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)

Hepatic monoacylglycerol acyltransferase is expressed during the perinatal period in rats and guinea pigs and appears to be related temporally to the availability of fatty acids and to the development of hepatic steatosis. In order to determine when monoacylglycerol acyltransferase activity is expressed in an avian species, its ontogeny was investigated in chick liver total particulate preparations. In livers from 11- to 21-day-old chick embryos, monoacylglycerol acyltransferase specific activity was 34.5 +/- 8.1 nmol/min per mg of total particulate protein. The specific activity decreased 93% to 2.6 +/- 1.3 nmol/min per mg by the 6th day after hatching. The specific activities of fatty acid CoA ligase, diacylglycerol acyltransferase, and microsomal and mitochondrial glycerol-P acyltransferases changed comparatively little during this time period. In the embryos, the monoacylglycerol acyltransferase activity per liver rose 28-fold between the 11th and 21st day, corresponding exactly to the increase in liver total particulate protein during this time. Monoacylglycerol acyltransferase activity in other tissues was 25- to 115-fold lower than observed in liver. Optimal activity was measured using 25 microM palmitoyl-CoA and 50 microM sn-2-monooleoylglycerol. The activity with the 1- and 2-monooleoylglycerol ethers and 1-monooleoylglycerol was very low. In contrast to microsomes from rat liver, about 70% of the product with the 1- and 2-monooleoylglycerol ethers was triradylglycerol, suggesting that the diacylglycerol acyltransferase from chick liver can acylate acyl, alkylglycerols. The activity with sn-2-monooleoylglycerol amide was 12.5% of that observed with the corresponding 2-monooleoylglycerol suggesting that the ester bond is important; the 1-monooleoylglycerol amide was not a substrate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hepatic monoacylglycerol acyltransferase: ontogeny and characterization of an activity associated with the chick embryo. 254 43

Fatty liver was induced in six sheep by fasting and treatment with phloridzin and epinephrine. Treatment was associated with a rise in the concentration in serum and hepatic uptake of nonesterified fatty acid (NEFA) compared with pretreatment (P less than .01). At 24 h after the start of the treatment, concentrations of serum lipoprotein in each density class were not different from baseline, but all were elevated (P less than .01) by 120 h of treatment. Hepatic triacylglycerol (TG) concentration increased (P less than .01) 17-fold within the first 48 h of treatment, with no additional increase during the remaining 72 h. The activity of phosphatidate phosphohydrolase (PAP) in hepatic microsomes increased (P less than .01) fourfold over baseline by 48 h of treatment, then declined slightly by 120 h. The activities of diacylglycerol acyltransferase (DGAT) and glycerolphosphate acyltransferase (GPAT) in hepatic microsomes increased during treatment but appeared to follow a slightly different pattern from that of PAP. Activity of GPAT was not above baseline at 48 h, but was at 120 h (P less than .05); DGAT activity was increased (P less than .05) twofold at 48 h, with an apparent continued increase (P less than .01) to threefold over baseline by 120 h of treatment. Fatty liver appeared to develop during a period of rapid hepatic uptake of NEFA without a corresponding increase in serum lipoprotein concentrations. The activities of PAP, GPAT and DGAT, putative regulators of TG synthesis rate, all increased in liver microsomes during a period of high hepatic NEFA uptake, but that of PAP appeared to coincide most closely with the development of fatty liver.
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PMID:Hepatic triacylglycerol synthesis during a period of fatty liver development in sheep. 320 8

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

To study the effects of alcoholic liver injury on the ability of ethanol to promote hepatic fat accumulation and hyperlipemia, baboons were pair-fed liquid diets containing 50% of energy either as ethanol or as additional carbohydrate (controls) for 1 to 7 years. Alcohol consumption produced triacylglycerol accumulation in the liver, hypertriacylglyceridemia, and various degrees of liver injury, including cirrhosis. At the early stages of fatty liver (with or without perivenular fibrosis), there was increased activity of microsomal diacylglycerol acyltransferase and of both microsomal and cytosolic phosphatidate phosphohydrolase, with no changes in glycerol-3-phosphate acyltransferase. With progression of the liver injury and development of septal fibrosis and/or cirrhosis, the rate of hepatic triacylglycerol accumulation and the magnitude of the hyperlipemia decreased, despite continuous ethanol intake. These changes were associated with disappearance of the increases in microsomal diacylglycerol acyltransferase and cytosolic phosphatidate phosphohydrolase activities, whereas those of microsomal phosphatidate phosphohydrolase remained elevated and glycerol-3-phosphate acyltransferase was unaffected. Thus, changes in the activity of two enzymes of the triacylglycerol-synthesizing pathway, namely the microsomal diacylglycerol acyltransferase and the cytosolic phosphatidate phosphohydrolase, may contribute to the differences in the rate of hepatic triacylglycerol accumulation and the degree of hyperlipemia during progression of the alcoholic liver damage.
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PMID:Hepatic triacylglycerol synthesizing activity during progression of alcoholic liver injury in the baboon. 649 27

