Kegg Pathway: Fatty acid metabolism

Am J Physiol Gastrointest Liver Physiol. 2009 Nov 19;
Sugimoto H, Okada K, Shoda J, Warabi E, Ishige K, Ueda T, Taguchi K, Yanagawa T, Nakahara A, Hyodo I, Ishii T, Yamamoto M

Oxidative stress is a critical mediator in liver injury of steatohepatitis. The transcription factor Nrf2 serves as a cellular stress sensor and is a key regulator for induction of hepatic detoxification and antioxidative stress systems. The involvement of Nrf2 in defense against the development of steatohepatitis remains unknown. We aimed to investigate the protective roles of Nrf2 in nutritional steatohepatitis using wild-type (WT) and Nrf2 gene-null (Nrf2-null) mice. WT and Nrf2-null mice were fed a methionine- and choline- deficient (MCD) diet for 3 and 6 weeks, and the liver tissues were analyzed for pathology and for expression levels of detoxifying enzymes and antioxidative stress genes via the Nrf2 transcriptional pathway. In WT mice fed an MCD diet, Nrf2 was potently activated in the livers, and steatohepatitis did not develop over the observation periods. However, in Nrf2-null mice fed an MCD diet, the pathological state of the steatohepatitis was aggravated in terms of Fatty changes, inflammation, fibrosis, and iron accumulation. In the livers of the Nrf2-null mice, oxidative stress was significantly increased compared to that of WT mice based on the increased levels of 4-hydroxy-2-nonenal and malondialdehyde. This change was associated with the decreased levels of glutathione, detoxifying enzymes, catalase, and superoxide dismutase activity. Correlating well with the liver pathology, the mRNA levels of factors involved in Fatty acid metabolism, inflammatory cytokines, and fibrogenesis-related genes were significantly increased in the livers of the Nrf-null mice. These findings demonstrate that Nrf2 deletion in mice leads to rapid onset and progression of nutritional steatohepatitis induced by an MCD diet. Activation of Nrf2 could be a promising target toward developing new options for prevention and treatment of steatohepatitis.

Microbiology. 2009 Nov 19;
McKain N, Shingfield KJ, Wallace RJ

Cultures of ruminal bacteria known to metabolize unsaturated Fatty acids were grown in medium containing 50 mug/ml of geometric and positional isomers of conjugated linoleic acid (CLA) or 18:1 Fatty acids and 37.4% deuterium oxide to investigate the mechanisms responsible for Fatty acid metabolism. Butyrivibrio fibrisolvens JW11 converted cis-9,trans-11-18:2 and trans-9,trans-11-18:2 to trans-11-18:1 as the main product, labelled at C-9, and metabolized trans-10,cis-12-18:2 to trans-10-18:1, labelled at C-13, and smaller amounts of trans-12-18:1 and cis-12-18:1. Butyrivibrio proteoclasticus P-18 did not grow in the presence of cis-9,trans-11-18:2 or trans-10,cis-12-18:2, but grew in medium containing trans-9,trans-11-18:2, forming 18:0. Propionibacterium acnes, a ruminal species that isomerizes linoleic acid to trans-10,cis-12-18:2, did not metabolize CLA isomers further. B. fibrisolvens metabolized small amounts of trans-10-18:1, trans-11-18:1 and cis-9-18:1, but the products formed were not detected. B. proteoclasticus, on the other hand, carried out substantial conversion of 18:1 substrates to 18:0. P. acnes hydrated cis-9-18:1 and trans-11-18:1 to 10-OH-18:0, which was further oxidized to yield 10-O-18:0. The deuterium enrichment in the intermediates formed during incubations with 9,11 geometric isomers of CLA was about half that of the products from trans-10,cis-12 CLA and 18:1 isomers, suggesting that the reduction of 9,11 geometric isomers CLA by ruminal bacteria occurs via different mechanisms compared with the metabolism of other unsaturated Fatty acids.

