Effects of progesterone metabolites on fatty acids of the hepatic endoplasmic reticulum membranes

The effect of 2 selected progesterone metabolites on the phospholipid fatty acid composition of the liver and microsomal function was studied in the female rat. 16α-Hydroxyprogesterone significantly increased microsomal phospholipid content and the total amount of fatty acids esterified to phospholipids parallel with aminopyrine N-demethylase activity. Phospholipid changes were attributable to phosphatidylcholine and phosphatidylethanolamine. Both saturated and unsaturated fatty acids were enhanced. In contrast, 5β-pregnane-3α-ol-20-one caused a reduction of microsomal phospholipids, phosphatidycholine, together with decreased aminopyrine N-demethylase activity and total microsomal fatty acid content. Pregnanolone decreased both saturated and unsaturated fatty acids and its action on unsaturated acyl components was greater than on the saturated ones. Changes in fatty acids were manifested in palmitic, stearic and lignoceric acids among saturated fatty acids and in palmitoleic, oleic, linoleic, eicosaenoic, eicosadienoic, eicosatrienoic, arachidonic, eicosapentenoic, docosatrienoic, docosapentenoic and docosahexenoic acids among unsaturated ones. Total liver phospholipids were unaltered by either 16α-hydroxyprogesterone or 5β-pregnane-3α-ol-20-one. These test compounds, however, modified total hepatic fatty acid content. 16α-Hydroxyprogesterone increased total fatty acids and both saturated and unsaturated acyl components, whereas 5β-pregnane-3α-ol-20-one decreased these parameters. Major changes were manifested in saturated fatty acids such as stearic, arachidic and lignoceric acids, and in unsaturated ones such as palmitoleic, linoleic, eicosatrienoic and docosapentenoic acids. The action of these compounds on phospholipid fatty acids of hepatic microsomes may be causally related to their effect on drug-metabolizing activity of the endoplasmic reticulum.     

The effect of cadmium on the composition and metabolism of hepatic fatty acids in zinc-adequate and zinc-deficient rats

Exposure to cadmium (Cd) caused changes in the fatty acid composition of phospholipids, such as increases in levels of saturated and (n-6) fatty acids and decreases in levels of (n-9) fatty acids, in the liver phospholipids of rats fed a fat-free diet. These changes were similar to those caused by dietary zinc deficiency. The changes in fatty acid composition after administration of Cd were greater in zinc-deficient (ZD) rats than zinc-adequate (ZA) rats. When [¹⁴C]18:0 was injected intravenously in order to examine the metabolism of (n-9) fatty acids, a decrease in the rate of conversion of [¹⁴C]18:0 to [¹⁴C]18:1 was observed in liver phospholipids after treatment of ZD rats with Cd. These results suggested that Cd can affect the metabolism of fatty acids in relation to zinc status and, in particular, causes a reduction in the activity of Δ⁹-desaturase which converts 18:0 to 18:1.     

Fatty acid oxidation in hepatic peroxisomes and mitochondria after treatment of rats with di(2-ethylhexyl)phthalate

Rats were fed a diet containing di(2-ethylhexyl)-phthalate, which increases the number of peroxisomes and mitochondria in the liver. This proliferation does not change the ratio of phospholipid to protein in mitochondria or microsomes, but causes certain changes in the fatty acid composition of the phospholipids. The highest rates of peroxisomal and mitochondrial beta-oxidation are obtained with 12:0 and 16:0 fatty acids as substrates, respectively. A 3-4 fold increase in the rate of beta-oxidation by both organelles is caused by DEHP treatment, but there are no qualitative changes in the relative rates of oxidation of individual fatty acids. Short- and medium-chain carnitine acyltransferases in peroxisomes, microsomes and mitochondria, as well as the mitochondrial long-chain carnitine acyltransferase are induced to various extents. These results indicate that the increased beta-oxidation of fatty acids caused by phthalate treatment involves the same peroxisomal and mitochondrial pathways which operate under normal conditions.     

