Hepatic Triacylglycerol Accumulation Research Articles

Adaptations to fasting in the American mink ( Mustela vison): carbohydrate and lipid metabolism

The aim of this study was to investigate whether the actively wintering American mink Mustela vison is strictly dependent on continuous food availability or if it has evolved physiological adaptations to tolerate nutritional scarcity. Fifty farm-bred male minks were divided into a fed control group and four experimental groups fasted for 2, 3, 5 or 7 days. The rate of weight loss was several-fold higher (1.5–3.2% day −1) in the mink than recorded previously in larger carnivores utilizing passive wintering strategies. The minks remained normoglycaemic, although their liver glycogen stores and glucose-6-phosphatase activities decreased during fasting. Adipose tissue constituted approximately 36% of their body mass after 7 days of food deprivation. Intra-abdominal fat, especially retroperitoneal but also mesenteric adipose tissue, were the most important fat depots to be hydrolyzed, but the ability of the mink to utilize its body lipids during fasting may be limited. The increased liver size, hepatic triacylglycerol accumulation and increases in the activities of plasma aminotransferases indicated liver dysfunction. Food deprivation also affected the red blood cell indices, and the blood monocyte and lymphocyte counts decreased suggesting immunosuppression during fasting. The results of the present study suggest that the mink has not evolved sophisticated adaptations to wintertime fasting.

Requirement of PPARα in maintaining phospholipid and triacylglycerol homeostasis during energy deprivation

The peroxisome proliferator-activated receptor alpha (PPARalpha) has been implicated as a key control of fatty acid catabolism during the cellular fasting. However, little is known regarding changes of individual fatty acids in hepatic triacylglycerol (TG) and phospholipid (PL) as a result of starvation. In the present work, the effects of 72 h fasting on hepatic TG and PL fatty acid profiles in PPARalpha-null (KO) mice and their wild-type (WT) counterparts were investigated. Our results indicated that mice deficient in PPARalpha displayed hepatomegaly and hypoketonemia following 72 h starvation. Histochemical analyses revealed that severe fatty infiltration was observed in the livers of KO mice under fasted conditions. Furthermore, 72 h fasting resulted in a 2.8-fold higher accumulation of hepatic TG in KO mice than in WT mice fasted for the same length of time. Surprisingly, the total hepatic PL contents in fasted KO mice decreased by 45%, but no significant change in hepatic PL content was observed in WT mice following starvation. Gas chromatographic analysis indicated that KO mice were deprived of arachidonic (20:4n-6) and docosahexaenoic (22:6n-3) acids during fasting. Taken together, these results show that PPARalpha plays an important role in regulation of fatty acid metabolism as well as phospholipid homeostasis during energy deprivation.

Alleviation of Fatty Liver by .ALPHA.-Linolenic Acid

We compared the efficacy of alpha-linolenic acid (alpha-LNA, n-3) and linoleic acid (LA, n-6) on orotic acid (OA)-induced fatty liver in Sprague-Dawley rats. Rats were fed semi-synthetic diets containing either LA or alpha-LNA with or without 1% OA for 2 wk. OA supplementation lowered serum lipids in LA+OA groups. In addition to the decline of serum lipids in alpha-LNA groups compared to LA groups, a further decrease was found in alpha-LNA+OA groups compared to LA+OA groups. OA-containing diets significantly increased the liver weights and triacylglycerol (TG) accumulations compared with the OA-free diets. These results were attributed to the significant increases in the activities of phosphatidate phosphohydrolase (PAP), a rate-limiting enzyme of TG synthesis, and glucose-6-phosphate dehydrogenase, a fatty acid synthesis-related enzyme. However, the increase of PAP activity was significantly less in the alpha-LNA+OA group as compared with the LA+OA group. These results suggest that dietary alpha-LNA alleviates OA-induced hepatic TG accumulation through the attenuation of hepatic TG synthesis in rats.

