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)

Recently numerous reports show deleterious effects of alcohol abuse on pregnant women giving their children a high risk of stillbirth and/or several developmental abnormalities and mental retardation, i.e. the Fetal alcohol syndrome (FAS). In the present study, the effects of maternal alcohol consumption on lipid metabolism in the litter liver were investigated in rats. These rats showed not only quite less lipid deposition in spite of large amount of alcohol consumption up to adulthood, but also showed increased FFA oxidation in the livers. In addition, increased level of very low density lipoprotein and hypoglucagonemia were found. 40 micrograms/kg of glucagon which is known as an inhibitory factor of apoprotein production in the liver, was injected for 2 weeks into the rat tail vein and resulted in apparent fatty liver and hypolipoproteinemia. Norepinephrine injection (1 mg/kg) caused plasma glucagon to be depressed in the rat as compared with adult alcohol rats. Plasma cyclic AMP response to glucagon was also depressed in these rats. From these results, it is suggested that the deranged glucagon secretion from the pancreas and lowered glucagon-induced cyclic AMP response would relate to the abnormal lipoprotein metabolism in the rat.
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PMID:[Experimental studies on lipoprotein metabolism in rats reared with liquid alcohol diet from the fetal life]. 298 81

Alcohol has at least two actions on essential fatty acid (EFA) and Prostaglandin (PG) metabolism. It enhances the conversion of dihomogammalinolenic acid (DGLA) to PGE1 but it blocks the activity of the delta-6-desaturase, an enzyme necessary for replenishment of DGLA stores from dietary precursors. The acute effect of ethanol is therefore an increased production of PGE1 but chronic consumption will lead to depletion of DGLA and PGE1. Withdrawal from alcohol will lead to a precipitous fall in PGE1. PGE1 is known to have profound effects on the nervous system and behaviour. Patients with mania produce more PGE1 than normal while those with depression make less. Alcoholics may drink to maintain a normal PGE1 level, something which will require more and more ethanol as DGLA is depleted. In both animals and humans PGE1 or its precursor, gamma-linolenic acid (GLA) have been shown to attenuate the acute withdrawal syndrome. PGE1 injections prevent the development of fatty liver in alcohol-treated animals. Defective EFA and PGE1 metabolism are known to lead to increased fibrosis, reproductive failure, cardiomyopathy, cardiovascular disorders, gastritis and pancreatitis and could therefore be the basis for these disorders in alcoholics. A PGE1 deficiency could also be responsible for the fetal alcohol syndrome. Three other agents are known to produce constellations of fetal defects very similar to those found in the alcohol syndrome. These other factors are dihphenylhydantoin, lithium, and a deficiency of zinc. These three factors and excessive alcohol consumption all lead to PGE1 deficiency by different routes. If this concept is correct, the key to the management of alcoholism and its medical complications lies in the provision of GLA or DGLA, fatty acids which by-pass the alcohol blocked step and which are unfortunately unlikely to be present in any normal diet. Unlike many concepts of alcoholism and alcohol damage, the EFA/PGE1 idea is very readily testable and already has considerable experimental support.
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PMID:A biochemical basis for alcoholism and alcohol-induced damage including the fetal alcohol syndrome and cirrhosis: interference with essential fatty acid and prostaglandin metabolism. 625 73

The technique of feeding ethanol as part of a totally liquid diet was invented two decades ago and its successful application for the intervening period is reviewed. This technique results in much higher ethanol intake than with conventional procedures. As a consequence, various complications observed in alcoholics were reproduced in animal models, including fatty liver, hyperlipemia, various metabolic and endocrine disorders, tolerance to ethanol and other drugs, physical dependence and withdrawal, the fetal alcohol syndrome and, in the baboon, liver fibrosis and cirrhosis. Variations of the liquid diet formulation are compared and three standardized basic formulas are being proposed for the rat: (1) a regular diet, comparable to the diet previously referred to as the "Lieber-DeCarli Formula" and suitable for most experimental applications, particularly those intended to mimic the clinical situation in which the various effects of alcohol occur in the setting of liver changes characterized by a fatty liver; (2) a low fat diet comparable in all respects to the preceding diet but with a lower fat content, intended to minimize the hepatic changes; and (3) a high protein formula particularly useful in those circumstances in which an oversupply of dietary protein might be recommended (i.e., pregnancy and lactation).
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PMID:The feeding of alcohol in liquid diets: two decades of applications and 1982 update. 675 24