Mechanism of liver mitochondrial dysfunction associated with bile duct obstruction

To elucidate the mechanism of liver mitochondrial dysfunction induced by obstructive jaundice, the following experiments were performed. In vivo study: Using Wistar male rats, bile ducts were ligated, and serum levels of total bilirubin (T-Bil), GOT, GPT, mitochondrial GOT (mGOT) and total bile acids (TBA) were measured at 3 and 7 days after the ligation. Then, the liver was isolated to determine mitochondrial functions and to measure the content of fatty acids in mitochondrial phospholipids by high performance liquid chromatography. The levels of T-Bil, GOT, GPT, mGOT and TBA were elevated by the bile duct ligation. Mitochondrial functions were deteriorated, and contents of arachidonic acid, palmitic acid and stearic acid in mitochondrial phospholipids decreased. Pretreatment with coenzyme Q10 (E-0216, CoQ10), an antidetergent agent, prevented not only the development of mitochondrial dysfunction and the decrease in mitochondrial phospholipids but also the elevation of GOT, GPT, and mGOT although CoQ10 did not prevent the elevation of T-Bil and TBA levels. In vitro study: Using intact rat liver mitochondria, the effect of taurocholic acid (TCA), one of the physiological bile salts, on the mitochondrial function and on mitochondrial phospholipids was examined. Incubation of mitochondria with TCA induced a dose-dependent deterioration of mitochondrial function and the increase in the content of solubilized phospholipids. The protective effect of CoQ10 was also observed in the in vitro study. These results indicate that degradation of mitochondrial phospholipids by bile acids is responsible for the early phase of liver dysfunction induced by obstructive jaundice.     

Effect of gentamicin on lipid peroxidation in rat renal cortex

We examined the hypothesis that lipid peroxidation participates in the pathogenesis of aminoglycoside-induced nephrotoxicity. Male Sprague-Dawley rats were injected subcutaneously with gentamicin, 100 mg/kg per day, for 1-4 days. Twenty-four or forty-eight hours after the last injection the rats were killed and the renal cortex was processed for total phospholipids, malondialdehyde (MDA), phospholipid fatty acid composition, superoxide dismutase, catalase and glutathione. Gentamicin induced a significant increase in total renal cortical phospholipids which was evident after a single injection and by the third injection reached a plateau 17% above the baseline level. MDA, an end product of lipid peroxidation, increased from 0.674 +/- 0.021 nmole/mg protein in the control group to 0.931 +/- 0.053 nmole/mg protein (P less than 0.001) 48 hr after the fourth injection. As another index of lipid peroxidation, we determined the shift from polyunsaturated to saturated fatty acids of renal cortical phospholipids. By the second injection of gentamicin we detected a significant decline of arachidonic acid (20:4) present in phospholipid. By the fourth injection, arachidonic acid had fallen 48% below control and was accompanied by reciprocal increases of more saturated fatty acids including linoleic (18:2), oleic (18:1) and palmitic (16:0) acids. The number of double bonds per mole of fatty acid declined from a baseline value of 1.62 +/- 0.01 to 1.20 +/- 0.02 (P less than 0.001) by the fourth injection of drug. Superoxide dismutase showed no consistent alteration, whereas catalase activity (k) fell from the control value of 0.221 +/- 0.007 min to 0.155 +/- 0.009 min (P less than 0.01) by the third injection, where k is the first-order rate constant. Total and reduced glutathione declined after the fourth injection of gentamicin accompanied by a shift to oxidized glutathione with an increase in the ratio of oxidized to total glutathione. These data support the conclusion that accelerated lipid peroxidation occurs early in the course of gentamicin administration and raise the possibility that lipid peroxidation is a proximal event in the injury cascade of gentamicin nephrotoxicity.     