Dietary effect of pomegranate seed oil rich in 9cis, 11trans, 13cis conjugated linolenic acid on lipid metabolism in obese, hyperlipidemic OLETF Rats

Conjugated fatty acid, the general term of positional and geometric isomers of polyunsaturated fatty acids with conjugated double bonds, has attracted considerable attention because of its potentially beneficial biological effects. In the present study, dietary effect of pomegranate seed oil rich in punicic acid (9cis, 11trans, 13cis-conjugated linolenic acid; 9c, 11t, 13c-CLNA) on lipid metabolism was investigated in obese, hyperlipidemic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. After 2 weeks feeding period, OLETF rats revealed obesity and hyperlipidemia compared with their progenitor LETO rats. Feeding of the diet supplemented with 9% safflower oil and 1% pomegranate seed oil (9c, 11t, 13c-CLNA diet) did not affect abdominal white adipose tissue weights and serum lipid levels compared with the diet supplemented with 10% safflower oil (control diet) in OLETF rats. However, the accumulated hepatic triacylglycerol was markedly decreased by 9c, 11t, 13c-CLNA diet in OLETF rats. Activities of hepatic enzymes related to fatty acid synthesis and fatty acid β-oxidation were not altered by 9c, 11t, 13c-CLNA diet. Levels of monounsaturated fatty acid (MUFA), major storage form of fatty acid, in serum triacylglycerol were markedly higher in obese, hyperlipidemic OLETF rats than in lean LETO rats. In addition, 9c, 11t, 13c-CLNA diet significantly decreased MUFA levels in OLETF rats. This is the first study showing that 9c, 11t, 13c-CLNA suppresses delta-9 desaturation in vivo, and we suggest that the alleviation of hepatic triacylglycerol accumulation by 9c, 11t, 13c-CLNA diet was, at least in part, attributable to the suppression of delta-9 desaturation in OLETF rats.

The LXR ligand T0901317 induces severe lipogenesis in the db/db diabetic mouse

Liver X receptor (LXR) ligands are currently being evaluated as potential therapeutic agents for the treatment of low HDL. The LXR ligand T0901317 elevates ATP binding cassette transporter A1 (ABCA1) and HDL levels in animal models and induces moderate lipogenesis through upregulation of sterol regulatory element binding protein 1c (SREBP1c). Because insulin may also regulate lipogenesis through SREBP1c and fatty acid synthase (FAS), we investigated the effect of an LXR ligand in hyperinsulinemic mice. Administration of T0901317 to male db/db mice for 12 days resulted in a more severe hypertriacylglycerolemia and hepatic triacylglycerol accumulation than observed in nondiabetic mice. The LXR target genes ABCA1, SREBP1c, FAS, and stearoyl-CoA desaturase 1 were upregulated by T0901317 treatment in both diabetic db/db and nondiabetic C57BLKS mice. Changes in lipogenic gene expression were independent of mouse strain, indicating that the severe lipogenesis observed in LXR ligand-treated db/db mice was not due to additive effects of insulin on lipogenic gene expression. Phosphoenolpyruvate carboxykinase expression was suppressed, suggesting that a shift from gluconeogenesis toward lipogenesis could partially explain our observations in db/db mice. Our data suggest that LXR ligands that have effects on both fatty acid and carbohydrate metabolism should be carefully evaluated in obesity, insulin, and leptin resistance.

Peroxisome-proliferator-activated receptor-alpha (PPARalpha) deficiency leads to dysregulation of hepatic lipid and carbohydrate metabolism by fatty acids and insulin.

The aim of the present study was to determine whether peroxisome-proliferator-activated receptor-alpha (PPARalpha) deficiency disrupts the normal regulation of triacylglycerol (TAG) accumulation, hepatic lipogenesis and glycogenesis by fatty acids and insulin using PPARalpha-null mice. In wild-type mice, hepatic TAG concentrations increased (P<0.01) with fasting (24 h), with substantial reversal after refeeding (6 h). Hepatic TAG levels in fed PPARalpha-null mice were 2.4-fold higher than in the wild-type (P<0.05), increased with fasting, but remained elevated after refeeding. PPARalpha deficiency also impaired hepatic glycogen repletion (P<0.001), despite normal insulin and glucose levels after refeeding. Higher levels of plasma insulin were required to support similar levels of hepatic lipogenesis de novo ((3)H(2)O incorporation) in the PPARalpha-null mice compared with the wild-type. This difference was reflected by corresponding changes in the relationship between plasma insulin and the mRNA expression of the lipogenic transcription factor sterol-regulatory-element-binding protein-1c, and that of one of its known targets, fatty acid synthase. In wild-type mice, hepatic pyruvate dehydrogenase kinase (PDK) 4 protein expression (a downstream marker of altered fatty acid catabolism) increased (P<0.01) in response to fasting, with suppression (P<0.001) by refeeding. Although PDK4 up-regulation after fasting was halved by PPARalpha deficiency, PDK4 suppression after refeeding was attenuated. In summary, PPARalpha deficiency leads to accumulation of hepatic TAG and elicits dysregulation of hepatic lipid and carbohydrate metabolism, emphasizing the importance of precise control of lipid oxidation for hepatic fuel homoeostasis.