PLoS One. 2009; 4(11): e7791
Gurvitz A

Our recognition of the mitochondria as being important sites of Fatty acid biosynthesis is continuously unfolding, especially in light of new data becoming available on compromised Fatty acid synthase type 2 (FASII) in mammals. For example, perturbed regulation of murine 17beta-HSD8 encoding a component of the mitochondrial FASII enzyme 3-oxoacyl-thioester reductase is implicated in polycystic kidney disease. In addition, over-expression in mice of the Mecr gene coding for 2-trans-enoyl-thioester reductase, also of mitochondrial FASII, leads to impaired heart function. However, mouse knockouts for mitochondrial FASII have hitherto not been reported and, hence, there is a need to develop alternate metazoan models such as nematodes or fruit flies. Here, the identification of Caenorhabditis elegans W09H1.5/MECR-1 as a 2-trans-enoyl-thioester reductase of mitochondrial FASII is reported. To identify MECR-1, Saccharomyces cerevisiae etr1Delta mutant cells were employed that are devoid of mitochondrial 2-trans-enoyl-thioester reductase Etr1p. These yeast mutants fail to synthesize sufficient levels of lipoic acid or form cytochrome complexes, and cannot respire or grow on non-fermentable carbon sources. A mutant yeast strain ectopically expressing nematode mecr-1 was shown to contain reductase activity and resemble the self-complemented mutant strain for these phenotype characteristics. Since MECR-1 was not intentionally targeted for compartmentalization using a yeast mitochondrial leader sequence, this inferred that the protein represented a physiologically functional mitochondrial 2-trans-enoyl-thioester reductase. In accordance with published findings, RNAi-mediated knockdown of mecr-1 in C. elegans resulted in life span extension, presumably due to mitochondrial dysfunction. Moreover, old mecr-1(RNAi) worms had better internal organ appearance and were more mobile than control worms, indicating a reduced physiological age. This is the first report on RNAi work dedicated specifically to curtailing mitochondrial FASII in metazoans. The availability of affected survivors will help to position C. elegans as an excellent model for future pursuits in the emerging field of mitochondrial FASII research.

J Strength Cond Res. 2009 Nov 17;
Martínez-Lagunas V, Ding Z, Bernard JR, Wang B, Ivy JL

Martínez-Lagunas, V, Ding, Z, Bernard, JR, Wang, B, and Ivy, JL. Added protein maintains efficacy of a low-carbohydrate sports drink. J Strength Cond Res 24(x): 000-000, 2009-The purpose of the present study was to investigate the aerobic capacity characteristics of an isocaloric carbohydrate (CHO) plus protein (PRO) drink and a low-calorie CHO plus PRO drink against a traditional 6% CHO sports beverage. Twelve male and female trained cyclists exercised on 4 separate occasions at intensities that varied between 55 and 75% &OV0312;o2max for 2.5 hours and then at 80% &OV0312;o2max until fatigued. Supplements (255.4 +/- 9.1 mL) were provided every 20 minutes and consisted of a 4.5% carbohydrate plus 1.15% protein complex (CHO/PRO H), a 3% carbohydrate plus 0.75% protein complex (CHO/PRO L), a 6% carbohydrate supplement (CHO), or a placebo (PLA). Time to fatigue at 80% &OV0312;o2max was significantly longer (p < 0.05) during the CHO (26.9 +/- 6.1 minutes, mean +/- SE), the CHO/PRO H (30.5 +/- 5.9 minutes), and the CHO/PRO L (28.9 +/- 6.5 minutes) trials compared with the PLA trial (14.7 +/- 3.4 minutes), with no significant differences among the CHO, CHO/PRO H, and CHO/PRO L treatments. In general, blood glucose, plasma insulin, and carbohydrate oxidation were elevated above PLA during the CHO, CHO/PRO H, and CHO/PRO L trials, whereas plasma free Fatty acids, rating of perceived exertion, and fat oxidation values were lower during the CHO, CHO/PRO H, and CHO/PRO L trials compared with the PLA trial. Only minor differences in blood parameters occurred among the CHO, CHO/PRO H, and CHO/PRO L treatments. In summary, partially substituting PRO for CHO in a sports drink did not enhance aerobic capacity, but substitution was able to occur without loss of efficacy. Thus, adding PRO to a low-calorie CHO sports drink may be an effective strategy to enhance aerobic capacity while limiting carbohydrate and caloric consumption.

