Kegg Pathway: Fatty acid metabolism

Am J Physiol Regul Integr Comp Physiol. 2009 Nov 4;
van Straten EM, Bloks VW, Huijkman NC, Baller JF, van Meer H, Lutjohann D, Kuipers F, Plosch T

Prenatal nutrition as influenced by nutritional status of the mother has been identified as a determinant of adult disease. Feeding low-protein diets during pregnancy in rodents is a well-established model to induce "programming" events in offspring. We hypothesized that protein restriction would influence fetal lipid metabolism by inducing epigenetic adaptations. Pregnant C57BL/6J mice were exposed to a protein restriction protocol (9% vs. 18% casein). Shortly before birth, dams and fetuses were sacrificed. To identify putative epigenetic changes, CpG island methylation microarrays were performed on DNA isolated from fetal livers. 204 gene promoter regions were differentially methylated upon protein restriction. The liver X-receptor (Lxr) alpha promoter was hypermethylated in protein-restricted pups. Lxr alpha is a nuclear receptor critically involved in control of cholesterol and Fatty acid metabolism. The mRNA level of Lxra was reduced by 32% in fetal liver upon maternal protein restriction, whereas expression of the Lxr target genes Abcg5/Abcg8 was reduced by 56% and 51%, measured by real-time quantitative PCR.. The same effect, although less pronounced, was observed in the fetal intestine. In vitro methylation of a mouse Lxra-promoter/luciferase expression cassette resulted in a 24-fold transcriptional repression. Our study demonstrates that, in mice, protein restriction during pregnancy interferes with DNA methylation in fetal liver. Lxra is a target of differential methylation and Lxra transcription is dependent on DNA methylation. It is tempting to speculate that perinatal nutrition may influence adult lipid metabolism by DNA methylation which may contribute to the epidemiological relation between perinatal/neonatal nutrition and adult disease. Key words: Metabolic programming, epigenetics, DNA methylation, CpG island methylation microarray.

Mol Plant Microbe Interact. 2009 Dec; 22(12): 1492-503
Guenther JC, Hallen-Adams HE, Bücking H, Shachar-Hill Y, Trail F

Fusarium graminearum, a devastating pathogen of small grains, overwinters on crop residues and produces ephemeral perithecia. Accumulation of lipids in overwintering hyphae would provide reserves for overwinter survival and perithecium development. Fatty acid composition of cultures during perithecium development indicated a drop in neutral lipid levels during development but little change in Fatty acid composition across stages. Microscopic examination of cultures early in sexual development revealed hyphal cells engorged with lipid bodies. In comparison, vegetative hyphae contained few lipid bodies. Microarray analysis was performed on wheat stems at stages of colonization through perithecium development. Gene expression analysis during stages of perithecium development both in planta and in vitro (previously published) supports the view that lipid biosynthesis occurs during early stages of wheat colonization leading to sexual development and that lipid oxidation occurs as perithecia are developing. Analysis of gene expression during the stages of wheat stem colonization also revealed sets of genes unique to these stages. These results support the view that lipids accumulate in hyphae colonizing wheat stalks and are subsequently used in perithecium formation on stalk tissue. These results indicate that extensive colonization of plant tissue prior to harvest is essential for subsequent sporulation on crop residues and, thus, has important implications for inoculum reduction.

Am J Physiol Endocrinol Metab. 2009 Nov 3;
Bruss MD, Khambatta CF, Ruby MA, Aggarwal I, Hellerstein MK

Calorie restriction (CR) increases longevity and retards the development of many chronic diseases, but the underlying metabolic signals are poorly understood. Increased Fatty acid (FA) oxidation and reduced FA synthesis have been hypothesized to be important metabolic adaptations to CR. At metabolic steady state, however, FA oxidation must match FA intake plus synthesis; moreover, FA intake is low, not high, during CR. It is therefore not clear how FA dynamics are altered during CR. Accordingly, we measured food intake patterns, whole-body fuel selection, endogenous FA synthesis and gene expression in mice on CR. Within two days of starting CR, a shift occurred to a diurnal, cyclic pattern of whole-body FA metabolism, with an initial phase of elevated endogenous FA synthesis (respiratory exchange ratio [RER]>1.10, lasting 4-6 hours after food provision), followed by a prolonged phase of FA oxidation (RER=0.70, lasting 18-20 hours). CR mice oxidized four times as much fat per day as ad libitum fed (AL) controls (367 +/- 19 vs 97 +/- 14 mg/d, P< O.001) despite reduced energy intake from fat. This increase in FA oxidation was balanced by a 3-fold increase in FA synthesis compared to AL. Expression of Fatty acid synthase and acetyl-CoA carboxylase mRNA were increased in adipose and in liver in a time-dependent manner. We conclude that CR induces a surprising metabolic pattern characterized by periods of elevated FA synthesis alternating with periods of FA oxidation disproportionate to dietary FA intake. This pattern may have implications for oxidative damage and disease risk.