We investigated the activities of hepatic glycerolipid synthesizing enzymes during postpartum fatty liver development in 10 high-producing dairy cows that had free access to feed during the dry period; a parallel group of 8 control cows was fed according to recommended energy requirements. After calving, both test and control cows had free access to feed. In the period of 10-14 wk before calving, voluntary dry matter intake of the test cows was 20.6 kg/d (SEM 0.42); the restricted control cows received 7 kg/d. Postpartum triacylglycerol concentrations in liver biopsies were one- to twofold higher in the test than in the control cows. The higher plasma nonesterified fatty acid (NEFA) concentrations after parturition in the test vs. the control group were probably caused by a more negative energy balance in the test cows, which was associated with a slightly lower postpartum dry matter intake. After calving, hepatic mitochondrial glycerolphosphate acyltransferase (GPAT) activities were significantly lower in the test than in the restricted control cows. A low GPAT activity may divert fatty acids from esterification to beta-oxidation to protect the hepatocytes against further accumulation of triacylglycerols. The activities of hepatic phosphatidate phosphohydrolase, diacylglycerol acyltransferase, and cholinephosphate cytidylyltransferase were not different in the two groups. This study indicates that in cows given free instead of restricted access to feed during the dry period have a postpartum hepatic triacylglycerol accumulation that is mainly determined by a raised hepatic uptake of plasma NEFA.
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PMID:Higher postpartum hepatic triacylglycerol concentrations in dairy cows with free rather than restricted access to feed during the dry period are associated with lower activities of hepatic glycerolphosphate acyltransferase. 855 28

We studied development of fatty liver in high producing dairy cows with free access to feed during the dry period and thus showed the combined effects of parturition and prepartum overfeeding. Postpartum liver triacylglycerol concentrations at 1 wk postpartum, as measured in liver biopsies, had increased more than 6-fold, which was preceded or accompanied by an increase in plasma NEFA concentrations. Concentrations of hepatic phospholipid changed only slightly. The amounts of total lipids in serum, very low density lipoproteins, and high density lipoproteins significantly decreased by .5 wk after parturition, and concentrations of high density lipoproteins rose steadily. The pattern was similar for concentrations of total cholesterol and phospholipid in serum. Total lipid concentrations in low density lipoproteins were not altered after parturition. The activity of microsomal phosphatidate phosphohydrolase in the liver showed a transient increase at .5 wk after calving, but activity of microsomal glycerolphosphate acyltransferase remained relatively constant. The activities of diacylglycerol acyltransferase had increased about twice at 1 wk after calving and remained at this high level until at least 4 wk after parturition. The rise in activity of diacyglycerol acyltransferase was probably a response to the extra influx of fatty acids to channel them into triacylglycerol. Activities of microsomal cholinephosphate cytidylyltransferase initially increased after calving and then decreased slightly. Activities of hepatic choline kinase had increased after calving. This study indicates that hepatic triacylglycerol accumulates because of the increased hepatic uptake of NEFA and the simultaneous increase in activity of diacylglycerol acyltransferase.
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PMID:Time trends of plasma lipids and enzymes synthesizing hepatic triacylglycerol during postpartum development of fatty liver in dairy cows. 859 5

We have studied the ontogeny of the two functional diacylglycerol acyltransferase (DGAT) activities (overt and latent) during postnatal development in rat liver. We find that the ontogenic patterns of the two are highly distinct. Overt DGAT shows a transient rise in activity up to day 4 postnatally, after which it declines until weaning; thereafter, it increases steadily to reach high adult values that may contribute to the high rates of turnover of cytosolic triacylglycerol (TAG). By contrast, latent DGAT activity increases continuously during the suckling period but falls sharply upon weaning onto chow but not onto a high-fat diet. Rates of TAG secretion by hepatocytes are higher than in the adult during the first 7 days after birth, and are largely dependent on the mobilization of the abundant intrahepatocyte TAG as a source of acyl moieties. When the hepatic steatosis is cleared (after day 7) the TAG secretion rate declines by 80% to reach adult values. Quantification of the content of mRNA for the DGAT1 and DGAT2 genes does not show correlation with either of the DGAT activities. We conclude that post-translational modification may play an important role in the overt and latent distribution of DGAT activity in the liver microsomal membrane.
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PMID:Distinct ontogenic patterns of overt and latent DGAT activities of rat liver microsomes. 1223 88