J Dairy Sci. 2009 Dec; 92(12): 6134-6143
Nonnecke BJ, Foote MR, Miller BL, Fowler M, Johnson TE, Horst RL

The physiological response of the preruminant calf to sustained exposure to moderate cold has not been studied extensively. Effects of cold on growth performance and health of preruminant calves as well as functional measures of energy metabolism, fat-soluble vitamin, and immune responsiveness were evaluated in the present study. Calves, 3 to 10 d of age, were assigned randomly to cold (n = 14) or warm (n = 15) indoor environments. Temperatures in the cold environment averaged 4.7 degrees C during the study. Frequent wetting of the environment and the calves was used to augment effects of the cold environment. Temperatures in the warm environment averaged 15.5 degrees C during the study. There was no attempt to increase the humidity in the warm environment. Preventative medications or vaccinations that might influence disease resistance were not administered. Nonmedicated milk replacer (20% crude protein and 20% fat fed at 0.45 kg/d) and a nonmedicated starter grain fed ad libitum were fed to all calves. Relative humidity was, on average, almost 10% higher in the cold environment. Warm-environment calves were moderately healthier (i.e., lower respiratory scores) and required less antibiotics. Scour scores, days scouring, and electrolyte costs, however, were unaffected by environmental temperature. Growth rates were comparable in warm and cold environments, although cold-environment calves consumed more starter grain and had lower blood glucose and higher blood nonesterified Fatty acid concentrations. The nonesterified Fatty acid and glucose values for cold-stressed calves, however, did not differ sufficiently from normal values to categorize these calves as being in a state of negative-energy balance. Levels of fat-soluble vitamin, antibody, tumor necrosis factor-alpha, and haptoglobin were unaffected by sustained exposure to moderate cold. These results support the contention that successful adaptation of the dairy calf to cold is dependent upon the availability of adequate nutrition.

J Dairy Sci. 2009 Dec; 92(12): 6083-6094
Bernard L, Bonnet M, Leroux C, Shingfield KJ, Chilliard Y

Lipid in the diet is known to enhance milk fat secretion and alter milk Fatty acid composition in lactating goats. In the current experiment, the contribution of peripheral tissue and mammary gland lipid metabolism to changes in milk fat composition from plant oils was examined. Fourteen Alpine goats in midlactation were used in a 3 x 3 Latin square design with 28-d experimental periods. Treatments comprised maize silage-based diets containing no additional oil (M), sunflower-seed oil (MSO; 6.1% of diet DM), or linseed oil (MLO; 6.2% of diet DM). Compared with the control, milk yield was greater in goats fed MSO (3.37 and 3.62 kg/d, respectively), whereas MLO enhanced milk fat content (+3.9 g/kg), resulting in a 14% increase in milk fat secretion. Both MSO and MLO increased milk lactose secretion by 12 and 8%, respectively, compared with M. Relative to the control, plant oils decreased C10 to C16 secretion (32 and 24%, respectively, for MSO and MLO) and enhanced C18 output in milk (ca. 110%). Diets MSO and MLO increased cis-9 18:1 secretion in milk by 25 and 31%, respectively, compared with M. The outputs of trans-11 18:1 and cis-9, trans-11 18:2 in milk were increased 8.34- and 6.02-fold for MSO and 5.58- and 3.71-fold for MLO compared with M, and MSO increased trans-10 18:1 and trans-10, cis-12 18:2 secretion. Plant oils decreased milk fat cis-9 14:1/14:0; cis-9 16:1/16:0; cis-9 18:1/18:0; and cis-9, trans-11 18:2/trans-11 18:1 concentration ratios but had no effect on mammary stearoyl-CoA desaturase mRNA or activity. Furthermore, changes in milk Fatty acid secretion were not associated with alterations in mammary acetyl-CoA carboxylase mRNA and activity, abundance of mRNA encoding for lipoprotein lipase and Fatty acid synthase, or malic enzyme and glycerol-3-phosphate dehydrogenase activity in mammary tissue. Mammary lipoprotein lipase activity was increased with MSO relative to MLO. Treatments had no effect on glucose-6-phosphate dehydrogenase, malic enzyme, glycerol-3-phosphate dehydrogenase activity, or mRNA abundance and/or activity of lipoprotein lipase, acetyl-CoA carboxylase, Fatty acid synthase, and stearoyl-CoA desaturase in liver or adipose tissue. In conclusion, inclusion of sunflower-seed oil and linseed oil in maize silage-based diets alters milk Fatty acid secretion in goats via mechanisms independent of changes in mammary, hepatic, or adipose tissue lipogenic gene expression. Furthermore, data provided indications that the regulation of mammary lipogenic responses to plant oils on starch-rich diets differs between the caprine and bovine.

