Predictors of Organ Donation Among Patients With Brain Death in the Intensive Care Unit.

INTRODUCTION: Despite the improved care of potential organ donors with probable brain death (BD) in the intensive care unit (ICU), few epidemiologic and clinical data are available in developing countries. OBJECTIVES: To evaluate ICU patients with suspected BD aiming to identify factors possibly related to success (organ donation) or failure (nondonation). METHODS: Retrospective cohort study, from the patient records of an adult ICU of a Brazilian teaching hospital for 12 months. Data were tabulated, and descriptive statistics and univariate and multivariate analyses were performed. RESULTS: During the study period, 85 patients with acute neurologic diseases and suspected BD were admitted to the ICU and included for analysis. Of these, there were 9 organ donors (7 liver and 9 kidney donors); 77.7% were men, with a mean age of 39.6 years and admission Acute Physiology and Chronic Health Evaluation II of 25.5. Two-thirds of the patients were victims of trauma. The mean time between acute neurologic event and organ withdrawal was 269 hours. The main prognostic factors related to the success of organ donation were the maximum serum lactate and creatinine levels during ICU admission. CONCLUSIONS: The main clinical factors correlated with nonevolution for organ donation among ICU patients with clinical suspicion of BD were related to patient severity and organic dysfunction: serum lactate and creatinine level. Clinical care and monitoring are emphasized to improve the efficiency of the donation process.

Essential fatty acid synthesis and its regulation in mammals.

The tissue content of highly unsaturated fatty acids (HUFA) such as arachidonic acid and docosahexaenoic acid is maintained in a narrow range by feedback regulation of synthesis. Delta-6 desaturase (D6D) catalyzes the first and rate-limiting step of the HUFA synthesis. Recent identification of a human case of D6D deficiency underscores the importance of this pathway. Sterol regulatory element binding protein-1c (SREBP-1c) is a key transcription factor that activates transcription of genes involved with fatty acid synthesis. We recently identified sterol regulatory element (SRE) that is required for activation of the human D6D gene by SREBP-1c. Moreover, the same SRE also mediates the suppression of the D6D gene by HUFA. The identification of SREBP-1c as a key regulator of D6D suggests that the major physiological function of SREBP-1c in liver may be the regulation of phospholipid synthesis rather than triglyceride synthesis. Peroxisome proliferators (PP) induce fatty acid oxidation enzymes and desaturases in rodent liver. However, the induction of desaturases by PP is slower than the induction of oxidation enzymes. This delayed induction may be a compensatory reaction to the increased demand of HUFA caused by increased HUFA oxidation and peroxisome proliferation in PP administration. Recent studies have demonstrated a critical role of peroxisomal beta-oxidation in DHA synthesis, and identified acyl CoA oxidase and D-bifunctional protein as the key enzymes.

Gene regulation of mammalian desaturases.

Stearoyl-CoA desaturase (SCD) catalyses the synthesis of oleic acid (18:1, n -9), which is mostly esterified into triacylglycerols (TAGs) as an energy reserve. Delta-6 Desaturase (D6D) and Delta-5 desaturase (D5D) are the key enzymes for the synthesis of highly unsaturated fatty acids (HUFAs), such as arachidonic acid (20:4, n -6) and docosahexaenoic acid (22:6, n -3), that are incorporated in phospholipids (PLs) and perform essential physiological functions. Despite these different physiological roles of SCD and D6D/D5D, these desaturases share common regulatory features, including dependence of expression on insulin, suppression by HUFAs, and induction by peroxisome proliferators (PPs). A key regulator of desaturase gene expression is sterol-regulatory element binding protein-1c (SREBP-1c), which mediates transcriptional activation of the SCD and D6D genes by insulin and inhibition by HUFAs. Because HUFAs are poorly incorporated into TAGs, the primary role of SREBP-1c in liver may be monitoring and regulating fatty acid composition in PLs rather than the regulation of TAG synthesis. The induction of desaturases by PPs is enigmatic because the major effect of PPs is induction of fatty acid oxidation enzymes by activating PP-activated receptor-alpha (PPARa). To our knowledge, no other gene that is induced by both SREBP-1 and PP has been identified. It is yet to be determined whether PPARa mediates the process directly. Available data suggest that the induction of desaturases by PPs may be a compensatory response to an increased demand for unsaturated fatty acids because PPs increase fatty acid degradation and induce proliferation of peroxisomes.

Metabolism and functions of highly unsaturated fatty acids: an update.