Arch Latinoam Nutr. 2009 Sep; 59(3): 296-303
González Rodríguez DC, Solano R L, González Martínez JC

Adiponectin one of the cytokines secreted by the adipose tissue that regulates the energetic metabolism through glucose and insulin interactions, stimulates the oxidation of Fatty acids, reduces the plasmatic triglycerides and improves glucose metabolism by increasing insulin sensibility. Serum concentrations of adiponectin, insulin and glucose were assessed in order to establish association to weight loss after a dietary regime based on consumption of complex carbohydrates (fiber) during six weeks. Overweight and obese subjects (n=56) were studied by anthropometry. Adiponectin and insulin were measured by ELISA and glucose by Colorimetry. Data was analyzed by non parametric tests to compare independent or related samples. 12 men and 44 women, aged 20 to 55 years, 17 overweight and 39 obese were assessed. Adiponectin concentration was significantly low at basal determination in all the subjects (4,47 +/- 1,64); being higher in women (4,62 +/- 1,57 vs 3,93 +/- 1,86 microU/mL in men), while glucose and insulin values were at normal range (82,46 +/-26,51 mg/dL and 14,12 +/- 10,15 microU/mL) respectively with no significant differences for sex. Overweight subjects had significantly higher adiponectin concentrations than obese participants, at all measurements. Dietary regime promoted significant increase in adiponectin concentration at second and sixth week, with a negative correlation to body mass index and gender as they lost body weight.

Int J Mol Med. 2009 Dec; 24(6): 825-8
Nakamuta M, Yada R, Fujino T, Yada M, Higuchi N, Tanaka M, Miyazaki M, Kohjima M, Kato M, Yoshimoto T, Harada N, Taketomi A, Maehara Y, Koga M, Nishinakagawa T, Nakashima M, Kotoh K, Enjoji M

Recent investigations indicate that hepatitis C virus (HCV) infection is closely associated with hepatocytic lipid metabolism and induces hepatic steatosis. However, the actual lipid metabolism in HCV-infected liver has not been extensively investigated in humans. In this study, we evaluated the expression of lipid metabolism-associated genes in patients with HCV infection by real-time PCR. Sterol regulatory element-binding protein (SREBP)-2 expression was unchanged and low density lipoprotein receptor expression was markedly reduced by 90% in HCV-infected liver. The expression of apolipoprotein B100, microsomal triglyceride transfer protein and ATP-binding cassette G5 was significantly increased. Up-regulation of cholesterol synthesis-associated genes, including HMG-CoA reductase, HMG-CoA synthase, farnesyl-diphosphate synthase and squalene synthase, confirmed enhanced de novo cholesterol synthesis. The expression of cholesterol 7alpha-hydroxylase and farnesoid X receptor was enhanced, while bile salt export pump expression was unchanged. Fatty acid synthase expression was increased which was accompanied by increased expression of liver X receptor alpha and SREBP-1c. In summary, the regulation of lipid metabolism was impaired and cholesterol and Fatty acid synthesis continued to increase without negative feedback in HCV-infected liver. These changes may be beneficial for HCV replication.