Am J Clin Nutr. 2009 Nov 18;
Bouwens M, Grootte Bromhaar M, Jansen J, Müller M, Afman LA

BACKGROUND: Dietary polyunsaturated Fatty acids (PUFAs) have a variety of beneficial effects, and immune cells play an important role in these effects. The mechanisms of action of PUFAs are still not completely understood, but it is known that PUFAs can influence the expression of a broad set of genes. OBJECTIVE: The objective was to determine the postprandial effects of intake of different Fatty acids on the gene expression profiles of peripheral blood mononuclear cells (PBMCs). DESIGN: In a single-blind crossover study, 21 healthy male volunteers consumed shakes enriched in PUFAs, monounsaturated Fatty acids (MUFAs), or saturated Fatty acids (SFAs) in random order. Blood samples were collected before and at several time points after intake. Whole-genome gene expression profiles of PBMCs were examined before and 6 h after intake of the PUFA and SFA shakes. Additionally, ex vivo incubation of human PBMCs with different Fatty acids was performed. RESULTS: Whole-genome expression analysis showed distinct differences between PUFA and SFA consumption. PUFA intake decreased the expression of genes in liver X receptor signaling, whereas SFA intake increased the expression of these genes. PUFA intake also increased the expression of genes related to cellular stress responses. MUFA intake had an intermediate effect on several genes. Ex vivo experiments showed a direct effect of free Fatty acids on PBMC gene expression. CONCLUSIONS: This study showed that PBMCs can reveal Fatty acid-specific gene expression profiles in young healthy men after the consumption of different Fatty acids, as evidenced by the opposite effects of PUFA and SFA intakes on the expression of genes involved in liver X receptor signaling. This trial was registered at www.clinicaltrials.gov as NCT01000194.

Am J Clin Nutr. 2009 Nov 18;
Friesen RW, Innis SM

BACKGROUND: Arachidonic (ARA), eicosapentaenoic (EPA), and docosahexaenoic (DHA) acids are important in membrane glycerophospholipids. Higher maternal blood ARA, EPA, and DHA concentrations in gestation are associated with higher maternal-to-fetal transfer of ARA, EPA, and DHA, respectively, which emphasizes the importance of maternal Fatty acid status in gestation. As in the brain, red blood cell (RBC) ethanolamine phosphoglycerides (EPGs) are high in plasmalogen, ARA, and DHA. OBJECTIVE: We determined the relation between dietary n-6 (omega-6) and n-3 (omega-3) Fatty acid intakes and n-6 and n-3 Fatty acids in RBC EPGs and phosphatidylcholine in near-term pregnant women. DESIGN: The subjects were 105 healthy Canadian pregnant (36 wk gestation) women. Fatty acid intakes were estimated by food-frequency questionnaire, and fasting venous blood samples were collected. RESULTS: DHA and EPA intakes were positively associated with RBC EPG and phosphatidylcholine concentrations of DHA (rho = 0.309 and 0.369, respectively; P < 0.001) and EPA (rho = 0.391 and 0.228, respectively; P < 0.001) and inversely associated with RBC EPG 22:4n-6 and 22:5n-6 (P < 0.001). In RBCs, concentrations of linoleic acid (LA, 18:2n-6) were inversely associated with DHA, EPA, and ARA, respectively, in EPGs (r = -0.432, P < 0.01; r = -0.201, P < 0.04; and r = -0.303, P < 0.01) and phosphatidylcholine (r = -0.460, -0.490, and -0.604; P < 0.01 for all). CONCLUSIONS: Membrane Fatty acids are influenced by the amount and balance of Fatty acid substrates. Our results suggest the competitive interaction of LA with ARA, EPA, and DHA, with no evidence that higher LA increases ARA. Biochemical indicators to suggest that DHA is limiting are present in our population. This trial was registered at clinicaltrials.gov as NCT00620672.