The effect of phenobarbital and carbon tetrachloride on fatty acid content and composition of phospholipids from rat liver

The administration of phenobarbital or carbon tetrachloride to rats caused various changes in hepatic fatty acid content and composition. Phenobarbital elicited no effect on the total amount of fatty acids but significantly decreased myristic, pentadecanoic, and arachidonic acids and increased eicosatrienoic, eicosapentenoic, lignoceric, and docosatrienoic acid. In contrast, carbon tetrachloride enhanced significantly the total content and several components such as pentadecanoic, palmitic, palmitoleic, oleic, linoleic, arachidic, eicosenoic, eicosadienoic, eicosatrienoic, docosapentenoic, lignoceric and docosahexenoic acids. It elicited no effect on arachidonic acid. Unsaturated fatty acid moieties participating in the structure of these phosphatides were increased by phenobarbital and diminished by carbon tetrachloride. Phenobarbital caused a reduction in the ratio of saturated/unsaturated fatty acids mainly because of the decreased palmitic and increased oleic, linoleic, eicosatrienoic, arachidonic, docosapentenoic, and docosahexenoic acids. The significant variation brought about by phenobarbital and carbon tetrachloride on tissue fatty acids and in particular on fatty acid composition of phosphatidylcholine and phosphatidylethanolamine fractions reflects the opposing effects of these compounds on the liver cell. The major action of phenobarbital and carbon tetrachloride is associated with changes of the endoplasmic reticulum. Thus, their contrasting effect on fatty acid composition and metabolism may suggest that the disposition of lipid constituents plays a determinant role in the hepatic action of foreign compounds.     

Lipid composition and fluidity of liver mitochondria, microsomes and plasma membrane of rats with chronic dietary iron overload

The effect of chronic dietary iron overload on the lipid composition and physical state of rat liver mitochondria, microsomes and plasma membranes was investigated. After 9 weeks of iron treatment, a significant decrease of polyunsaturated and a parallel increase of saturated fatty acids was observed in mitochondrial and plasma membrane phospholipids. By contrast, no appreciable modification of the fatty acid composition of microsomal membranes was detected. The cholesterol/phospholipid molar ratio as well as the lipid/protein ratio, did not reveal any significant difference in any of the fractions studies. Finally, no change in the molecular order of the various membranes, as assessed by electron spin resonance spectrometry, was observed following iron intoxication. These data indicate that, although in vivo chronic hepatic iron overload induces a modification of fatty acid profile in cellular structures consistent with the in vivo occurrence of lipid peroxidation, these changes do not bring about appreciable modifications of other physico-chemical parameters relevant to membrane integrity and cell viability.     

Phospholipids in the liver of the pregnant rat: changes in fatty acid content and composition

Pregnancy in the rat was associated with changes in hepatic phospholipids. All changes returned to the prepregnancy levels 2 to 3 weeks postpartum. The total phospholipid content was reduced significantly, mainly representing a reduction of phosphatidylcholine, -ethanolamine, and lysophosphatidylcholine fractions. Hepatic fatty acid content was also reduced and the composition was modified since both saturated and unsaturated acyl components were decreased with more pronounced changes in unsaturated acids. Total liver saturated fatty acids with 14 to 16 carbon atoms remained unaltered; stearic acid was reduced and arachidic and lignoceric acids were elevated. Among unsaturated fatty acids, palmitoleic, oleic, eicosatrienoic, arachidonic, eicosapentaenoic, and docosapentaenoic were decreased, docosatrienoic and docosahexaenoic were raised, whereas eicosaenoic and eicosadienoic did not change. In the phosphatidylcholine and -ethanolamine fractions, unsaturated acyl components also showed significant reduction. By and large they reflected the fatty acid changes occurring in total liver with the exception of the docosahexaenoic acid which was diminished in both fractions. The overall effect of pregnancy thus indicated a modification in unsaturated fatty acid content leading to the construction of less fluid membranes which may be responsible for the reduced enzyme activity of the endoplasmic reticulum.     