Nat Rev Cardiol. 2009 Nov 3;
Aggarwal NR, Martinez MW, Gersh BJ, Chareonthaitawee P

Cardiac resynchronization has emerged as a highly effective therapy for heart failure. However, up to 40% of patients do not benefit from this treatment. In this Review, we discuss the potential role of MRI and nuclear molecular imaging in providing additional insights into the response to cardiac resynchronization therapy. Variables with potential prognostic and therapeutic values include the evaluation of cardiac dyssynchrony, scar, cardiac sympathetic function, myocardial blood flow, myocardial glucose and oxidative metabolism. Other molecular targets to characterize apoptosis, Fatty acid metabolism, angiogenesis and angiotensin-converting enzyme activity will also be described. The potential use of these techniques in identifying and measuring responses to cardiac resynchronization therapy and future areas of research will be explored.

J Insect Physiol. 2009 Oct 30;
Guo L, Zeng XY, Wang DY, Li GQ

Plants produce and release large quantities of methanol, especially when attacked by herbivores. It seems that the herbivores may suffer from methanol intoxication. Here we reported the tolerance to and the metabolism of methanol by Ostrinia furnacalis third-instar larvae. When larvae were exposed to dietary methanol, formaldehyde and formic acid for 72h, the estimated LC(50) value was 28, 40 and 29mg/g diet, respectively. Toxicity of methanol was enhanced by 4-methylpyrazole, 3-amino-1,2,4-triazole and piperonyl butoxide, and toxicity of formaldehyde was increased by 3-amino-1,2,4-triazole and piperonyl butoxide. However, triphenyl phosphate had little synergistic effects on both methanol and formaldehyde. These data indicate that alcohol dehydrogenase, and probably catalase and cytochrome P450 monooxygenase oxidize methanol to formaldehyde, catalase and cytochrome P450 monooxygenase catalyze formaldehyde to formic acid, water and carbon dioxide, and carboxylesterase may have a minor effect. Several Fatty acid methyl esters (FAMEs) were identified from extracts of the frass of larvae which had been exposed to a methanol-contained diet, in contrast to those on a methanol-free artificial diet. In vitro tests revealed that a crude enzyme solution from the larvae could synthesize FAMEs from corresponding Fatty acids and methanol. In addition, dietary methanol induced higher esterase activities in the first-, second- and third-instar larvae. These findings demonstrate that both oxidative metabolism and non-oxidative metabolism are partially responsible for methanol elimination in O. furnacalis larvae.

Cell Metab. 2009 Nov; 10(5): 405-18
Leavens KF, Easton RM, Shulman GI, Previs SF, Birnbaum MJ

Insulin drives the global anabolic response to nutrient ingestion, regulating both carbohydrate and lipid metabolism. Previous studies have demonstrated that Akt2/protein kinase B is critical to insulin's control of glucose metabolism, but its role in lipid metabolism has remained controversial. Here, we show that Akt2 is required for hepatic lipid accumulation in obese, insulin-resistant states induced by either leptin deficiency or high-fat diet feeding. Lep(ob/ob) mice lacking hepatic Akt2 failed to amass triglycerides in their livers, associated with and most likely due to a decrease in lipogenic gene expression and de novo lipogenesis. However, Akt2 is also required for steatotic pathways unrelated to Fatty acid synthesis, as mice fed high-fat diet had reduced liver triglycerides in the absence of hepatic Akt2 but did not exhibit changes in lipogenesis. These data demonstrate that Akt2 is a requisite component of the insulin-dependent regulation of lipid metabolism during insulin resistance.

Cell Metab. 2009 Nov; 10(5): 366-78
Costanzo-Garvey DL, Pfluger PT, Dougherty MK, Stock JL, Boehm M, Chaika O, Fernandez MR, Fisher K, Kortum RL, Hong EG, Jun JY, Ko HJ, Schreiner A, Volle DJ, Treece T, Swift AL, Winer M, Chen D, Wu M, Leon LR, Shaw AS, McNeish J, Kim JK, Morrison DK, Tschöp MH, Lewis RE

Kinase suppressors of Ras 1 and 2 (KSR1 and KSR2) function as molecular scaffolds to potently regulate the MAP kinases ERK1/2 and affect multiple cell fates. Here we show that KSR2 interacts with and modulates the activity of AMPK. KSR2 regulates AMPK-dependent glucose uptake and Fatty acid oxidation in mouse embryonic fibroblasts and glycolysis in a neuronal cell line. Disruption of KSR2 in vivo impairs AMPK-regulated processes affecting Fatty acid oxidation and thermogenesis to cause obesity. Despite their increased adiposity, ksr2(-/-) mice are hypophagic and hyperactive but expend less energy than wild-type mice. In addition, hyperinsulinemic-euglycemic clamp studies reveal that ksr2(-/-) mice are profoundly insulin resistant. The expression of genes mediating oxidative phosphorylation is also downregulated in the adipose tissue of ksr2(-/-) mice. These data demonstrate that ksr2(-/-) mice are highly efficient in conserving energy, revealing a novel role for KSR2 in AMPK-mediated regulation of energy metabolism.