Am J Physiol Regul Integr Comp Physiol. 2009 Nov 18;
Epperson LE, Rose JC, Carey HV, Martin SL

Hibernators are unique among mammals in their ability to survive extended periods of time with core body temperatures near freezing and with dramatically reduced heart, respiratory and metabolic rates in a state known as torpor. In order to gain insight into the molecular events underlying this remarkable physiological phenotype, we applied a proteomic screening approach to identify liver proteins that differ between summer active (SA) and the entrance (Ent) phase of winter hibernation in 13-lined ground squirrels. The relative abundance of 1600 protein spots separated on 2D gels was quantitatively determined using fluorescence Difference Gel Electrophoresis (DiGE) and 74 unique proteins exhibiting significant differences between the two states were identified using liquid chromatography followed by tandem mass spectrometry (LC-MS/MS). Proteins elevated in Ent hibernators included liver Fatty acid binding protein, Fatty acid transporter and 3-hydroxy-3-methylglutaryl CoA synthase, which support the known metabolic fuel switch to lipid and ketone body utilization in winter. Several proteins involved in protein stability and protein folding were also elevated in Ent, agreeing with previous work. In contrast to transcript screening results, there was a surprising increase in the abundance of proteins involved in protein synthesis during Ent hibernation, including several initiation and elongation factors. This finding, coupled with decreased abundance of numerous proteins involved in amino acid and nitrogen metabolism, supports the intriguing hypothesis that protein preservation and re-synthesis is a mechanism used by hibernating ground squirrels to help avoid nitrogen toxicity and ensure preservation of essential amino acids throughout the long winter fast. Key words: Ictidomys tridecemlineatus, metabolism, starvation, TCA cycle.

metabolism. 2009 Nov 17;
Ryu S, Chang Y, Woo HY, Yoo SH, Choi NK, Lee WY, Kim I, Song J

In the absence of existing research, we examined the association between longitudinal changes in serum gamma-glutamyltransferase (GGT) levels and the risk for metabolic syndrome (MetS). A MetS-free cohort of 9148 healthy male workers, who had participated in a health checkup program in 2002, was followed until September 2007. Metabolic syndrome was defined according to the modified National Cholesterol Education Program, using body mass index instead of waist circumference. Standard Cox proportional hazards and time-dependent Cox models were performed. During 37 663.4 person-years of follow-up, 1056 men developed MetS. The risk of incident MetS increased across the baseline GGT quartiles, even after further updating GGT values during the follow-up. A longitudinal increase in GGT as a time-dependent variable as well as a non-time-dependent variable was significantly related to MetS after adjusting for age plus the elapsed time from visit 1 to visit 2, baseline MetS traits, uric acid, regular exercise, alcohol consumption, and smoking. Even within the GGT reference interval (<40 U/L), the fourth quartile of GGT change predicted the development of MetS (adjusted hazard risk, 1.61; 95% confidence interval, 1.26-2.07). Furthermore, these associations were consistently observed within the subgroups-those with body mass index less than 23 kg/m(2), C-reactive protein less than 3.0 mg/L, homeostasis model assessment of insulin resistance less than 2.04, alcohol intake not exceeding 20 g/d, alanine aminotransferase less than 35 U/L, an absence of ultrasonographically detected Fatty liver, and an absence of any MetS traits. A longitudinal increase in the GGT level, even within the GGT reference interval, may be an independent predictor for MetS, regardless of the baseline GGT.

Am J Physiol Endocrinol Metab. 2009 Nov 17;
Torres N, Bautista CJ, Tovar AR, Ordaz G, Rodriguez-Cruz M, Ortiz V, Granados O, Nathanielsz PW, Larrea F, Zambrano E

Suboptimal developmental environments program offspring to lifelong metabolic problems. The aim of this study was to determine the impact of protein restriction in pregnancy on maternal liver lipid metabolism at 19 days of gestation (dG) and its effect on fetal brain development. Control (C) and restricted (R) mothers were fed with isocaloric diets containing 20 and 10% of casein. At 19 dG maternal blood and livers and fetal livers and brains were collected. Serum insulin and leptin levels were determinate in mothers. Maternal and fetal liver lipids and fetal brain lipids quantification were performed. Maternal liver and fetal brain Fatty acids were quantified by gas chromatography. In mothers, liver desaturases and elongases mRNAs were measured by RT-PCR. Maternal body and liver weights were similar in both groups. However, fat body composition, including liver lipids was lower in R mothers. A higher fasting insulin at 19 dG in R group was observed (C = 0.2 +/- 0.04 vs R = 0.9 +/- 0.16 ng/ml, p<0.01) and was inversely related to early growth retardation. Serum leptin in R mothers was significantly higher than that observed in C rats (C = 5 +/- 0.1 vs R = 7 +/- 0.7 ng/ml, p<0.05). In addition, protein restriction significantly reduced gene expression in maternal liver of desaturases and elongases, and the concentration of arachidonic (AA) and docosahexanoic (DHA) acids. In fetus from restricted mothers, a low body weight (C = 3 +/- 0.3 vs R = 2 +/- 0.1 g, p<0.05), as well as liver and brain lipids, including the content of DHA in the brain was reduced. This study showed that protein restriction during pregnancy may impact negatively normal fetal brain development by changes in maternal lipid metabolism.