Inhibition of long-chain acyl-CoA synthetase by the peroxisome proliferator perfluorodecanoic acid in rat hepatocytes

Perfluorodecanoic acid (PFDA) is a potent peroxisome proliferator and is known to affect hepatic lipid metabolism in rats. The effects of PFDA on fatty acid utilization were examined in isolated rat hepatocyte suspensions and in rat liver mitochondria and microsomes. PFDA inhibited the oxidation of palmitic acid but not octanoic or pyruvic acids when hepatocytes were incubated with 1 mM PFDA. At this PFDA concentration the esterification of palmitic acid into triacylglycerols was also reduced. The activity of long-chain acyl-CoA synthetase (ACS), an enzyme essential for both oxidation and esterification of fatty acids, was reduced in hepatocytes incubated with 1 mM PFDA. Carnitine palmitoyltransferase (CPT), an important enzyme for the oxidation of long-chain fatty acids, was not altered in hepatocytes incubated with this PFDA concentration. In rat liver mitochondria, palmitate oxidation and ACS activity were reduced significantly (P less than 0.01) at a PFDA concentration that had no effect on CPT activity. The inhibition of ACS by PFDA was similar in liver mitochondria and microsome preparations. In mitochondria incubated with PFDA, the inhibition of ACS appears to be noncompetitive for the substrates palmitic acid and CoA. However, the ACS inhibition by PFDA appeared to be competitive for the ATP binding site of the enzyme. Several chain length perfluorinated fatty acids were examined for their ability to inhibit mitochondrial ACS. Short-chain perfluorinated fatty acids (perfluoroproprionic and -butyric acid) did not inhibit ACS activity. However, medium-chain perfluorinated acids (perfluorooctanoic, -ananoic and -decanoic acid) were found to be potent inhibitors of ACS in isolated mitochondria. Whether ACS inhibition is causally related to PFDA-induced peroxisome proliferation and altered lipid metabolism seen in vivo is yet to be determined.     

海参磷脂型EPA对血清及肝脏脂肪酸组成的改善作用

目的 本文研究了海参磷脂型EPA(Eicosapntemacnioc acid-enriched phosphatidylcholine from sea cucumber,EPA-PC) 对非酒精性脂肪肝(Nonalcoholic fatty live disease, NAFLD)大鼠血清和肝脏脂肪酸组成的改善作用。方法 以NAFLD大鼠为模型,灌胃EPA-PC 4w,检测血清中和肝脏中脂质水平及脂肪酸组成。结果 EPA-PC显著降低模型大鼠血清和肝脏总脂中甘油三酯(Triglyceride,TG)和总胆固醇(Total cholesterol,TC)水平,显著升高血清高密度脂蛋白(High density lipoprotein cholesterol,HDLC)/TC水平;显著升高血清和肝脏中多不饱和脂肪酸(Polyunsaturated fatty acids,PUFA)的比例,降低n6/n3PUFA比例,升高DHA比例,降低肝脏总脂和磷脂去饱和C18：1/C18：0指数的比例,改善脂肪酸组成。结论 EPA-PC可以使血清和肝脏脂质水平下降,改变血清和肝脏脂肪酸组成,使NAFLD大鼠脂质水平紊乱状态得到改进。     

Properties of the mitochondrial membrane and carnitine palmitoyltransferase in the periportal and the perivenous zone of the liver. Effects of chronic ethanol feeding

