scholarly journals Novel Insights Into Fatty Acid Oxidation, Amino Acid Metabolism, and Insulin Secretion From Studying Patients With Loss of Function Mutations in 3-Hydroxyacyl-CoA Dehydrogenase

2013 ◽  
Vol 98 (2) ◽  
pp. 496-501 ◽  
Author(s):  
Amanda J. Heslegrave ◽  
Khalid Hussain
Keyword(s):  
Insulin Secretion ◽  
Fatty Acid ◽  
Amino Acid ◽  
Fatty Acid Oxidation ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Acid Oxidation ◽  
Loss Of Function ◽  
Hydroxyacyl Coa Dehydrogenase

scholarly journals Impaired amino acid metabolism contributes to fasting-induced hypoglycemia in fatty acid oxidation defects

2013 ◽  
Vol 22 (25) ◽  
pp. 5249-5261 ◽  
Author(s):  
Sander M. Houten ◽  
Hilde Herrema ◽  
Heleen te Brinke ◽  
Simone Denis ◽  
Jos P.N. Ruiter ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Amino Acid ◽  
Fatty Acid Oxidation ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Acid Oxidation

Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with hyperinsulinism: a novel glucose–fatty acid cycle?

2003 ◽  
Vol 31 (6) ◽  
pp. 1137-1139 ◽  
Author(s):  
S. Eaton ◽  
I. Chatziandreou ◽  
S. Krywawych ◽  
S. Pen ◽  
P.T. Clayton ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Dehydrogenase Deficiency ◽  
Short Chain ◽  
Acid Oxidation ◽  
Β Cells ◽  
Molecular Defects ◽  
Glucose Fatty Acid Cycle ◽  
Hydroxyacyl Coa Dehydrogenase

Hyperinsulinism of infancy is caused by inappropriate insulin secretion in pancreatic β-cells, even when blood glucose is low. Several molecular defects are known to cause hyperinsulinism of infancy, such as KATP channelopathies and regulatory defects of glucokinase and glutamate dehydrogenase. Although defects of fatty acid oxidation have not previously been known to cause hyperinsulinism, patients with deficiency in SCHAD (short-chain 3-hydroxyacyl-CoA dehydrogenase; an enzyme of mitochondrial β-oxidation) have hyperinsulinism. A novel link between fatty acid oxidation and insulin secretion may explain hyperinsulinism in these patients.

scholarly journals Pancreatic Islet Adaptation to Fasting Is Dependent on Peroxisome Proliferator-Activated Receptor α Transcriptional Up-Regulation of Fatty Acid Oxidation

Endocrinology ◽  
2005 ◽  
Vol 146 (1) ◽  
pp. 375-382 ◽  
Author(s):  
Sandrine Gremlich ◽  
Christopher Nolan ◽  
Raphaël Roduit ◽  
Rémy Burcelin ◽  
Marie-Line Peyot ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Pancreatic Islet ◽  
Cellular Response ◽  
Uncoupling Protein ◽  
Acid Oxidation ◽  
Hyperinsulinemic Hypoglycemia ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

The cellular response to fasting and starvation in tissues such as heart, skeletal muscle, and liver requires peroxisome proliferator-activated receptor-α (PPARα)-dependent up-regulation of energy metabolism toward fatty acid oxidation (FAO). PPARα null (PPARαKO) mice develop hyperinsulinemic hypoglycemia in the fasting state, and we previously showed that PPARα expression is increased in islets at low glucose. On this basis, we hypothesized that enhanced PPARα expression and FAO, via depletion of lipid-signaling molecule(s) for insulin exocytosis, are also involved in the normal adaptive response of the islet to fasting. Fasted PPARαKO mice compared with wild-type mice had supranormal ip glucose tolerance due to increased plasma insulin levels. Isolated islets from the PPARα null mice had a 44% reduction in FAO, normal glucose use and oxidation, and enhanced glucose-induced insulin secretion. In normal rats, fasting for 24 h increased islet PPARα, carnitine palmitoyltransferase 1, and uncoupling protein-2 mRNA expression by 60%, 62%, and 82%, respectively. The data are consistent with the view that PPARα, via transcriptionally up-regulating islet FAO, can reduce insulin secretion, and that this mechanism is involved in the normal physiological response of the pancreatic islet to fasting such that hypoglycemia is avoided.