This review briefly examines the recent progress in knowledge about the synthesis and degradation of highly unsaturated fatty acids (HUFA) and their functions. Following the cloning of mammalian Delta6-desaturase (D6D), the D6D mRNA was found in many tissues, including adult brain, maternal organs, and fetal tissue, suggesting an active synthesis of HUFA in these tissues. The cloning also confirmed the long-postulated hypothesis that the same pathway is followed in n-6 and n-3 HUFA synthesis. Dietary n-6 and n-3 HUFA both induce fatty acid oxidation enzymes in peroxisomes when compared to their respective precursor polyunsaturated fatty acids. This suggests that peroxisomes may be the primary site of HUFA degradation when HUFA are supplied in excess from the diet. Peroxisome proliferators strongly induce the enzymes for the HUFA synthesis. The mechanism of this induction is currently unknown. Recent studies revealed new HUFA functions that are not mediated by eicosanoids. These functions include endocytosis/exocytosis, ion-channel modulation, DNA polymerase inhibition, and regulation of gene expression. These new discoveries will enable us to re-examine the underlying mechanisms for the classical symptoms of essential fatty acid deficiency as well as vitamin E deficiency. Progress has also been made in understanding the mechanism by which dietary HUFA reduce body fat deposition. One mechanism is induction of genes for fatty acid oxidation, which is mediated by peroxisome proliferator-activated receptor-alpha. Another likely mechanism is that HUFA suppress genes for fatty acid synthesis by reducing both mRNA and protein maturation of sterol regulatory element binding protein-1.

Involvement of a unique carbohydrate-responsive factor in the glucose regulation of rat liver fatty-acid synthase gene transcription.

Refeeding carbohydrate to fasted rats induces the transcription of genes encoding enzymes of fatty acid biosynthesis, e.g. fatty-acid synthase (FAS). Part of this transcriptional induction is mediated by insulin. An insulin response element has been described for the fatty-acid synthase gene region of -600 to +65, but the 2-3-fold increase in fatty-acid synthase promoter activity attributable to this region is small compared with the 20-30-fold induction in fatty-acid synthase gene transcription observed in fasted rats refed carbohydrate. We have previously reported that the fatty-acid synthase gene region between -7382 and -6970 was essential for achieving high in vivo rates of gene transcription. The studies of the current report demonstrate that the region of -7382 to -6970 of the fatty-acid synthase gene contains a carbohydrate response element (CHO-RE(FAS)) with a palindrome sequence (CATGTGn(5)GGCGTG) that is nearly identical to the CHO-RE of the l-type pyruvate kinase and S(14) genes. The glucose responsiveness imparted by CHO-RE(FAS) was independent of insulin. Moreover, CHO-RE(FAS) conferred glucose responsiveness to a heterologous promoter (i.e. l-type pyruvate kinase). Electrophoretic mobility shift assays demonstrated that CHO-RE(FAS) readily bound a unique hepatic ChoRF and that CHO-RE(FAS) competed with the CHO-RE of the l-type pyruvate kinase and S(14) genes for ChoRF binding. In vivo footprinting revealed that fasting reduced and refeeding increased ChoRF binding to CHO-RE(FAS). Thus, carbohydrate responsiveness of rat liver fatty-acid synthase appears to require both insulin and glucose signaling pathways. More importantly, a unique hepatic ChoRF has now been shown to recognize glucose responsive sequences that are common to three different genes: fatty-acid synthase, l-type pyruvate kinase, and S(14).

Polyunsaturated fatty acids suppress hepatic sterol regulatory element-binding protein-1 expression by accelerating transcript decay.

The reduction in hepatic abundance of sterol regulatory element binding protein-1 (SREBP-1) mRNA and protein associated with the ingestion of polyunsaturated fatty acids (PUFA) appears to be largely responsible for the PUFA-dependent inhibition of lipogenic gene transcription. Our initial studies indicated that the induction of SREBP-1 expression by insulin and glucose was blocked by PUFA. Nuclear run-on assays suggested PUFA reduced SREBP-1 mRNA by post-transcriptional mechanisms. In this report we demonstrate that PUFA enhance the decay of both SREBP-1a and -1c. When rat hepatocytes in monolayer culture were treated with albumin-bound 20:4(n-6) or 20:5(n-3) the half-life of total SREBP-1 mRNA was reduced by 50%. Ribonuclease protection assays revealed that the decay of SREBP-1c mRNA was more sensitive to PUFA than was SREBP-1a, i.e. the half-life of SREBP-1c and -1a was reduced from 10.0 to 4.6 h and 11.6 to 7.6 h, respectively. Interestingly, treating the hepatocytes with the translational inhibitor, cycloheximide, prevented the PUFA-dependent decay of SREBP-1. This suggests that SREBP-1 mRNA may need to undergo translation to enter the decay process, or that the decay process requires the synthesis of a rapidly turning over protein. Although the mechanism by which PUFA accelerate SREBP-1 mRNA decay remains to be determined, cloning and sequencing of the 3'-untranslated region for the rat SREBP-1 transcript revealed the presence of an A-U-rich region that is characteristic of a destablizing element.