Rats were fed for 35 days a high-fat diet containing either 36% of total calories as ethanol (ethanol group) or an isocaloric amount of carbohydrate (control group). Then, mitochondria were isolated from the periportal and the perivenous zone of the liver in order to study the acinar heterogeneity of the effects of prolonged ethanol administration upon the properties of carnitine palmitoyltransferase I (CPT-I) and its membrane environment. Chronic ethanol ingestion selectively decreased CPT-I activity in periportal hepatocytes but equally increased enzyme sensitivity to malonyl-CoA and enzyme energy of activation in the two zones of the liver. In control animals, mitochondrial membrane showed higher fluidity and lower degree of saturation of phospholipid fatty acyl moieties in periportal than in perivenous hepatocytes. Prolonged ethanol feeding (i) decreased mitochondrial membrane fluidity; (ii) increased the proportion of palmitic acid and decreased that of arachidonic acid in mitochondrial phosphatidylcholine and phosphatidylethanolamine, whereas it drastically reduced the content of linoleic acid and concomitantly increased that of saturated and monoenoic fatty acids in cardiolipin; (iii) suppressed the disordering effects of the addition of ethanol to mitochondrial suspensions. All these ethanol-induced alterations of membrane fluidity and fatty acyl composition were not significantly different between periportal and perivenous mitochondria. In conclusion, chronic ethanol feeding changes the activity of CPT-I in a zone-selective manner but modifies both the regulatory properties of the enzyme and the properties of its lipid environment in a non-zone-selective manner. Hence factors in addition to the properties of the mitochondrial membrane seem to be involved in the ethanol-induced alterations of the CPT-I enzyme.     

An integrated metabonomic investigation of acetaminophen toxicity in the mouse using NMR spectroscopy

An integrated metabonomics study using high-resolution 1H NMR spectroscopy has been applied to investigate the biochemical composition of intact liver tissue (using magic angle spinning), liver tissue extracts, and blood plasma samples obtained from control and acetaminophen-treated mice. Principal components analysis was used to visualize similarities and differences in biochemical profiles. The time- and dose-dependent biochemical effects of acetaminophen were related to the drug toxicity, as determined using histopathology. Metabolic effects in intact liver tissue and lipid soluble liver tissue extracts from animals treated with the high dose level of acetaminophen included an increase in lipid triglycerides and monounsaturated fatty acids together with a decrease in polyunsaturated fatty acids, indicating mitochondrial malfunction with concomitant compensatory increase of peroxisomal activity. In addition, a depletion of phospholipids was observed in treated liver tissue, which suggested an inhibition of enzymes involved in phospholipid synthesis. There was also a depletion in the levels of liver glucose and glycogen. In addition, the aqueous soluble liver tissue extracts from high dose animals also revealed an increase in lactate, alanine, and other amino acids, together with a decrease in glucose. Plasma spectra showed increases in glucose, acetate, pyruvate, and lactate. These observations all provide evidence for an increased rate of glycolysis. These findings could indicate a mitochondrial inability to use pyruvate in the citric acid cycle and also reveal the impairment of fatty acid beta-oxidation in liver mitochondria of such treated mice.     

Protective role of 20-OH ecdysone on lipid profile and tissue fatty acid changes in streptozotocin induced diabetic rats

Hyperlipidemia is an associated complication of diabetes mellitus. The association of hyperglycemia with an alteration of lipid parameters presents a major risk for cardiovascular complications in diabetes. The present study was designed to examine the antihyperlipidemic effect of 20-OH ecdysone on lipid profile and tissue fatty acid changes in streptozotocin induced diabetic rats. The levels of blood glucose, cholesterol, triglycerides, free fatty acids, phospholipids, low density lipoprotein, very low density lipoprotein, high density lipoprotein, lipoprotein lipase, lecithin cholesterol acyl transferase, 3-hydroxy 3-methylglutaryl coenzyme A reductase and fatty acid composition were estimated in plasma, liver and kidneys of control and experimental groups of rats. Oral administration of 20-OH ecdysone at a dose of 5 mg/kg bodyweight per day to STZ-induced diabetic rats for a period of 30 days resulted in a significant reduction in fasting blood glucose, cholesterol, triglycerides, free fatty acids, phospholipids, low density lipoprotein, very low density lipoprotein, 3-hydroxy 3-methylglutaryl coenzyme A reductase and elevation of high density lipoprotein, lipoprotein lipase and lecithin cholesterol acyl transferasein comparison with diabetic untreated rats. Moreover, administration of 20-OH ecdysone to diabetic rats also decreased the concentrations of fatty acids, viz., palmitic, stearic (16:1) and oleic acid (18:1), whereas linolenic (18:3) and arachidonic acid (20:4) were elevated. The antihyperlipidemic effect of 20-OH ecdysone was compared with glibenclamide a well-known antihyperglycemic drug. The result of the present study indicates that 20-OH ecdysone showed an antihyperlipidemic effect in addition to its antidiabetic effect in experimental diabetes.     