Dietary fatty acid composition modifies hepatic lipid metabolism. To determine the effects of fatty acids on hepatic triglyceride storage, rats were fed diets enriched in carbohydrates (control), fish oil, or lard. After 4 weeks, the animals were fasted overnight. In the morning, the animals were either sacrificed or fed 8 g of their respective diets before sacrifice. Animals ingested more food calories with diets containing fish oil than with other diets. However, fish oil-fed animals weighed less and had less body fat. In fish oil-fed animals, liver triglyceride was lower by 27% (P <.05) and 73% (P <.01) than in control- and lard-fed animals, respectively. Fish oil altered the postprandial gene expression of hepatic regulators of fatty acid degradation and synthesis. Fish oil feeding blunted the normal postprandial decline in fatty acid degradation genes (PPARalpha, CPT1, and ACO) and blunted the normal postprandial rise in triglyceride synthesis genes (SREBP1-c, FAS, SCD-1). Therefore, the direct postprandial effect of fish oil ingestion decreases the propensity for hepatic triglyceride storage. In conclusion, n-3 polyunsaturated fatty acids decrease total body weight, total body fat, and hepatic steatosis.
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PMID:Dietary n-3 polyunsaturated fatty acids decrease hepatic triglycerides in Fischer 344 rats. 1499 79

In vitro studies suggest that the mitochondrial glycerol-3-phosphate acyltransferase-1 (mtGPAT1) isoform catalyzes the initial and rate-controlling step in glycerolipid synthesis and aids in partitioning acyl-CoAs toward triacylglycerol synthesis and away from degradative pathways. To determine whether the absence of mtGPAT1 would increase oxidation of acyl-CoAs and restrict the development of hepatic steatosis, we fed wild type and mtGPAT1-/- mice a diet high in fat and sucrose (HH) for 4 months to induce the development of obesity and a fatty liver. Control mice were fed a diet low in fat and sucrose (LL). With the HH diet, absence of mtGPAT1 resulted in increased partitioning of acyl-CoAs toward oxidative pathways, demonstrated by 60% lower hepatic triacylglycerol content and 2-fold increases in plasma beta-hydroxybutyrate, acylcarnitines, and hepatic mRNA expression of mitochondrial HMG-CoA synthase. Despite the increase in fatty acid oxidation, liver acyl-CoA levels were 3-fold higher in the mtGPAT1-/- mice fed both diets. A lack of difference in CPT1 and FAS mRNA expression between genotypes suggested that the increased acyl-CoA content was not because of increased de novo synthesis, but instead, to an impaired ability to use long-chain acyl-CoAs derived from the diet, even when the dietary fat content was low. Hyperinsulinemia and reduced glucose tolerance on the HH diet was greater in the mtGPAT1-/- mice, which did not suppress the expression of the gluconeogenic genes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. This study demonstrates that mtGPAT1 is essential for normal acyl-CoA metabolism, and that the absence of hepatic mtGPAT1 results in the partitioning of fatty acids away from triacylglycerol synthesis and toward oxidation and ketogenesis.
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PMID:Mitochondrial glycerol-3-phosphate acyltransferase-1 is essential in liver for the metabolism of excess acyl-CoAs. 1587 74

Nonalcoholic steatohepatitis (NASH) is a common feature of the metabolic syndrome and toxic reactions to pharmacological drugs. Tamoxifen, (TMX) a widely used anti-breast cancer drug, can induce NASH and changes in plasma cholesterol levels through mechanisms that are unclear. We studied primary actions of TMX using a short-term treatment (5 days) that induces microvesicular hepatic steatosis and marked hypercholesterolemia in male rats. Using a combined approach of gene expression profiling and NMR-based metabolite analysis, we found that TMX-treated livers have increased saturated fatty acid content despite changes in gene expression, indicating decreased de novo lipogenesis and increased fatty acid oxidation. Our results show that TMX predominantly down-regulates FAS expression and activity as indicated by the accumulation of malonyl-CoA, a known inhibitor of mitochondrial beta-oxidation. In the face of a continued supply of exogenous free fatty acids, the blockade of fatty acid oxidation produced by elevated malonyl-CoA is likely to be the major factor leading to steatosis. Use of a combination of metabolomic and transcriptomic analysis has allowed us to identify mechanisms underlying important metabolic side effects of a widely prescribed drug. Given the broader importance of hepatic steatosis, the novel molecular mechanism revealed in this study should be examined in other forms of steatosis and nonalcoholic steatohepatitis.
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PMID:Transcript and metabolite analysis of the effects of tamoxifen in rat liver reveals inhibition of fatty acid synthesis in the presence of hepatic steatosis. 1598 34