J Agric Food Chem. 2009 Nov 25; 57(22): 10964-10971
Aizawa K, Matsumoto T, Inakuma T, Ishijima T, Nakai Y, Abe K, Amano F

To examine whether the expression of hepatic genes, including biomarkers, is affected by the ingestion of tomato or paprika, mice were given tomato beverage (TB), paprika beverage (PB), or water (control) ad libitum for 6 weeks. The body weights in the TB and PB groups were significantly lower than those in the control group. Administration of PB significantly increased the plasma high-density lipoprotein-cholesterol level. Hepatic gene expression was investigated using DNA microarrays. The ingestion of TB or PB up-regulated the expression of 687 and 1045 genes and down-regulated the expression of 841 and 653 genes, respectively (false discovery rate < 0.05). These changes in gene expression suggest that TB ingestion promotes glycogen accumulation and stimulates some specific steps in Fatty acid oxidation. PB ingestion promoted the entire glucose and Fatty acid metabolic pathways to improve lipid profiles. These results provide useful genetic information about a variety of biochemical processes by which vegetables can contribute to good health.

Diabetes Care. 2009 Nov 16;
Dirksen C, Hansen DL, Madsbad S, Hvolris LE, Naver LS, Holst JJ, Worm D

Objective: To examine after gastric bypass the effect of peroral vs. gastroduodenal feeding on glucose metabolism. Research Design and Methods: A type 2 diabetic patient was examined on two consecutive days 5 weeks after gastric bypass. A standard liquid meal was given, on the first day into the bypassed gastric remnant and on the second day perorally. Plasma glucose, insulin, C peptide, glucagon, incretin hormones, peptide YY and free Fatty acids were measured. Results: Peroral feeding reduced 2-h-postprandial plasma glucose (7.8 vs. 11.1 mM) and incremental-area-under-the-glucose-curve (0.33 vs. 0.49 mMxmin) compared with gastroduodenal feeding . beta-cell function (iAUC(Cpeptide/Glu)) was more than 2-fold improved during peroral feeding and the GLP-1 response increased nearly 5-fold. Conclustions: Improvement in postprandial glucose metabolism after gastric bypass is an immediate and direct consequence of the gastrointestinal rearrangement, associated with exaggerated GLP-1 release and independent of changes in insulin sensitivity, weight-loss and caloric restriction.

Mol Cell. 2009 Nov 13; 36(3): 379-92
Ide T, Brown-Endres L, Chu K, Ongusaha PP, Ohtsuka T, El-Deiry WS, Aaronson SA, Lee SW

The p53 tumor suppressor protein has a well-established role in cell-fate decision-making processes. However, recent discoveries indicate that p53 has a non-tumor-suppressive role. Here we identify guanidinoacetate methyltransferase (GAMT), an enzyme involved in creatine synthesis, as a p53 target gene and a key downstream effector of adaptive response to nutrient stress. We show that GAMT is not only involved in p53-dependent apoptosis in response to genotoxic stress but is important for apoptosis induced by glucose deprivation. Additionally, p53-->GAMT upregulates Fatty acid oxidation (FAO) induced by glucose starvation, utilizing this pathway as an alternate ATP-generating energy source. These results highlight that p53-dependent regulation of GAMT allows cells to maintain energy levels sufficient to undergo apoptosis or survival under conditions of nutrient stress. The p53-->GAMT pathway represents a new link between cellular stress responses and processes of creatine synthesis and FAO, demonstrating a further role of p53 in cellular metabolism.

Mol Cell. 2009 Nov 13; 36(3): 351-2
Zhu Y, Prives C

In this issue of Molecular Cell, Ide et al. (2009) have identified the enzyme guanidinoacetate methyltransferase (GAMT) that regulates creatine metabolism as a p53 target involved in apoptosis, reactive oxygen species (ROS), and Fatty acid metabolism.