Lipid metabolism in liver of rat exposed to cadmium.

We investigated the effect of exposition to cadmium (Cd, 15ppm for 8 weeks) through drinking water on liver lipid metabolism in adult male Wistar rats. As compared to metal non-exposed (control) rats, the serum triglycerides, cholesterol and LDL+VLDL cholesterol concentrations increased. This was associated to a decrease of lipoprotein lipase activity in post heparinic plasma. The VLDL secretion from liver was not modified. Cd treatment increased triglycerides and decreased esterified cholesterol contents in liver. The high triglyceride mass was related to the increased glycerol-3-phosphate acyltransferase mRNA expression. In addition, the liver fatty acids synthesis increased, as determined by an increment of fatty acid synthetase and isocitrate dehydrogenase activities, and [(14)C]-acetate incorporation into saponifiable lipid fraction. The relative percentage of palmitic acid (16:0) and total saturated fatty acids were increased compared with control. Hepatic glucose-6-phosphate dehydrogenase, malic dehydrogenase and cholesteryl ester hydrolase activities were unchanged. In liver, the Cd treatment decreased triglyceride and cholesterol in mitochondria, also increased triglyceride in cytosol, and cholesterol and phospholipid contents in nuclei, compared with control. In addition, an increase of nuclei phosphatidylcholine synthesis was observed. Cd exposure alters directly or indirectly the serum lipid content and liver lipid metabolism.     

Effect of long term fluoride exposure on lipid composition in rat liver

Chronic fluorosis can severely damage many systems of human body, but its pathogenesis is unclear. Normal composition and structure of cellular membrane lipids are a basic factor to maintain cell function. In this investigation, cellular membrane lipids of the liver were analysed after a long term fluoride treatment for rats and the results are discussed in order to give an explanation for the pathogenesis of this disease. Wistar rats were supplied with drinking water containing either 30 or 100 ppm fluoride (NaF) for seven months. Contents of phospholipid and neutral lipid in rat liver were analyzed by high-performance liquid chromatography, and fatty acid composition from individual phospholipids was measured by gas chromatography. Results showed that the total liver phospholipid content decreased in the rats treated with high dose of fluoride due to a lower content of phosphatidylethanolamine (PE), phosphatidylcholine (PC) and phosphatidylserine (PS). Among the fatty acid compositions of PE and PC in the livers of fluoride poisoned animals, the proportion of polyunsaturated fatty acids (20:4 and 22:6) decreased, whereas saturated fatty acids (16:0 and 18:0) increased. No changes could be detected in the amounts of liver cholesterol and dolichol. Total ubiquinone contents in rat liver were reduced by 11% in the group treated with 30 ppm fluoride and by 42% in the group treated with 100 ppm fluoride. In the subclasses of ubiquinone, both ubiquinone-9 and ubiquinoine-10 amounts decreased after fluoride treatment. These modifications of membrane lipids might be induced by oxidative stress, which might be an important factor in the pathogenesis of chronic fluorosis.     