Effect of dietary oils enriched with n-3 fatty acids on survival of mice

Female mice were fed a conventional diet, shifted at 119 days of age to a diet supplemented with 10 wt % lard (Lar), high-linoleic (n-6) safflower oil (Saf), rapeseed oil (low-erucic, Rap), high-α-linolenic (n-3) perilla oil (Per) or a mixture (1:9) of ethyl docosahexaenoate (n-3) and soybean oil (DHA/Soy). Weight gain was less in the Per group than in the other groups at 497 days of age. In the Rap group, proteinuria was more severe than in the Saf, Per and DHA/Soy group, and hepatic triacylglycerol accumulation was greater than in the other groups. The mean survival time of the DHA/Soy group (753 days) was significantly longer than in the Lar group (672 days) and Saf group (689 days); the differences among other groups (e.g., 701 days in the Per group and 712 days in the Rap group) were not statistically significant. Although DHA is more susceptible to auto-oxidation than other major fatty acids in the air, an oil containing DHA was found to increase the survival of mice. Rapeseed oil that decreases the survival time of SHRSP rats was found to be safe in the mouse strain used in this study when survival was an end point.

Effect of hesperetin, a citrus flavonoid, on the liver triacylglycerol content and phosphatidate phosphohydrolase activity in orotic acid-fed rats.

The effect of dietary hesperetin on the hepatic lipid content and the enzyme activities involved in triacylglycerol (TG) synthesis in rats fed diets with or without 1% orotic acid (OA) was studied. Hepatic TG content was raised by approximately 5-fold after administration of OA for 10 days. The OA-feeding significantly increased the activity of hepatic microsomal phosphatidate phosphohydrolase (PAP), which is the rate-limiting enzyme for TG synthesis. Hepatic glucose-6-phosphate dehydrogenase (G6PDH) and malic enzyme activities were also increased. An addition of 1% hesperetin to the OA-supplemented diet resulted in the decrease of the hepatic TG content by 44% and of microsomal PAP activity. Dietary hesperetin alone neither affected liver TG content nor PAP activity significantly. OA-feeding caused an increased liver cholesterol level, whereas simultaneous addition of hesperetin and OA reduced its content to the control level. A slight reduction of hepatic cholesterol by hesperetin was also observed in the OA-free dietary group. The present study demonstrated that dietary hesperetin can reduce the hepatic TG accumulation induced by OA, and this was associated with the reduced activity of TG synthetic enzyme, PAP.

Effects of milk diets containing beef tallow or coconut oil on the fatty acid metabolism of liver slices from preruminant calves

Coconut oil (CO) induces a triacylglycerol infiltration in the hepatocytes of preruminant calves when given as the sole source of fat in the milk diet over a long-term period. Metabolic pathways potentially involved in this hepatic triacylglycerol accumulation were studied by in vitro methods on liver slices from preruminant Holstein x Friesian male calves fed a conventional milk diet containing CO (n 5) or beef tallow (BT, n 5) for 19 d. Liver slices were incubated for 12 h in the presence of 0.8 mm-[14C]oleate or -[14C]laurate added to the medium. Fatty acid oxidation was determined by measuring the production of CO2 (total oxidation) and acid-soluble products (partial oxidation). Production of CO2 was 1. 7-3.6-fold lower (P 0.0490) and production of acid-soluble products tended to be lower (P = 0.0625) in liver slices of CO- than BT-fed calves. Fatty acid esterification as neutral lipids was 2.6- to 3. 1-fold higher (P = 0.0088) in liver slices prepared from calves fed the CO diet compared with calves fed the BT diet. By contrast with what occurs in the liver of rats fed CO, the increase in neutral lipid production did not stimulate VLDL secretion by the hepatocytes of calves fed with CO, leading to a triacylglycerol accumulation in the cytosol. It could be explained by the reduction of fatty acid oxidation favouring esterification in the form of triacylglycerols, in association with a limited availability of triacylglycerols and/or apolipoprotein B for VLDL packaging and subsequent secretion.