Diabetes Obes Metab. 2009 Nov 16;
Hassanali Z, Ametaj B, Field CJ, Proctor SD, Vine DF

Background: Postprandial dyslipidaemia occurs in obesity and insulin resistance (IR), and is associated with an increased risk of developing cardiovascular disease. We have recently established that the JCR:LA-cp rodent model develops postprandial dyslipidaemia concomitant with complications of the metabolic syndrome. Dietary n-3 polyunsaturated Fatty acids (n-3 PUFAs) are proposed to modulate plasma lipids, serum hormone levels, lipoprotein metabolism and the inflammatory state; however, results remain inconsistent during conditions of IR. Aim: To assess the acute metabolic and inflammatory effects of dietary fish oil supplementation on existing postprandial dyslipidaemia in the JCR:LA-cp model. Methods: JCR:LA-cp rats (14 weeks of age) were fed either a control, isocaloric, lipid balanced diet (15% w/w total fat, 1.0% cholesterol, P:S ratio 0.4), a lipid balanced diet with 5% n-3 PUFA [fish oil derived eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA)] or a lipid balanced diet with 10% n-3 PUFA for 3 weeks. Fasting plasma lipid, cytokine levels, postprandial chylomicron (apoB48) metabolism and the postprandial inflammatory response [haptoglobin and lipopolysaccharide binding protein (LBP)] were assessed following a standardized 'oral fat challenge'. Results: n-3 PUFA treatment resulted in a significant improvement (i.e. decrease) in the postprandial response for triglyceride (45%) (p < 0.05), apoB48 (45%) (p < 0.03) and LBP (33%) (p < 0.05) compared to controls (measured as area under the clearance curve). In contrast, we observed a significant elevation in postprandial haptoglobin (165%) (p < 0.001) in obese rats supplemented with 10% n-3 PUFA. Treatment with 5% n-3 PUFA in the JCR:LA-cp obese animals resulted in a complementary decrease in total body weight gain (6%) (p < 0.001) and an increase (i.e. improvement) in adiponectin (33%) (p < 0.05) compared to controls, without a concomitant reduction in food intake. Conclusion: Acute dietary n-3 PUFA dietary supplementation can improve fasting as well as postprandial lipid metabolism and components of the associated inflammatory response in the JCR:LA-cp rat. Further, moderate dose n-3 PUFA supplementation may reduce corresponding body weight during conditions of hypercholesterolaemia and/or modulate inflammation associated with obesity and the metabolic syndrome.

Appl Microbiol Biotechnol. 2009 Nov 14;
Tisch D, Schmoll M

Light represents a major carrier of information in nature. The molecular machineries translating its electromagnetic energy (photons) into the chemical language of cells transmit vital signals for adjustment of virtually every living organism to its habitat. Fungi react to illumination in various ways, and we found that they initiate considerable adaptations in their metabolic pathways upon growth in light or after perception of a light pulse. Alterations in response to light have predominantly been observed in carotenoid metabolism, polysaccharide and carbohydrate metabolism, Fatty acid metabolism, nucleotide and nucleoside metabolism, and in regulation of production of secondary metabolites. Transcription of genes is initiated within minutes, abundance and activity of metabolic enzymes are adjusted, and subsequently, levels of metabolites are altered to cope with the harmful effects of light or to prepare for reproduction, which is dependent on light in many cases. This review aims to give an overview on metabolic pathways impacted by light and to illustrate the physiological significance of light for fungi. We provide a basis for assessment whether a given metabolic pathway might be subject to regulation by light and how these properties can be exploited for improvement of biotechnological processes.

J Mol Med. 2009 Nov 14;
Wang W, Wong CW

Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) serves as an inducible coactivator for a number of transcription factors to control energy metabolism. Insulin signaling through Akt kinase has been demonstrated to phosphorylate PGC-1alpha at serine 571 and downregulate its activity in the liver. Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors that reduce cholesterol synthesis in the liver. In this study, we found that statins reduced the active form of Akt and enhanced PGC-1alpha activity. Specifically, statins failed to activate an S571A mutant of PGC-1alpha. The activation of PGC-1alpha by statins selectively enhanced the expression of energy metabolizing enzymes and regulators including peroxisome proliferator-activated receptor alpha, acyl-CoA oxidase, carnitine palmitoyl transferase-1A, and pyruvate dehydrogenase kinase 4. Importantly, a constitutively active form of Akt partially reduced the statin-enhanced gene expression. Our study thus provides a plausible mechanistic explanation for the hypolipidemic effect of statin through elevating the rate of beta-oxidation and mitochondrial Kreb's cycle capacity to enhance Fatty acid utilization while reducing the rate of glycolysis.