scholarly journals Lactobacillus frumenti mediates energy production via fatty acid β-oxidation in the liver of early-weaned piglets

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhichang Wang ◽  
Jun Hu ◽  
Wenyong Zheng ◽  
Tao Yang ◽  
Xinkai Wang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Amino Acid ◽  
Gut Microbiota ◽  
Oral Administration ◽  
Energy Production ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Critical Role ◽  
Guanosine Monophosphate ◽  
Weaned Piglets

Abstract Background Early-weaning of piglets is often accompanied by severe disorders, especially diarrhea. The gut microbiota and its metabolites play a critical role in the maintenance of the physiologic and metabolic homeostasis of the host. Our previous studies have demonstrated that oral administration of Lactobacillus frumenti improves epithelial barrier functions and confers diarrhea resistance in early-weaned piglets. However, the metabolic response to L. frumenti administration remains unclear. Then, we conducted simultaneous serum and hepatic metabolomic analyses in early-weaned piglets administered by L. frumenti or phosphate-buffered saline (PBS). Results A total of 100 6-day-old crossbred piglets (Landrace × Yorkshire) were randomly divided into two groups and piglets received PBS (sterile, 2 mL) or L. frumenti (suspension in PBS, 108 CFU/mL, 2 mL) by oral administration once per day from 6 to 20 days of age. Piglets were weaned at 21 days of age. Serum and liver samples for metabolomic analyses were collected at 26 days of age. Principal components analysis (PCA) showed that L. frumenti altered metabolism in serum and liver. Numerous correlations (P < 0.05) were identified among the serum and liver metabolites that were affected by L. frumenti. Concentrations of guanosine monophosphate (GMP), inosine monophosphate (IMP), and uric acid were higher in serum of L. frumenti administration piglets. Pathway analysis indicated that L. frumenti regulated fatty acid and amino acid metabolism in serum and liver. Concentrations of fatty acid β-oxidation related metabolites in serum (such as 3-hydroxybutyrylcarnitine, C4-OH) and liver (such as acetylcarnitine) were increased after L. frumenti administration. Conclusions Our findings suggest that L. frumenti regulates lipid metabolism and amino acid metabolism in the liver of early-weaned piglets, where it promotes fatty acid β-oxidation and energy production. High serum concentrations of nucleotide intermediates, which may be an alternative strategy to reduce the incidence of diarrhea in early-weaned piglets, were further detected. These findings broaden our understanding of the relationships between the gut microbiota and nutrient metabolism in the early-weaned piglets.

scholarly journals Fatty acid oxidation inhibitor etomoxir suppresses tumor progression and induces cell cycle arrest via PPARγ-mediated pathway in bladder cancer

2019 ◽  
Vol 133 (15) ◽  
pp. 1745-1758 ◽  
Author(s):  
Songtao Cheng ◽  
Gang Wang ◽  
Yejinpeng Wang ◽  
Liwei Cai ◽  
Kaiyu Qian ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bladder Cancer ◽  
Fatty Acid ◽  
Tumor Progression ◽  
Cell Cycle Arrest ◽  
Fatty Acid Oxidation ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Acid Oxidation ◽  
Cycle Arrest

Abstract Tumor cells rely on aerobic glycolysis as their main energy resource (Warburg effect). Recent research has highlighted the importance of lipid metabolism in tumor progression, and certain cancers even turn to fatty acids as the main fuel. Related studies have identified alterations of fatty acid metabolism in human bladder cancer (BCa). Our microarray analysis showed that fatty acid metabolism was activated in BCa compared with normal bladder. The free fatty acid (FFA) level was also increased in BCa compared with paracancerous tissues. Inhibition of fatty acid oxidation (FAO) with etomoxir caused lipid accumulation, decreased adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide phosphate (NADPH) levels, suppressed BCa cell growth in vitro and in vivo, and reduced motility of BCa cells via affecting epithelial–mesenchymal transition (EMT)-related proteins. Furthermore, etomoxir induced BCa cell cycle arrest at G0/G1 phase through peroxisome proliferator-activated receptor (PPAR) γ-mediated pathway with alterations in fatty acid metabolism associated gene expression. The cell cycle arrest could be reversed by PPARγ antagonist GW9662. Taken together, our results suggest that inhibition of FAO with etomoxir may provide a novel avenue to investigate new therapeutic approaches to human BCa.