Differential channelling of liver lipids in relation to susceptibility to hepatic steatosis in the goose

In response to overfeeding for the production of “foie gras,” the Poland goose differs from the Landes goose by a lesser susceptibility to hepatic steatosis, resulting in a lower accumulation of hepatic triacylglycerol (TG), together with a greater exportation of hepatic phospholipid (PL) in very low density lipoproteins (VLDL) and high density lipoproteins (HDL) (Fournier et al., 1997). A study was designed 1) to compare the liver composition in overfed and nonoverfed geese of the two breeds of geese and 2) to determine whether the differential channelling of lipids in response to overfeeding is reflected in the PL and fatty acid profiles of the different hepatic lipids, whether stored or secreted. In nonoverfed geese, there were no breed-related differences in liver weight (approximately 90 to 100 g), hepatic lipid content (3 to 4%), and lipid and PL composition. However, plasma VLDL and HDL of the Landes breed contained a higher phosphatidylcholine (PC) to phosphatidylethanolamine (PE) ratio than those of the Poland breed (20.7 and 33.8 vs 12.6 and 25.6 in VLDL and HDL, respectively). After 14 d of overfeeding, hepatic PL profiles were identical in the two breeds and similar to that in control livers; choline-containing PL accounted for 95% of total PL. In contrast, plasma HDL concentrations of the Landes geese were lower than those of the Poland geese (9.4 vs 12.9 g/L) and their PC:PE (13.6%) and PL-polyunsaturated fatty acids (PUFA) content (25%) were decreased compared with the Poland geese (21.2 and 30%). It is likely that the higher susceptibility to fatty liver of the Landes breed involves a differential channelling of PL, resulting in a greater hepatic retention of PC and PUFA that are necessary for plasma membrane growth and cell hypertrophy.

Effects of dietary coconut oil on fatty acid oxidation capacity of the liver, the heart and skeletal muscles in the preruminant calf

The oxidative capacity of the liver, the heart and skeletal muscles for fatty acids were investigated in preruminant calves fed for 19 d on a milk-replacer containing either coconut oil (CO, rich in 12:0) or tallow (rich in 16:0 and 18:1). Weights of the total body and tissues did not differ significantly between the two groups of animals but plasma glucose and insulin concentrations were lower in the CO group. Feeding on the CO diet induced an 18-fold increase in the hepatic concentration of triacylglycerols. Rates of total and peroxisomal oxidation of [1-14C]laurate, [1-14C]palmitate and [1-14C]oleate were measured in fresh tissue homogenates. Higher rates of total oxidation in liver homogenate and of peroxisomal oxidation in liver, heart and rectus abdominis muscle homogenates were observed with laurate used as substrate. Furthermore, the relative contribution of peroxisomes to total oxidation was 1.9-fold higher in the liver and in the heart with laurate than with oleate or palmitate. Finally, the peroxisomal oxidation rate of oleate was 1.5-fold higher in the hearts of calves fed on the CO diet. Whatever the tissue, citrate synthase (CS, EC 4.1.3.7) and cytochrome c oxidase (COX, EC 1.9.3.1) activities were similar between the two groups of calves but the COX: CS activity ratio was lower in the liver of the CO group. In conclusion, laurate is better catabolized by peroxisomes than long-chain fatty acids, especially in the liver. Elongation of lauric acid after partial oxidation might explain the hepatic triacylglycerol accumulation in calves fed on the CO diet.

Association between hepatic triacylglycerol accumulation induced by administering orotic acid and enhanced phosphatidate phosphohydrolase activity in rats.

Orotic acid is known to cause fatty liver, but it is unclear whether this is caused partly by stimulation of the enzymes for triacylglycerol (TG) synthesis. To understand the change of hepatic TG metabolism in fatty liver induced by orotic acid, we determined the liver tissue TG level and phosphatidate phosphohydrolase (PAP) activity over time in rats fed on a diet containing orotic acid (OA). A dietary lipid content of 10% was achieved by using n-6 fatty acid-rich corn oil in experiment 1, and n-6 fatty acid-rich safflower oil (SO) and n-3 fatty acid-rich fish oil (FO) with the same polyunsaturated fatty acid/monounsaturated fatty acid/saturated fatty acid (P/M/S) ratio in experiment 2. In experiment 1, an increase in the hepatic TG level due to OA intake was observed from day 5 onwards, the level rising approximately 6-fold by day 10. The activity of hepatic microsomal PAP, the rate-limiting enzyme in TG synthesis, increased markedly from day 5 onwards, concurrent with the liver diacylglycerol concentration. A strong correlation (r = 0.974) was observed between the hepatic TG level and microsome-bound PAP activity. In experiment 2, we investigated the effects of dietary fatty acid on OA-induced fatty liver. Compared with the n-6 fatty acid-rich vegetable oil diet, the relative increase in hepatic TG was smaller with the n-3 fatty acid-rich FO diet, and hepatic PAP activity fell markedly to the level for an OA-free diet. In addition, the hepatic TG accumulation and serum TG concentration were lower in the FO group than in the SO group. Nevertheless, because the hepatic TG level was low, it seems that the inhibition of liver PAP activity by FO possibly had a strong influence on the accumulation of TG in the liver. In conclusion, enhanced TG synthesis mediated by changes in liver PAP activity was involved in the hepatic TG accumulation induced by OA administration, this change being markedly suppressed by dietary n-3 fatty acids.