Radiat Res. 2009 Nov; 172(5): 607-16
Zhang Q, Hu JZ, Rommereim DN, Murphy MK, Phipps RP, Huso DL, Dicello JF

Herein we demonstrate that high-resolution magic angle spinning (MAS) 1H NMR can be used to profile the pathology of bone marrow rapidly and with minimal sample preparation. The spectral resolution obtained allows several metabolites to be analyzed quantitatively. The level of NMR-detectable metabolites in the epiphysis + metaphysis sections of mouse femur were significantly higher than that observed in the diaphysis of the same femur. The major metabolite damage to bone marrow resulting from either 3.0 Gy or 7.8 Gy of whole-body gamma radiation 4 days after exposure were (1) decreased total choline content, (2) increased Fatty acids in bone marrow, and (3) decreased creatine content. These results suggest that the membrane choline phospholipid metabolism (MCPM) pathway and the Fatty acid biosynthesis pathway were altered as a result of radiation exposure. We also found that the metabolic damage induced by radiation in the epiphysis + metaphysis sections of mouse femur was higher than that of the diaphysis of the same femur. Traditional histopathology analysis was also carried out to correlate radiation damage with changes in metabolites. Importantly, the molecular information gleaned from high-resolution MAS 1H NMR complements the pathology data.

Proteomics. 2009 Oct 30;
Couté Y, Brunner Y, Schvartz D, Hernandez C, Masselot A, Lisacek FE, Wollheim CB, Sanchez JC

Pancreatic beta-cells are responsible for insulin secretion that regulates blood glucose homeostasis. In the development of type II diabetes, a progressive impairment of insulin secretion by the pancreatic beta-cells occurs called beta-cell dysfunction or beta-cell failure. Chronic hyperglycemia has been shown being involved in beta-cell dysfunction, a phenomenon known as glucotoxicity. The molecular mechanisms underlying the impairment of insulin secretion by beta-cells induced by glucotoxicity are still not fully understood. In this work, quantitative proteomics was employed to identify early key players involved in beta-cell dysfunction induced by glucotoxicity. For this, the stable isotope labeling by amino acids in cell culture (SILAC) strategy was used on the slowly-growing rat â-cell line INS-1E. We showed that the SILAC approach did not induce any detectable biological effects on these beta-cells, as measured at both the transcriptomic and proteomic levels. Proteins differentially expressed between control cells and cells submitted to chronic high glucose concentrations were identified and verified. The results obtained reinforce the link between glucotoxicity and lipogenesis and suggest that the Fatty acid metabolism pathway may rapidly be stimulated in beta-cells submitted to chronic high glucose concentrations.

Chem Pharm Bull (Tokyo). 2009 Nov; 57(11): 1218-22
Yao Z, Gong S, Guan T, Li Y, Wu X, Sun H

The anti-anginal drug Ranolazine, a partial Fatty acid oxidation (pFOX) inhibitor, is thought to modulate the metabolism during myocardial ischemia by activating pyruvate dehydrogenase activity to promote glucose oxidation. Ranolazine and its five principal metabolites: CVT-2512, CVT-2513, CVT-2514, CVT-2738 and CVT-4786, were synthesized. The effect of Ranolazine and its metabolites on the ECG (electrocardiogram) of mice with myocardial ischemia induced by isoprenaline and their effect on alleviating the symptom of myocardial ischemia were tested and compared. The results showed that CVT-2738 and CVT-2513 could be protective against mice myocardial ischemia induced by isoprenaline. Within all the metabolites tested in this study, CVT-2738 exhibited the best potency, however, it was still less potent than Ranolazine.