Fatty acid content and composition of phospholipids bound to the hepatic endoplasmic reticulum of the rat: effect of pregnancy

Phospholipid and fatty acid content were decreased and fatty acid composition of hepatic microsomes was altered in the rat during pregnancy. These changes were reversible 2 to 3 weeks after parturition. Pregnancy-related fatty acid changes were mainly localized in phosphatidylcholine and -ethanolamine fractions. Both saturated and unsaturated fatty acids were altered, but the reduction of the unsaturated fraction was more pronounced. Saturated acyl components, such as palmitic, stearic, and lignoceric acids, and unsaturated ones, including palmitoleic, oleic, linoleic, eicosatrienoic, arachidonic, and eicosapentaenoic acids, were significantly decreased, whereas only docosahexaenoic acid was elevated. Fatty acid changes were greater in the unsaturated components in phosphatidylcholine and -ethanolamine fractions. The largest reduction was in palmitic, palmitoleic, stearic, oleic, linoleic, arachidonic, and eicosahexaenoic acid content. Pregnancy-related changes in fatty acid distribution and content, and in phospholipid fractions reflect a modified organization and disposition of the hepatic endoplasmic reticulum membranes. These membrane changes represent essentially topographical factors influencing the function and enzymatic activity of these membranes.     

Effect of butylated hydroxytoluene on the lipid composition of rat liver

Hepatic lipids were studied in Sprague-Dawley male rats given butylated hydroxytoluene (BHT) at a level of 1.20% for 1 week. BHT significantly increased cholesterol esters and phospholipids but decreased triglycerides, non-esterified fatty acids and diglycerides. BHT also increased phosphatidylethylanolamine or decreased phosphatidylinositol and lysophosphatidylcholine. Fatty acid composition of each lipid class was also changed by BHT-feeding. The decrease in $\text{16:}\text{1}\text{16}\text{:0, 18:}\text{1}\text{18}\text{:0}\text{and}\text{20:}\text{4}\text{18}\text{:2}$ ratios of total lipids, non-esterified fatty acids or phospholipids of BHT-given rats suggests that BHT decreases the activity of fatty acid desaturase in the liver.     

Long-term effects of a single oral dose of polybrominated biphenyls on serum and liver lipids in rats

Adult (5 months) male Sherman strain rats received a single dose of either 0 or 500 mg polybrominated biphenyls (PBB) in corn oil/kg body weight by stomach tube. After an 18-month recovery period, serum and liver samples were examined. The primary serum lipid response was an increase in cholesterol (both free and esterified) and in total phospholipids. The percentage of esterified cholesterol was not significantly different from that of the controls, and no significant differences in the cholesterol ester fatty acid composition were observed. Serum triglycerides were also unaffected. In the PBB-dosed animals, the total hepatic fatty acids contained significantly less palmitic acid and more stearic acid, consistent with an increase in palmitic acid chain elongation activity. No significant differences could be detected in the n-3 or n-6 acids except for a slight decline in the content of 22:6 (n-3). Hepatic microsomal phospholipids were slightly higher (per milligram protein) in the PBB-dosed animals, and the cholesterol content was lower. Consequently, the cholesterol-phospholipid ratio was reduced, and microsomes from the latter group appeared to have an altered lipid domain on the basis of steady-state fluorescence anisotrophy measurements. In addition, total hepatic thiobarbituric acid-reactive substances (assayed as malondialdehyde) were significantly increased in the PBB-dosed animals. This observation appeared to reflect an increased susceptibility to peroxidative stress in the latter group, probably resulting from reduced membrane antioxidant concentrations. The PBB-dosed rats had significantly lower serum retinol levels and a reduced content of this vitamin in liver microsomes. Microsomes were also deficient in alpha-tocopherol in the PBB-dosed animals, although serum levels were normal.     