scholarly journals Two mechanisms produce tissue-specific inhibition of fatty acid oxidation by oxfenicine

1985 ◽  
Vol 227 (2) ◽  
pp. 651-660 ◽  
Author(s):  
T W Stephens ◽  
A J Higgins ◽  
G A Cook ◽  
R A Harris
Keyword(s):  
Fatty Acid ◽  
Amino Acid ◽  
Fatty Acid Oxidation ◽  
Carnitine Palmitoyltransferase ◽  
Partial Purification ◽  
Acid Oxidation ◽  
Branched Chain Amino Acid ◽  
Malonyl Coa ◽  
Carnitine Palmitoyltransferase I ◽  
Branched Chain

Oxfenicine [S-2-(4-hydroxyphenyl)glycine] is transaminated in heart and liver to 4-hydroxyphenylglyoxylate, an inhibitor of fatty acid oxidation shown in this study to act at the level of carnitine palmitoyltransferase I (EC 2.3.1.21). Oxfenicine was an effective inhibitor of fatty acid oxidation in heart, but not in liver. Tissue specificity of oxfenicine inhibition of fatty acid oxidation was due to greater oxfenicine transaminase activity in heart and to greater sensitivity of heart carnitine palmitoyltransferase I to inhibition by 4-hydroxyphenylglyoxylate [I50 (concentration giving 50% inhibition) of 11 and 510 microM for the enzymes of heart and liver mitochondria, respectively]. Branched-chain-amino-acid aminotransferase (isoenzyme I, EC 2.6.1.42) was responsible for the transamination of oxfenicine in heart. A positive correlation was found between the capacity of various tissues to transaminate oxfenicine and the known content of branched-chain-amino-acid aminotransferase in these tissues. Out of three observed liver oxfenicine aminotransferase activities, one may correspond to asparagine aminotransferase, but the major activity could not be identified by partial purification and characterization. As reported previously for malonyl-CoA inhibition of carnitine palmitoyltransferase I, 4-hydroxyphenylglyoxylate inhibition of this enzyme was found to be very pH-dependent. In striking contrast with the kinetics of malonyl-CoA inhibition, 4-hydroxyphenylglyoxylate inhibition was not affected by oleoyl-CoA concentration, but was partially reversed by increasing carnitine concentrations.

Fatty Acid Oxidation by Skeletal Muscle During Rest and Activity

1958 ◽  
Vol 194 (2) ◽  
pp. 379-386 ◽  
Author(s):  
Irving B. Fritz ◽  
Don G. Davis ◽  
Robert H. Holtrop ◽  
Harold Dundee
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Palmitic Acid ◽  
Fatty Acid Oxidation ◽  
Latissimus Dorsi ◽  
Acid Metabolism ◽  
Fat Metabolism ◽  
Acid Oxidation ◽  
Stimulation Of

The metabolism of C14-labeled acetate, octanoate and palmitate by isolated skeletal muscle (latissimus dorsi and diaphragm) from normal, fed rats has been examined. The rates at which these substrates were converted to C14O2 have been shown to vary with concentration, temperature, functional state of the muscle, and the presence of albumin. Increased concentration of fatty acids led to enhanced conversion of substrate to C14O2. Electrical stimulation of muscles under tension resulted in approximately a 60% increase in oxygen consumption and about a 100% rise in fatty acid oxidation. The addition of glucose did not alter the rate of fatty acid metabolism by muscle. The addition of bovine albumin at concentrations up to approximately 1 µm albumin/7 µm palmitate resulted in augmented palmitic acid oxidation. However, at concentrations of albumin greater than 1 µm albumin/7 µm palmitate, palmitic acid degradation by resting diaphragm was inhibited, suggesting a firmer binding of fatty acid to albumin. The Q10 for palmitic acid oxidation by resting diaphragm was 2.23 in the absence of added albumin between 25° and 37°C. The data are discussed in relation to the present concepts of fat metabolism and transport in vivo. It is suggested that fat degradation in isolated muscle may provide an energy source during activity.