Med Sci Sports Exerc. 2009 Dec; 41(12): 2136-2144
Wang L, Psilander N, Tonkonogi M, Ding S, Sahlin K

PURPOSE:: There is a debate whether interval or traditional endurance training is the most effective stimulus of mitochondrial biogenesis. Here, we compared the effects of acute interval exercise (IE) or continuous exercise (CE) on the muscle messenger RNA (mRNA) content for several genes involved in mitochondrial biogenesis and lipid metabolism. METHODS:: Nine sedentary subjects cycled for 90 min with two protocols: CE (at 67% V O2max) and IE (12 s at 120% and 18 s at 20% of V O2max). The duration of exercise and work performed with CE and IE was identical. Muscle biopsies were taken before and 3 h after exercise. RESULTS:: There were no significant differences between the two exercise protocols in the increases in V O2 and HR, the reduction in muscle glycogen (35%-40% with both protocols) or the changes in blood metabolites (lactate, glucose, and Fatty acids). The mRNA content for major regulators of mitochondrial biogenesis [peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1alpha (PGC-1alpha), PGC-1-related coactivator, PPAR/delta] and of lipid metabolism [pyruvate dehydrogenase kinase isozyme 4 (PDK4)] increased after exercise, but there was no significant difference between IE and CE. However, the mRNA content for several downstream targets of PGC-1alpha increased significantly only after CE, and mRNA content for nuclear respiratory factor 2 was significantly higher after CE (P < 0.025 vs IE). CONCLUSIONS:: The present findings demonstrate that, when the duration of exercise and work performed is the same, IE and CE influence the transcription of genes involved in oxidative metabolism in a similar manner.

J Pediatr Gastroenterol Nutr. 2009 Nov 12;
Subramaniam P, Clayton PT, Portmann BC, Mieli-Vergani G, Hadžić N

OBJECTIVE:: We studied the clinical features of children with 3beta-hydroxy-Delta-C27-steroid dehydrogenase (3beta-HSDH) deficiency presenting to King's College and Great Ormond Street hospitals between 1989 and 2005. The diagnosis was made biochemically by detection of sulphated dihydroxycholenoic acids and trihydroxycholenoic acids in urine by fast atom bombardment mass spectrometry or electrospray ionisation tandem mass spectrophotometry and a plasma bile acid profile showing absent or low cholic and chenodeoxycholic acid levels and high concentrations of 3beta-7alpha-dihydroxy-5-cholenoic acid and 3beta-7alpha-12alpha-trihydroxy-5-cholenoic acid. RESULTS:: Eighteen children (12 male) with 3beta-HSDH deficiency were identified and diagnosed at a median age of 1.35 years (range 8 weeks-11 years). The presenting features included neonatal cholestasis (n = 11), rickets (n = 8, 1 of whom also had hypocalcaemic tetany, seizures, and normal liver biochemical markers), hepatomegaly (n = 7), pruritus (n = 3), and steatorrhoea and failure to thrive (n = 3). Ten children had low serum 25-OH vitamin D levels, of whom 8 also had low vitamin E and 6 had low vitamin A serum levels. Liver histology showed giant cell change and hepatocyte disarray in all with added features of cholestasis in 11, bridging fibrosis in 6, micronodular cirrhosis in 1, Fatty change in 1, and active lobular and portal inflammation in 1. Five patients were treated with cholic acid and chenodeoxycholic acid (7 mg . kg . day of each), 7 with chenodeoxycholic acid only (7-18 mg . kg . day), and 1 with cholic acid (8 mg . kg . day) only. Repeated liver biopsies performed in 4 patients 6 months after starting replacement therapy showed improved histological changes. Three children died untreated before 5 years of age. After a median follow-up of 5.5 years (range 1-17 years) 12 out of 13 treated children have no clinical signs of liver disease or of fat-soluble vitamin deficiency. CONCLUSIONS:: 3beta-HSDH deficiency is a rare inborn error of metabolism with diverse clinical features. Early replacement treatment leads to clinical and biochemical control and prevents chronic liver and bone disease, at least in the medium term.