Effects of dietary fat level and aflatoxin B1 treatment on rat hepatic lipid composition

Sprague-Dawley rats were given either ten daily doses of aflatoxin B₁ (AFB₁) or the solvent tricaprylin intragastrically over a 2-wk period and were fed diets containing either 1.6 or 20% corn oil throughout the study. Hepatic lipid composition was analysed in groups of five rats both 3 and 13 wk after the start of treatment, in order to determine short-term and longer-term alterations. Total lipid and cholesterols (total, free and esterified) increased on the high-fat diet at wk 3. At wk 13 only total and esterified cholesterol were increased by 20% corn oil. AFB₁ treatment resulted in large intra-group variations in total lipid and cholesterol at wk 3, but these were no longer apparent by wk 13. AFB₁ produced various alterations in the fatty acid composition of hepatic phosphatidylcholine (PC) and phosphatidylethanolamine (PE), apparent at wk 3 but not at wk 13. The unsaturation index decreased but no changes were seen in the saturated fatty acids. Only in animals fed 20% corn oil did AFB₁ result in significant changes in 18:2, 20:3 and 22:6 fatty acids, while 20:4 and 22:5 tended to decrease and 18:1 to increase in response to AFB₁ treatment with both diets in both phospholipids. The high-corn oil diet was found to increase 18:2, 22:6, and total unsaturation in PC and PE, while the ratio of 20:4 to 18:2 tended to decrease in these phospholipids, γ-Glutamyltranspeptidase, an indicator of liver damage, was significantly increased in AFB₁-treated animals, with the greatest increase over controls in those fed the high-fat diet.     

The effect of phenobarbital and carbon tetrachloride on fatty acid content and composition of phospholipids from the endoplasmic reticulum of rat liver

The fatty acid content and composition of hepatic microsomes of separated smooth and rough components and of isolated phosphatidylcholine and phosphatidylethanolamine fractions were studied in male albino rats treated with phenobarbital or carbon tetrachloride. Both test compounds significantly altered the fatty acid composition of the endoplasmic reticulum. The total amount was significantly raised by phenobarbital and reduced by carbon tetrachloride. Phenobarbital enhanced palmitic, stearic, arachidic, palmitoleic, linoleic, eicosenoic, eicosadienoic, eicosatrienoic, eicosapentenoic, docosatrienoic, and docosahexenoic acids. Carbon tetrachloride diminished all these, excluding palmitic and palmitoleic acids. The fatty acid content of rough microsomes was significantly increased by phenobarbital and decreased by carbon tetrachloride, while in smooth microsomes fatty acids were raised by phenobarbital but mainly unaffected by carbon tetrachloride. In microsomal phosphatidylcholine fractions, phenobarbital significantly elevated oleic, linoleic, eicosatrienoic, arachidonic, eicosapentenoic, docosapentenoic, and docosahexenoic acids, whereas all these were significantly reduced with carbon tetrachloride. In phosphatidylethanolamine fractions, phenobarbital increased palmitoleic, oleic, linoleic, and arachidonic acids; carbon tetrachloride elicited opposite effects on these acids. Phenobarbital increased and carbon tetrachloride reduced the fatty acid content in the phosphatidylcholine fraction of rough membranes. Opposite effects were seen in oleic, linoleic, arachidonic, and eicosapentenoic acids. Both test compounds brought about similar changes in the fatty acid composition of the phosphatidylethanolamine fractions of rough microsomes. In smooth microsomes, phosphatidylcholine fatty acids were significantly enhanced by phenobarbital and reduced by carbon tetrachloride. The fatty acid content of phosphatidylethanolamine was increased by phenobarbital, mainly manifesting in palmitoleic, oleic, linoleic, arachidonic, docosapentenoic, and docosahexenoic acids. Carbon tetrachloride elicited no major change in this fraction. Phenobarbital increased the production of unsaturated fatty acids, whereas carbon tetrachloride elevated the relative amount of saturated fatty acids. The saturated/unsaturated fatty acids ratio was reduced by phenobarbital and increased by carbon tetrachloride, and thus may indicate a selective difference between an inducer and hepatotoxin on fatty acid synthesis of the hepatic endoplasmic reticulum.