Regulation of hepatic delta-6 desaturase expression and its role in the polyunsaturated fatty acid inhibition of fatty acid synthase gene expression in mice.

Dietary polyunsaturated fatty acids (PUFA) of the (n-6) and (n-3) families uniquely suppress the expression of lipogenic genes while concomitantly inducing the expression of genes encoding proteins of fatty acid oxidation. Although considerable progress has been made toward understanding the nuclear events affected by PUFA, the intracellular mediator responsible for the regulation of hepatic lipogenic gene expression remains unclear. On the basis of earlier fatty acid composition studies, we hypothesized that the Delta-6 desaturase pathway was essential for the production of the fatty acid regulator of gene expression. To address this hypothesis, male BALB/c mice (n = 8/group) were fed for 5 d a high glucose, fat-free diet (FF) or the FF plus 50 g/kg 18:2(n-6) with and without eicosa-5, 8,11,14-tetraynoic acid (ETYA) (200 mg/kg diet), a putative inhibitor of the Delta-6 desaturase pathway. ETYA had no effect on food intake or weight gain, but it completely prevented 18:2(n-6) from suppressing the hepatic abundance of fatty acid synthase mRNA. ETYA ingestion was associated with a decrease in the hepatic content of 20:4(n-6) and an increase in the amount of 18:2(n-6). The fatty acid composition changes elicited by ETYA were accompanied by a decrease in the enzymatic activity of Delta-6 desaturase. Interestingly, the hepatic abundance of Delta-6 desaturase mRNA was actually induced by ETYA one- to twofold. When the product of Delta-6 desaturase, i.e., 18:3(n-6), was added to the ETYA plus 18:2(n-6) diet, the hepatic content of 20:4(n-6) was normalized. In addition, 18:3(n-6) consumption reduced the level of hepatic Delta-6 desaturase mRNA by 50% and completely prevented the increase in fatty acid synthase mRNA that was associated with ETYA ingestion. Apparently, Delta-6 desaturation is an essential step for the PUFA regulation of the fatty acid synthase gene transcription. Finally, the suppression of Delta-6 desaturase by PUFA and its induction by ETYA suggest that the Delta-6 desaturase gene may be regulated by two different lipid-dependent mechanisms.

Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids. A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats.

Polyunsaturated fatty acids (PUFA) coordinately suppress the transcription of a wide array of hepatic lipogenic genes including fatty acid synthase (FAS) and acetyl-CoA carboxylase. Interestingly, the over-expression of sterol regulatory element binding protein-1 (SREBP-1) induces the expression of all of the enzymes suppressed by PUFA. This observation led us to hypothesize that PUFA coordinately inhibit lipogenic gene transcription by suppressing the expression of SREBP-1. Our initial studies revealed that the SREBP-1 and FAS mRNA contents of HepG2 cells were reduced by 20:4(n-6) in a dose-dependent manner (i.e. EC(50) approximately 10 microM), whereas 18:1(n-9) had no effect. Similarly, supplementing a fat-free, high glucose diet with oils rich in (n-6) or (n-3) PUFA reduced the hepatic content of precursor and nuclear SREBP-1 60 and 85%, respectively; however, PUFA had no effect on the nuclear content of upstream stimulatory factor (USF)-1. The PUFA-dependent decrease in nuclear content of mature SREBP-1 was paralleled by a 70-90% suppression in FAS gene transcription. In contrast, dietary 18:1(n-9), i.e. triolein, had no inhibitory influence on the expression of SREBP-1 or FAS. The decrease in hepatic expression of SREBP-1 and FAS associated with PUFA ingestion was mimicked by supplementing the fat-free diet with the PPARalpha-activator, WY 14, 643. Interestingly, nuclear run-on assays revealed that changes in SREBP-1 mRNA abundance were not accompanied by changes in SREBP-1 gene transcription. These results support the concept that PUFA coordinately inhibit lipogenic gene transcription by suppressing the expression of SREBP-1 and that the PUFA regulation of SREBP-1 appears to occur at the post-transcriptional level.

