males had elevated hepatic cholesterol levels. In response to dietary cholesterol, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase transcript levels were significantly reduced in females, whereas males showed more modest changes. Neither low density lipoprotein nor sterol regulatory element-binding protein expression levels were significantly altered by diet or genotype. The expression of Cyp7a, which encodes cholesterol 7 alpha-hydroxylase, was significantly reduced in ArKO females compared with wild-type females and was increased by cholesterol feeding. Cyp7a expression was significantly elevated in the wild-type males on the high cholesterol diet, although no difference was seen between genotypes on the control diet. The ATP-binding cassette G5 and ATP-binding cassette G8 transporters do not appear to be regulated by estrogen. The expression of acyl-coenzyme A:cholesterol acyltransferase 2 showed a sexually dimorphic response, where estrogen appeared to have a stimulatory effect in females, but not males. This study reveals a sexually dimorphic difference in mouse hepatic cholesterol homeostasis and roles for estrogen in the regulation of cholesterol uptake, biosynthesis, and catabolism in the female, but not in the male.
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PMID:The aromatase knockout mouse presents with a sexually dimorphic disruption to cholesterol homeostasis. 1293 63

The overproduction of very-low-density lipoprotein (VLDL) is a characteristic feature of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to use a high-fat diet-induced model of NAFLD in rats to investigate 1) the influence of the disease on hepatic VLDL processing in the endoplasmic reticulum and 2) the potential modulatory effects of dietary coenzyme Q (CoQ). Rats were fed a standard low-fat diet (control) or a diet containing 35% fat (57% metabolizable energy). After 10 wk, high-fat diet-fed animals were divided into three groups: the first group was given CoQ9 (30 mg*kg body wt(-1)*day(-1) in 0.3 ml olive oil), the second group was given olive oil (0.3 ml/day) only, and the third group received no supplements. Feeding (3 high-fat diets and the control diet) was then continued for 8 wk. In all high-fat diet-fed groups, the content of triacylglycerol (TG) and cholesterol in plasma VLDL, the liver, and liver microsomes was increased, hepatic levels of apolipoprotein B48 were raised, and the activities of microsomal TG transfer protein and acyl CoA:cholesterol acyltransferase were reduced. These findings provide new evidence indicating that VLDL assembly and the inherent TG transfer to the endoplasmic reticulum are altered in NAFLD and suggest a possible explanation for both the overproduction of VLDL associated with the condition and the disease etiology itself. Dietary CoQ caused significant increases in apolipoprotein B mRNA and microsomal TG levels and altered the phospholipid content of microsomal membranes. These changes, however, may not be beneficial as they may lead to the secretion of larger, more atherogenic VLDL.
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PMID:Hepatic VLDL assembly is disturbed in a rat model of nonalcoholic fatty liver disease: is there a role for dietary coenzyme Q? 1960 32


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