Placenta. 2009 Oct 30;
Johnsen GM, Weedon-Fekjær MS, Tobin KA, Staff AC, Duttaroy AK

Supplementation of long-chain polyunsaturated Fatty acids (LCPUFAs) is advocated during pregnancy in some countries although very little information is available on their effects on placental ability to take up these Fatty acids for fetal supply to which the fetal growth and development are critically dependent. To identify the roles of LCPUFAs on placental Fatty acid transport function, we examined the effects of LCPUFAs on the uptake of Fatty acids and expression of Fatty acid transport/metabolic genes using placental trophoblast cells (BeWo). Following 24 h incubation of these cells with 100 muM of LCPUFAs (arachidonic acid, 20:4n-6, eicosapentaenoic acid, 20:5n-3, or docosahexaenoic acid, 22:6n-3), the cellular uptake of [(14)C] Fatty acids was increased by 20-50%, and accumulated Fatty acids were preferentially incorporated into phospholipid fractions. Oleic acid (OA, 18:1n-9), on the other hand, could not stimulate Fatty acid uptake. LCPUFAs and OA increased the gene expression of ADRP whilst decreased the expression of ASCL3, ACSL4, ACSL6, LPIN1, and FABP3 in these cells. However, LCPUFAs but not OA increased expression of ACSL1 and ACSL5. Since acyl-CoA synthetases are involved in cellular uptake of Fatty acids via activation for their channelling to lipid metabolism and/or for storage, the increased expression of ACSL1 and ACLS5 by LCPUFAs may be responsible for the increased Fatty acid uptake. These findings demonstrate that LCPUFA may function as an important regulator of general Fatty acid uptake in trophoblast cells and may thus have impact on fetal growth and development.

Biochim Biophys Acta. 2009 Oct 29;
Catalá A

The mammalian pineal gland is a prominent secretory organ with a high metabolic activity. Melatonin (N-acetyl-5-methoxytryptamine), the main secretory product of the pineal gland, efficiently scavenges both the hydroxyl and peroxyl radicals counteracting lipid peroxidation in biological membranes. Approximately 25% of the total Fatty acids present in the rat pineal lipids are represented by arachidonic acid (20:4n-6) and docosahexaenoic acid (22:6n-3). These very long-chain polyunsaturated Fatty acids play important roles in the pineal gland. In addition to the production of melatonin, the mammalian pineal gland is able of convert these polyunsaturated Fatty acids into bioactive lipid mediators. Lipoxygenation is the principal lipoxygenase (LOX) activity observed in the rat pineal gland. Lipoxygenation in the pineal gland is exceptional because no other brain regions express significant LOX activities under normal physiological conditions. The rat pineal gland expresses both 12- and 15- lipoxygenase (LOX) activities, producing 12- and 15- hydroperoxyeicosatetraenoic acid (12- and 15-HpETE) from arachidonic acid, and 14- and 17-hydroxydocosahexaenoic acid (14- and 17-HdoHE) from docosahexaenoic acid respectively. The rat pineal also produces hepoxilins via LOX pathways. The hepoxilins are bioactive epoxy-hydroxy products of the arachidonic acid metabolism via the 12S-lipoxygenase (12S-LOX) pathway. The two key pineal biochemical functions, lipoxygenation and melatonin synthesis, may be synergistically regulated by the status of n-3 essential Fatty acids.

Prog Lipid Res. 2009 Oct 29;
Joyard J, Ferro M, Masselon C, Seigneurin-Berny D, Salvi D, Garin J, Rolland N

Recent advances in the proteomic field have allowed high throughput experiments to be conducted on chloroplast samples and the data are available in several databases such as the Plant Protein Database (PPDB), or the SubCellular Proteomic Database (SUBA). However, the accurate localization of many proteins that were identified in different subplastidial compartments often remains hypothetical, thus making quantitative proteomics important for going a step further into the knowledge of Arabidopsis thaliana chloroplast proteins with regard to their accurate localization within the chloroplast. Spectral counting, a semi-quantitative proteomic strategy based on accurate mass and time tags (AMT), was used to build up AT_CHLORO, a comprehensive chloroplast proteome database with curated subplastidial localization. In this review, we focus on about a hundred enzymes involved in Fatty acid biosynthesis, export and metabolism (desaturation and oxylipin metabolism), in the synthesis of chloroplast-specific glycerolipids either with a eukaryotic or a prokaryotic structure. Two main chloroplast compartments play a major role in lipid biosynthesis: the initial steps of Fatty acid biosynthesis take place in the stroma, then the envelope membranes concentrate most of the proteins involved in chloroplast glycerolipid metabolism.