Because the ability to make triglycerides is essential for the accumulation of adipose tissue, inhibition of triglyceride synthesis may ameliorate obesity and its related medical consequences. Acyl coenzyme A (CoA):diacylglycerol acyltransferase 1 (DGAT1) is 1 of 2 DGAT enzymes that catalyze the final reaction in the known pathways of mammalian triglyceride synthesis. Mice lacking DGAT1 are resistant to obesity and have increased sensitivity to insulin and leptin. DGAT1-deficient mice are also resistant to diet-induced hepatic steatosis. The effects of DGAT1 deficiency on energy and glucose metabolism result in part from the altered secretion of adipocyte-derived factors. Although complete DGAT1 deficiency causes alopecia and impairs development of the mammary gland, these abnormalities are not observed in mice with partial DGAT1 deficiency. These findings suggest that pharmacological inhibition of DGAT1 may be a feasible therapeutic strategy for human obesity and type 2 diabetes.
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PMID:Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice. 1556 18

In this study, we investigated the role of acyl-coenzyme A:diacylglycerol acyltransferase 2 (DGAT2) in glucose and lipid metabolism in obese mice by reducing its expression in liver and fat with an optimized antisense oligonucleotide (ASO). High-fat diet-induced obese (DIO) C57BL/6J mice and ob/ob mice were treated with DGAT2 ASO, control ASO, or saline. DGAT2 ASO treatment reduced DGAT2 messenger RNA (mRNA) levels by more than 75% in both liver and fat but did not change DGAT1 mRNA levels in either of these tissues, which resulted in decreased DGAT activity in liver but not in fat. DGAT2 ASO treatment did not cause significant changes in body weight, adiposity, metabolic rate, insulin sensitivity, or skin microstructure. However, DGAT2 ASO treatment caused a marked reduction in hepatic triglyceride content and improved hepatic steatosis in both models, which was consistent with a dramatic decrease in triglyceride synthesis and an increase in fatty acid oxidation observed in primary mouse hepatocytes treated with DGAT2 ASO. In addition, the treatment lowered hepatic triglyceride secretion rate and plasma triglyceride levels, and improved plasma lipoprotein profile in DIO mice. The positive effects of the DGAT2 ASO were accompanied by a reduction in the mRNA levels of several hepatic lipogenic genes, including SCD1, FAS, ACC1, ACC2, ATP-citrate lyase, glycerol kinase, and HMG-CoA reductase. In conclusion, reduction of DGAT2 expression in obese animals can reduce hepatic lipogenesis and hepatic steatosis as well as attenuate hyperlipidemia, thereby leading to an improvement in metabolic syndrome.
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PMID:Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. 1600 99

Mice lacking acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the terminal step in triacylglycerol synthesis, have enhanced insulin sensitivity and are protected from obesity, a result of increased energy expenditure. In these mice, factors derived from white adipose tissue (WAT) contribute to the systemic changes in metabolism. One such factor, adiponectin, increases fatty acid oxidation and enhances insulin sensitivity. To test the hypothesis that adiponectin is required for the altered energy and glucose metabolism in DGAT1-deficient mice, we generated adiponectin-deficient mice and introduced adiponectin deficiency into DGAT1-deficient mice by genetic crosses. Although adiponectin-deficient mice fed a high-fat diet were heavier, exhibited worse glucose tolerance, and had more hepatic triacylglycerol accumulation than wild-type controls, mice lacking both DGAT1 and adiponectin, like DGAT1-deficient mice, were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis. These findings indicate that adiponectin is required for normal energy, glucose, and lipid metabolism but that the metabolic changes induced by DGAT1-deficient WAT are independent of adiponectin and are likely due to other WAT-derived factors. Our findings also suggest that the pharmacological inhibition of DGAT1 may be useful for treating human obesity and insulin resistance associated with low circulating adiponectin levels.
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PMID:Effects of DGAT1 deficiency on energy and glucose metabolism are independent of adiponectin. 1659 53


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