Hepatic steatosis is commonly present during the development of insulin resistance, and it is a clear sign of lipotoxicity attributable in part to an accelerated lipogenesis. There is evidence that a soy protein diet prevents the overexpression of hepatic sterol-regulatory element binding protein-1 (SREBP-1), decreasing lipid accumulation. Therefore, the aim of the present work was to study whether a soy protein diet may prevent the development of fatty liver through the regulation of transcription factors involved in lipid metabolism in hyperinsulinemic and hyperleptinemic Zucker obese fa/fa rats. Serum and hepatic cholesterol and triglyceride levels, as well as VLDL-triglyceride and LDL-cholesterol, were significantly lower in rats fed soy protein than in rats fed a casein diet for 160 days. The reduction in hepatic cholesterol was associated with a low expression of liver X receptor-alpha and its target genes, 7-alpha hydroxylase and ABCA1. Soy protein also decreased the expression of SREBP-1 and several of its target genes, FAS, stearoyl-CoA desaturase-1, and delta5 and delta6 desaturases, decreasing lipogenesis even in the presence of hyperinsulinemia. Reduction in SREBP-1 was not associated with the presence of soy isoflavones. Finally, soy protein reduced SREBP-1 expression in adipocytes, preventing hypertrophy, which also helps prevent the development of hepatic lipotoxicity.
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PMID:Soy protein reduces hepatic lipotoxicity in hyperinsulinemic obese Zucker fa/fa rats. 1599 77

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

ChREBP (Carbohydrate response element binding protein) is considered to mediate the stimulatory effect of glucose on the expression of lipogenic genes. Its activity is stimulated by glucose. Less is known on the control of its expression. This expression could be controlled by nutritional (glucose, fatty acids) and hormonal (insulin) factors. We examined the in vivo nutritional control of ChREBP expression in liver and adipose tissue of Wistar rats. Compared respectively to the fed state and to a high carbohydrate diet, ChREBP mRNA concentrations were not modified by fasting or a high fat diet in rat liver and adipose tissue. FAS and ACC1 mRNA concentrations were on the contrary decreased as expected by fasting and high fat diets and these variations of FAS and ACC1 mRNA were positively related to those of SREBP-1c mRNA and protein, but not of ChREBP mRNA. Therefore i) ChREBP expression appears poorly responsive to modifications of nutritional condition, ii) modifications of the expression of ChREBP do not seem implicated in the physiological control of lipogenesis. To investigate the possible role of ChREBP in pathological situations we measured its mRNA concentrations in the liver and adipose tissue of obese Zucker rats. ChREBP expression was increased in the liver but not the adipose tissue of obese rats compared to their lean littermates. These results support a role of ChREBP in the development of hepatic steatosis and hypertriglyceridemia but not of obesity in this experimental model.
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PMID:In vivo expression of carbohydrate responsive element binding protein in lean and obese rats. 1635 4

Tamoxifen can induce hepatic steatosis in women. In this study, we wanted to elucidate the mechanism behind the tamoxifen-induced accumulation of triacylglycerol in liver in female rats, and we hoped to prevent this development by combination treatment with the modified fatty acid tetradecylthioacetic acid (TTA). The increased hepatic triacylglycerol level after tamoxifen treatment was accompanied by decreased acetyl-coenzyme A carboxylase (ACC) and FAS activities, increased glycerol-3-phosphate acyltransferase (GPAT) activity, and a tendency to increased diacylglycerol acyltransferase (DGAT) activity. The activities and mRNA levels of enzymes involved in beta-oxidation, ketogenesis, and uptake of lipids from liver were unaffected by tamoxifen, whereas the uptake of lipoproteins was unchanged and the uptake of fatty acids was decreased. Combination treatment with tamoxifen and TTA (Tam+TTA) normalized the hepatic triacylglycerol level and increased the activities of ACC, FAS, GPAT, and DGAT compared with tamoxifen-treated rats. The activities and mRNA levels of enzymes involved in beta-oxidation, ketogenesis, and uptake of lipids were increased after Tam+TTA treatment. In conclusion, tamoxifen increased the hepatic triacylglycerol level, probably as a result of increased triacylglycerol biosynthesis combined with unchanged beta-oxidation. The tamoxifen-induced accumulation of triacylglycerol was prevented by cotreatment with TTA, through mechanisms of increased mitochondrial and peroxisomal beta-oxidation.
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PMID:Causes and prevention of tamoxifen-induced accumulation of triacylglycerol in rat liver. 1686 97


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