Adv Cancer Res. 2009; 104: 25-32
Pucci S, Bettuzzi S

Cell transformation is strictly linked to important metabolic changes which are instrumental for initial survival of cancer cells and subsequent spreading of disease. Early (i.e., anerobic glycolysis) and late metabolic changes (i.e., Fatty acid metabolism) are required for progression and clinical emergence of cancer. Besides well-known tumor suppressors and oncogenes, several metabolic genes have been found implicated in this multistep process, among which are Fatty acid synthase (FASN) and carnitine palmitoyl transferase I (CPT I). An intriguing link between these metabolic shifts and a change in the balance between nuclear and secreted forms of CLU (nCLU/sCLU) has been suggested. The shifting balance between CLU forms during tumor progression, by affecting the fate of the cell, seems to be strongly influenced by the metabolic shift occurring in the different steps of tumor progression.

Biochim Biophys Acta. 2009 Oct 27;
Cho KH, Kim HJ, Kamanna VS, Vaziri ND

Background: Mounting evidence point to lipid accumulation in the diseased kidney and its contribution to progression of nephropathy. We recently found heavy lipid accumulation and marked dysregulation of lipid metabolism in the remnant kidneys of rats with chronic renal failure (CRF). Present study sought to determine efficacy of niacin supplementation on renal tissue lipid metabolism in CRF. Methods: Kidney function, lipid content, and expression of molecules involved in cholesterol and Fatty acid metabolism were determined in untreated CRF (5/6 nephrectomized), niacin-treated CRF (50 mg/Kg/day in drinking water for 12 weeks) and control rats. Results: CRF resulted in hypertension, proteinuria, renal tissue lipid accumulation, up-regulation of scavenger receptor A1 (SR-A1), acyl-CoA cholesterol acyltransferase-1 (ACAT1), carbohydrate-responsive element binding protein (ChREBP), Fatty acid synthase (FAS), acyl-CoA carboxylase (ACC), liver X receptor (LXR), ATP binding cassette (ABC) A-1, ABCG-1, and SR-B1 and down-regulation of sterol responsive element binding protein-1 (SREBP-1), SREBP-2, HMG-CoA reductase, PPAR-alpha, Fatty acid binding protein (L-FABP), and CPT1A. Niacin therapy attenuated hypertension, proteinuria, and tubulo-interstitial injury, reduced renal tissue lipids, CD36, ChREBP, LXR, ABCA-1, ABCG-1, and SR-B1 abundance and raised PPAR-alpha and L-FABP. Conclusions and General Significance: Niacin administration improves renal tissue lipid metabolism improves renal function and structure in experimental CRF.

Endocr Res. 2009; 34(4): 130-41
Lv Q, Wang Y, Wang W, Wang L, Zhou X

OBJECTIVE: To investigate the effect of pioglitazone on visfatin expression. METHODS: We studied the effect of pioglitazone on visfatin expression in 3T3-L1 adipocytes and serum concentrations and tissue expression of visfatin in normal Sprague-Dawley rats and rats with insulin resistance induced by high-fat diet (HF). Metabolic and anatomical parameters of the rats were also performed. RESULTS: In 3T3-L1 adipocytes, visfatin expression increased during the differentiation and it was not regulated by pioglitazone. In the rats, 12 weeks of HF feeding induced obesity and increased fast blood glucose (FBG), serum insulin and circulating visfatin. Pioglitazone treatment ameliorated insulin resistance with concomitant reduction in serum visfatin, free Fatty acid, and triglyceride (TG) of the rats fed HF. Compared with subcutaneous adipose tissue and muscle, visfatin protein expression was much higher in visceral adipose tissue on both diets (p < 0.05 for all). Visfatin expression decreased in visceral adipose tissue but not subcutaneous adipose tissue or muscle after pioglitazone treatment in HF-fed rats. Visfatin expression in the rats fed chow diet was not affected by pioglitazone. Additionally, we demonstrated that serum visfatin was positively correlated with visceral adipose tissue weight, visfatin in visceral adipose tissue, TG and FBG (p < 0.05 for all). CONCLUSION: Visfatin is preferentially produced by visceral fat and peroxisome proliferator-activated receptor-gamma agonist ameliorates the development of insulin resistance in HF-fed rats with a major decrease in visfatin expression, the effect of pioglitazone on visfatin in HF-fed rats is dependent on glucose and lipid metabolism in the animals.