Effects of physical training on fatty acid metabolism in liver and skeletal muscle of rats fed four different high-carbohydrate diets

The adaptation of regulatory enzymes of fatty acid metabolism to endurance training and to the administration of four different diets containing fructose, sucrose, maltodextrins, or starch as carbohydrate (CH) was studied in rat liver and skeletal muscle (soleus). (i) In the soleus, physical training induced carnitine palmitoyltransferase I (CPT-I) acitivity upon complex (but not simple) CH feeding, whereas citrate synthase activity was enhanced by endurance exercise in the four different diets. No effect of diet or training was evident on glycerol 3-phosphate acyltransferase (G3PAT) activity or intramuscular triacylglycerol content. Glycogen levels were notably diminished in the soleus of trained rats fed simple-CH diets compared with their corresponding sedentary controls. (ii) In liver, CPT-I activity was depressed in trained animals fed the fructose diet, whereas citrate synthase was induced by endurance exercise in the four different diets. The activity of key lipogenic enzymes (acetyl-CoA carboxylase, fatty acid synthase, G3PAT) was induced by simple-CH feeding, and this increase was blunted by physical exercise. However, triacylglycerol accumulation and glycogen depletion ensued in liver of trained rats fed simple-CH diets. In these animals this was accompanied by a remarkable decrease of serum triacylglycerol levels and a strong increase of circulating non-esterified fatty acids (NEFA) and glycerol. Results thus suggest that in trained rats fed simple-CH diets (i) the preferential mobilization of adipose tissue triacylglycerols, by increasing the availability of circulating NEFA, may be responsible for liver triacylglycerol accumulation as well as for liver and muscle glycogen depletion, and (ii) decreased triacylglycerol secretion by the liver—but not changes in the activity of regulatory lipogenic enzymes—may be involved in hepatic triacylglycerol accumulation.

Aspirin promotes hepatic triacylglycerol accumulation in essential fatty acid-deficient Japanese quail.

This study was conducted to investigate whether the effect of a high dose of aspirin on hepatic triacylglycerol content is altered by dietary essential fatty acids (EFA) in Japanese quail. The birds were given an EFA-free or EFA-adequate [containing 2% (w/w) linoleic acid] diet ad libitum from 7 to 24 days of age. On the final experimental day, the birds received vehicle or 800 mg aspirin/kg body weight intraperitoneally and were killed 4 h subsequently. In birds fed the EFA-free diet, hepatic triacylglycerol content was more than 2 times higher after aspirin compared with vehicle treatment; in contrast, aspirin had no affect in birds fed the EFA-adequate diet. Liver malic enzyme and phosphatidate phosphohydrolase activities, which are related to lipid synthesis, were not affected by dietary EFA or aspirin treatment. Liver carnitine palmitoyltransferase activity in the birds fed the EFA-free diet was significantly lower than that in the birds fed the EFA-adequate diet, but aspirin did not affect this activity. In groups given the EFA-free diet, peroxisomal beta-oxidation was increased by the aspirin treatment. We conclude that acute administration of aspirin to Japanese quail on an EFA-free diet induces hepatic triacylglycerol accumulation, and that changes in lipid synthesis and degradation do not contribute to this phenomenon.

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.

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.

What factors control hepatic triacylglycerol accumulation in alcohol abuse?