Identification of a novel enhancer sequence in the distal promoter of the rat fatty acid synthase gene.

The proximal promoter and first intron of the fatty acid synthase (FAS) gene contains response sequences for insulin and glucose, but the 2- to 3-fold increase in FAS promoter activity attributable to these sequences falls short of the 20- to 30-fold induction in hepatic FAS gene transcription observed in fasted-refed rats. Using DNase I hypersensitivity site (HSS) mapping, two new liver specific sites were localized to the regions of: -8600 to -8500 (HSS 1) and -7300 to -7000 (HSS 2). DNase sensitivity of the -7300 to -7000 region was increased when fasted rats were refed glucose. When rat hepatocytes were transfected with a CAT construct that linked the region of -9700 and -4606 with the insulin response region located between -265 to +65, FAS promoter activity was induced 15-fold. This increase required the presence of both insulin and glucocorticoids. Deleting HSS 2 abolished the 15-fold induction in FAS promoter activity, but removing HSS 1 was without effect. Apparently the in vivo regulation of hepatic FAS gene transcription requires response elements located in the region of -7300 to -7000 and -265 to +65.

Cloning, expression, and nutritional regulation of the mammalian Delta-6 desaturase.

Arachidonic acid (20:4(n-6)) and docosahexaenoic acid (22:6(n-3)) have a variety of physiological functions that include being the major component of membrane phospholipid in brain and retina, substrates for eicosanoid production, and regulators of nuclear transcription factors. The rate-limiting step in the production of 20:4(n-6) and 22:6(n-3) is the desaturation of 18:2(n-6) and 18:3(n-3) by Delta-6 desaturase. In this report, we describe the cloning, characterization, and expression of a mammalian Delta-6 desaturase. The open reading frames for mouse and human Delta-6 desaturase each encode a 444-amino acid peptide, and the two peptides share an 87% amino acid homology. The amino acid sequence predicts that the peptide contains two membrane-spanning domains as well as a cytochrome b5-like domain that is characteristic of nonmammalian Delta-6 desaturases. Expression of the open reading frame in rat hepatocytes and Chinese hamster ovary cells instilled in these cells the ability to convert 18:2(n-6) and 18:3(n-3) to their respective products, 18:3(n-6) and 18:4(n-3). When mice were fed a diet containing 10% fat, hepatic enzymatic activity and mRNA abundance for hepatic Delta-6 desaturase in mice fed corn oil were 70 and 50% lower than in mice fed triolein. Finally, Northern analysis revealed that the brain contained an amount of Delta-6 desaturase mRNA that was several times greater than that found in other tissues including the liver, lung, heart, and skeletal muscle. The RNA abundance data indicate that prior conclusions regarding the low level of Delta-6 desaturase expression in nonhepatic tissues may need to be reevaluated.

Fatty acid regulation of gene expression. Its role in fuel partitioning and insulin resistance.

Dietary polyenoic (n-6) and (n-3) fatty acids uniquely regulate fatty acid biosynthesis and fatty acid oxidation. They exercise this effect by modulating the expression of genes coding for key metabolic enzymes and, in doing this, PUFA govern the intracellular as well as the interorgan metabolism of glucose and fatty acids. During the past 20 years, we have gradually elucidated the cellular and molecular mechanism by which dietary PUFA regulate lipid metabolism. Central to this mechanism has been our ability to determine that dietary PUFA regulate the transcription of genes. We have only begun to elucidate the nuclear mechanisms by which PUFA govern gene expression, but one point is clear and that is that it is unlikely that one mechanism will explain the variety of genes governed by PUFA. The difficulty in providing a unifying hypothesis at this time stems from (a) the many metabolic routes taken by PUFA upon entering a cell and (b) the lack of identity of a specific PUFA-regulated trans-acting factor. Nevertheless, our studies have revealed that PUFA are not only utilized as fuel and structural components of cells, but also serve as important mediators of gene expression, and that in this way they influence the metabolic directions of fuels and they modulate the development of nutritionally related pathophysiologies such as diabetes.

Increased hepatic delta 6-desaturase activity with growth hormone expression in the MG101 transgenic mouse.