Hepatology. 2009 Aug 25;
Fiorentino L, Vivanti A, Cavalera M, Marzano V, Ronci M, Fabrizi M, Menini S, Pugliese G, Menghini R, Khokha R, Lauro R, Urbani A, Federici M

Tumor necrosis factor alpha-converting enzyme (TACE, also known as ADAM17) was recently involved in the pathogenesis of insulin resistance. We observed that TACE activity was significantly higher in livers of mice fed a high-fat diet (HFD) for 1 month, and this activity was increased in liver > white adipose tissue > muscle after 5 months compared with chow control. In mouse hepatocytes, C(2)C(12) myocytes, and 3T3F442A adipocytes, TACE activity was triggered by palmitic acid, lipolysaccharide, high glucose, and high insulin. TACE overexpression significantly impaired insulin-dependent phosphorylation of AKT, GSK3, and FoxO1 in mouse hepatocytes. To test the role of TACE activation in vivo, we used tissue inhibitor of metalloproteinase 3 (Timp3) null mice, because Timp3 is the specific inhibitor of TACE and Timp3(-/-) mice have higher TACE activity compared with wild-type (WT) mice. Timp3(-/-) mice fed a HFD for 5 months are glucose-intolerant and insulin-resistant; they showed macrovesicular steatosis and ballooning degeneration compared with WT mice, which presented only microvesicular steatosis. Shotgun proteomics analysis revealed that Timp3(-/-) liver showed a significant differential expression of 38 proteins, including lower levels of adenosine kinase, methionine adenosysltransferase I/III, and glycine N-methyltransferase and higher levels of liver Fatty acid-binding protein 1. These changes in protein levels were also observed in hepatocytes infected with adenovirus encoding TACE. All these proteins play a role in Fatty acid uptake, triglyceride synthesis, and methionine metabolism, providing a molecular explanation for the increased hepatosteatosis observed in Timp3(-/-) compared with WT mice. Conclusion: We have identified novel mechanisms, governed by the TACE-Timp3 interaction, involved in the determination of insulin resistance and liver steatosis during overfeeding in mice. (HEPATOLOGY 2009.).

Obesity (Silver Spring). 2009 Oct 29;
Araya J, Rodrigo R, Pettinelli P, Araya AV, Poniachik J, Videla LA

Steatosis in obese nonalcoholic Fatty liver disease (NAFLD) patients is a clinicopathological condition associated with depletion of n-3 polyunsaturated Fatty acids (PUFA), a feature that may be related to PUFA desaturation. Liver Delta-6 and Delta-5 desaturase (Delta-6D and Delta-5D) activities, homeostasis model assessment of insulin resistance (HOMA(IR)), and ferric reducing ability of plasma (FRAP) were evaluated in 13 obese patients who underwent subtotal gastrectomy with gastro-jejunal anastomosis in Roux-en-Y and 15 nonobese patients who underwent laparoscopic cholecystectomy (controls). Liver Delta-6D and Delta-5D activities in obese patients were 87% and 66% lower than controls (P < 0.001), respectively, with a 62% diminution in the Delta-6D/Delta-5D activity ratio (P < 0.02). Delta-6D inversely correlated with both HOMA(IR) (r = -0.70, P < 0.0001) and oxidative stress assessed as the reciprocal value of FRAP (r = -0.40, P < 0.05). Delta-5D negatively correlated with HOMA(IR) (r = -0.48, P < 0.01) but not with FRAP(-1) (r = -0.13, not significant). In conclusion, liver PUFA desaturation is diminished in obese NAFLD patients, in association with underlying insulin resistance and oxidative stress, which may play a role in altering lipid metabolism favoring Fatty infiltration.