Conference Article| June 01 1988 What factors control hepatic triacylglycerol accumulation in alcohol abuse? DAVID N. BRINDLEY DAVID N. BRINDLEY * 1Department of Biochemistry, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, U.K. Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1988) 16 (3): 251–253. https://doi.org/10.1042/bst0160251 Article history Received: December 11 1987 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation DAVID N. BRINDLEY; What factors control hepatic triacylglycerol accumulation in alcohol abuse?. Biochem Soc Trans 1 June 1988; 16 (3): 251–253. doi: https://doi.org/10.1042/bst0160251 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search Keywords: VLDL, very low density lipoprotein This content is only available as a PDF. © 1988 Biochemical Society1988 Article PDF first page preview Close Modal You do not currently have access to this content.

Fatty acid synthesis and triacylglycerol accumulation in rat liver after chronic ethanol consumption.

1. Liver slices from chronically alcohol-fed rats incubated with 3H2O showed less than half the fatty acid synthesis rates of pair-fed controls. Addition of 50 mmol/l ethanol or of 10 mmol/l lactate and 1 mmol/l pyruvate to the incubation medium did not alter the fatty acid synthesis rates in either groups. Hepatic fatty acid synthesis rates measured in vivo with 3H2O were also significantly reduced in alcohol-fed rats. 2. Time-course experiments showed that after 1 week on the ethanol diet hepatic fatty acid synthesis rates in vitro were similar to control rats, although the liver triacylglycerol content was significantly increased. From the second week of feeding, fatty acid synthesis rates were significantly lower in alcohol-fed rats and the liver triacylglycerol content progressively increased compared with controls. 3. Fatty acid synthase activity in liver cytosolic fractions were similar to controls in the alcohol-fed group after 1 week of feeding but were significantly lower in alcohol-fed rats from the second week onwards. 4. These results indicate that hepatic triacylglycerol accumulation after alcohol feeding is not due to increased fatty acid synthesis. The reduced fatty acid synthesis observed is a consequence of triacylglycerol accumulation.

Metabolism and Function of myo-Inositol and Inositol Phospholipids

Alterations in the level of dietary inositol can significantly influence the concentration of free inositol and inositol-containing phospholipid in the circulation and in selected mammalian tissues and cells. The 1-stearoyl 2-arachidonyl molecular species that commonly predominates in cellular phosphoinositides may be of considerable importance for the functioning of these phospholipids in biological membranes. Retailoring reactions subsequent to the de novo biosynthesis of PI involving the acylation of lyso(1-acyl) PI allow for the preferential enrichment of this phospholipid in arachidonic acid. The impaired release of plasma lipoprotein, increased fatty acid mobilization from adipose tissue, and enhanced fatty acid synthesis in liver have all been implicated as causative factors in the hepatic triacylglycerol accumulation occurring with experimental inositol deficiency. The severe intestinal lipodystrophy that develops in female gerbils consuming inositol-deficient diets is likely mediated by a reduced synthesis of PI and the associated impairment of chylomicron assembly and secretion. Membrane PI can potentially regulate enzyme activities and transport processes as well as providing a source of free arachidonic acid for production of the eicosanoids. There has been mounting evidence recently to indicate that an accelerated turnover of the phosphoinositides may play a key role in mediating cellular responses to external stimuli. The transient rise of phosphoinositide-derived 1,2-diacylglycerol in stimulated cells may serve as a signal for the transmembrane control of protein phosphorylation by activating protein kinase C. Receptor occupancy also elicits the phosphodiesterase-catalyzed release of the second messenger inositol 1,4,5-trisphosphate, which appears to provide for the mobilization of calcium from internal stores. Subnormal levels of free inositol and inositol phospholipid, as found in the nerves of animals with experimental diabetes and in sciatic nerves removed postmortem from diabetic patients, have been implicated in the impaired nerve conduction of human diabetics. Patients with renal failure exhibit a dramatic hyperinositolemia that may have clinical significance. Nutritional intervention may offer an approach for counteracting abnormalities in inositol and inositol phospholipid profiles and associated physiological responses in certain disease states.

Hepatic triacylglycerol synthesizing activity during progression of alcoholic liver injury in the baboon.

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.

Inhibitory effect of D-galactosamine administration on fatty acid oxidation in rat hepatocytes

and viral hepatitis have been emphasized [l]. The necrosis induced by GaIN is however accompanied by hepatic triacylglycerol (TAG) accumulation [2], an association not present in human viral hepatitis. as 3 h after a single dose of GaIN. Having confirmed that no increase in the serum FFA level is apparent at this stage of intoxication, this preliminary report was devoted to the study of the rate of fatty acid oxidation in isolated hepatocytes and mitochondria from GaIN treated rats.