Growth hormone (GH) has many metabolic effects, but its mechanism(s) of action are not fully understood. We studied the short-term effects of endogenously produced GH on liver delta 6-desaturase activity and adipose and liver lipid fraction fatty acid composition in transgenic mice. MG101 transgenic mice ages 73-114 d received zinc to activate the ovine GH transgene for 7 d. Nontransgenic littermates, used as controls, also received zinc. Liver lipids were fractionated into phospholipids (PL), cholesteryl esters, and triglycerides (TG), and retroperitoneal adipose fractionated into PL and TG for fatty acid analysis. Liver microsomes were assayed for delta 6-desaturase activity. Animals expressing the ovine growth hormone transgene had a 2.5-fold higher liver delta 6-desaturase activity than controls. Arachidonate and docosahexaenoate were significantly higher in liver PL of GH transgenic animals compared to controls, but both were decreased in adipose PL in the GH animals. We conclude that increased production of GH affects both production and organ distribution of highly unsaturated fatty acids. The changes in arachidonate in various lipid pools following transgene expression may mediate the systemic actions of GH.

Selective reduction of delta 6 and delta 5 desaturase activities but not delta 9 desaturase in micropigs chronically fed ethanol.

This study investigated the mechanism by which chronic ethanol feeding reduces arachidonate and other highly unsaturated fatty acids in pig liver phospholipids. Five micropigs were fed a diet providing 89 kcal/kg body wt for 12 mo, with ethanol and fat as 40 and 34% of energy, respectively. Five control pigs were pairfed corn starch instead of ethanol. The activities of delta 6 and delta 5 desaturases (expressed as microsomal conversion of precursor to product) in liver from ethanol-fed pigs were reduced to less than half that of controls, whereas the activity of delta 9 desaturase was unaffected in the ethanol group. delta 5 Desaturase activity showed positive correlation with the abundance of its products in liver total phospholipids and microsomes in the ethanol group, but not in the controls. Correlation between delta 6 desaturase activity and its products showed similar pattern to that of delta 5 desaturase, but did not reach statistical significance. No difference was observed between the two groups in coenzyme A concentration in the liver. These results suggest that the selective reduction of delta 6 and delta 5 desaturase activities, not the microsomal electron transport system, are directly responsible for the altered profile of liver phospholipids.

The body composition and lipid metabolic effects of long-term ethanol feeding during a high omega 6 polyunsaturated fatty acid diet in micropigs.

Our previous research with miniature pigs has shown that long-term ethanol feeding with a low-fat diet decreases arachidonic acid (20:4 omega 6) levels in multiple tissues, but we did not find significant liver pathology. In this study, we investigated the effect of ethanol feeding with high dietary linoleic acid (18:2 omega 6) on tissue fatty acid (FA) profiles and body composition. Five Yucatan micropigs were fed 370 kJ (89 kcal)/kg body weight of a diet containing ethanol and fat as 40% and 34% of energy, respectively; five control pigs were pair-fed corn starch in place of ethanol. Corn oil, 61% 18:2 omega 6, supplied most of the dietary fat. Liver biopsies were performed at baseline (n = 2 per group) and at three other time points (n = 5 per group). Phospholipid (PL) FA levels were measured by thin-layer and gas chromatography. Body composition was analyzed by underwater weighing of carcasses. Body composition analysis demonstrated a marked reduction of carcass fat in the ethanol group, but no significant reduction of carcass lean weight after 12 months. In liver PLs, the ethanol group showed decreased 20:4 omega 6 and docosahexaenoic acid (22:6 omega 3) after 1 month. While the decreased 20:4 omega 6 remained constant after 1 month, 22:6 omega 3 showed a progressive decrease up to 12-months, resulting in a continuous decrease of the omega 3/omega 6 FA ratio. This slowly progressive decrease in the omega 3/omega 6 ratio in liver PLs with ethanol feeding may have enhanced the inflammatory response in the liver, contributing to liver pathology. Body composition results indicate marked wasting of energy in the ethanol group.

Abnormal polyunsaturated lipid metabolism in the obese Zucker rat, with partial metabolic correction by gamma-linolenic acid administration.