scholarly journals PERK participates in cardiac valve development via fatty acid oxidation and endocardial-mesenchymal transformation

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Takashi Shimizu ◽  
Kazuaki Maruyama ◽  
Takeshi Kawamura ◽  
Yoshihiro Urade ◽  
Youichiro Wada
Keyword(s):  
Endoplasmic Reticulum ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Umbilical Vein ◽  
Conditional Knockout ◽  
Cardiac Valve ◽  
Acid Oxidation ◽  
Loss Of Function ◽  
Mesenchymal Transformation ◽  
Valve Formation

AbstractProtein kinase R-like endoplasmic reticulum kinase (PERK) is one of the endoplasmic reticulum (ER) stress sensors. PERK loss-of-function mutations are known to cause Wolcott–Rallison syndrome. This disease is characterized by early-onset diabetes mellitus, skeletal dysplasia, and cardiac valve malformation. To understand the role of PERK in valve formation in vivo, we used an endothelial-specific PERK conditional knockout mice as well as in vitro PERK inhibition assays. We used ProteoStat dyes to visualize the accumulation of misfolded proteins in the endocardial cushion and valve mesenchymal cells (VMCs). Then, VMCs were isolated from E12.5 fetal mice, by fluorescence assisted cell sorting. Proteomic analysis of PERK-deleted VMCs identified the suppression of proteins related to fatty acid oxidation (FAO), especially carnitine palmitoyltransferase II (CPT2). CPT2 is a critical regulator of endocardial-mesenchymal transformation (EndoMT); however how TGF-β downstream signaling controls CPT2 expression remains unclear. Here, we showed that PERK inhibition suppressed, not only EndoMT but also CPT2 protein expression in human umbilical vein endothelial cells (HUVECs) under TGF-β1 stimulation. As a result, PERK inhibition suppressed mitochondrial metabolic activity. Taken together, these results demonstrate that PERK signaling is required for cardiac valve formation via FAO and EndoMT.

Effect of hyperglycemia-hyperinsulinemia on whole body and regional fatty acid metabolism

1999 ◽  
Vol 276 (3) ◽  
pp. E427-E434 ◽  
Author(s):  
Labros S. Sidossis ◽  
Bettina Mittendorfer ◽  
David Chinkes ◽  
Eric Walser ◽  
Robert R. Wolfe
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Fatty Acid Uptake ◽  
Whole Body ◽  
Acid Oxidation ◽  
Acid Uptake ◽  
Similar Extent ◽  
Body Level

The effects of combined hyperglycemia-hyperinsulinemia on whole body, splanchnic, and leg fatty acid metabolism were determined in five volunteers. Catheters were placed in a femoral artery and vein and a hepatic vein. U-13C-labeled fatty acids were infused, once in the basal state and, on a different occasion, during infusion of dextrose (clamp; arterial glucose 8.8 ± 0.5 mmol/l). Lipids and heparin were infused together with the dextrose to maintain plasma fatty acid concentrations at basal levels. Fatty acid availability in plasma and fatty acid uptake across the splanchnic region and the leg were similar during the basal and clamp experiments. Dextrose infusion decreased fatty acid oxidation by 51.8% (whole body), 47.4% (splanchnic), and 64.3% (leg). Similarly, the percent fatty acid uptake oxidized decreased at the whole body level (53 to 29%), across the splanchnic region (30 to 13%), and in the leg (48 to 22%) during the clamp. We conclude that, in healthy men, combined hyperglycemia-hyperinsulinemia inhibits fatty acid oxidation to a similar extent at the whole body level, across the leg, and across the splanchnic region, even when fatty acid availability is constant.

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