Below-normal proportions of phospholipid (PL) arachidonic acid (20:4 omega 6) have been reported in serum from obese humans and in liver from obese Zucker rats. This implies an abnormality of 20:4 omega 6 formation from linoleic acid (18:2 omega 6), possibly in the delta 6 desaturase step, or alternatively an abnormality in the catabolism or distribution of arachidonate. We previously speculated that a reduced proportion of 20:4 omega 6 in hepatic PL could contribute to the etiology of genetic obesity. Providing 18:3 omega 6 would bypass delta 6 desaturase and possibly normalize hepatic PL 20:4 omega 6. Therefore weanling Zucker rats were given free access to a defined diet (11% of energy as soy oil) and gavaged daily with 100 microL of either black currant oil concentrate ([BCO] 8% 18:2 omega 6 and 70% 18:3 omega 6) or soy oil ([Soy] 55% 18:2 omega 6 and < 0.1% 18:3 omega 6). Groups of eight lean and eight obese animals were randomized to receive Soy or BCO in a 2 x 2 design; 10 obese and 10 lean rats were fed a stock diet (nongavaged reference). All groups of lean rats had identical weight gain; food intake for Soy lean and BCO lean did not differ. The obese reference animals and Soy obese animals did not differ in weight gain. However, BCO obese animals ate less food (P < .06), gained less weight (P < .0001), and had lower percent body fat (P < .05) compared with the Soy obese animals. The fatty acid constituents from serum, liver, and adipose tissue showed marked differences between lean and obese animals. Hepatic PL 20:4 omega 6 was lower in Soy obese than in lean (P < .002), but was normalized by BCO gavage (diet effect, P < .007). The paucity of hepatic PL 20:4 omega 6 was not due to reduced desaturase activity, as the proportions of other desaturase products (20:3 omega 6, 20:3 omega 9, 20:5 omega 3) were significantly elevated in Soy obese rat liver and serum. Serum and hepatic cholesteryl ester 20:4 omega 6 levels were elevated in obese versus lean rats (P < .02 and P < .0001), indicating abnormal arachidonate distribution in the obese Zucker rat. Because BCO selectively reduced weight gain and percent body fat in obese Zucker rats, our results imply a role for abnormal omega 6 fatty acid metabolism in the etiology of Zucker obesity.(ABSTRACT TRUNCATED AT 400 WORDS)

Time-dependent effects of progressive gamma-linolenate feeding on hyperphagia, weight gain, and erythrocyte fatty acid composition during growth of Zucker obese rats.

Obese Zucker rats (fa/fa) have low levels of arachidonic acid (AA) in liver phospholipids (PL). We have previously shown that a 70% gamma-linolenate concentrate (GLA; an AA intermediate) fed at a fixed dose (0.07 g/day) normalized hepatic PL AA and reduced weight gain selectively in the obese animals. In a follow-up study, 16 obese (fa/fa) and 16 lean (Fa/Fa) 4-week-old male rats were randomized into 4 groups of 8 each and gavaged daily with soybean oil (SOY) containing 55% 18:2omega6 (an AA precursor) or GLA, using a progressive dose (< or = 5% of total calories) based on body weight. A defined diet with 11% of energy as SOY was fed ad libitum for 60 days. GLA obese had lower body weight (p<0.0001) and 60-day cumulative food intake (p<0.05) compared to SOY obese, but neither parameter differed between the lean groups. For the last twenty days cumulative food intake was identical for GLA obese and SOY lean, whereas SOY obese consumed 18% more (p<0.05). Thus the progressive dose of GLA selectively suppressed hyperphagia in obese Zucker rats. Erythrocytes collected at 15-day intervals showed parallel increases in AA in both genotypes over time, suggesting normal AA availability during rapid growth. Thus, the reduced PL AA in the livers from the obese rats probably reflects impaired distribution in selected tissues rather than reduced hepatic production. Due to the potential health risks of enriching tissue lipids with AA, great caution is advised in considering GLA as therapy for human obesity.

Reduced tissue arachidonic acid concentration with chronic ethanol feeding in miniature pigs.

The effect of ethanol feeding on the essential fatty acid content of tissues has been contradictory. To define the effect, we analyzed fatty acid profiles in various tissues from five miniature pigs fed daily 105 kJ basal diet/kg body wt and 146 kJ ethanol/kg body wt, and also five control pigs pair-fed the same amount of basal diet but with corn starch substituted for ethanol. After 12 mo, biopsy samples were taken, and tissue fatty acid profiles were analyzed. In the phospholipid fraction from the ethanol group there was a uniform decrease in arachidonic acid (AA) and an increase in oleic acid in liver, serum, and muscle. AA was consistently decreased in the triglyceride fractions of liver, serum and subcutaneous adipose of the ethanol group. Possible explanations for this general reduction in tissue AA with ethanol feeding include decreased activities of delta 6 and delta 5 desaturases, and a displacement of AA from lipid fractions by other fatty acids.