Malonyl–coenzyme A (malonyl-CoA), generated by acetyl-CoA carboxylases ACC1 and ACC2, is a key metabolite in the regulation of energy homeostasis. Here, we show that Acc2 −/− mutant mice have normal life span, higher fatty acid oxidation rate, lower amounts fat. In comparison to wild type, Acc2-deficient had 10- 30-fold levels malonyl-CoA heart muscle, respectively. The rate soleus muscle was 30% than wild-type not affected addition insulin; however, insulin reduced 45%. accumulated 50% less...

Animals, including humans, express two isoforms of acetyl-CoA carboxylase (EC 6.4.1.2 ), ACC1 ( M r = 265 kDa) and ACC2 280 kDa). The predicted amino acid sequence contains an additional 136 aa relative to ACC1, 114 which constitute the unique N-terminal ACC2. hydropathic profiles ACC generally are comparable, except for in residues 1–20 is highly hydrophobic, suggesting that it a leader targets insertion into membranes. subcellular localization mammalian cells was determined by performing...

Malonyl-CoA, generated by acetyl-CoA carboxylases ACC1 and ACC2, is a key metabolite in the control of fatty acid synthesis oxidation response to dietary changes. ACC2 associated mitochondria, Acc2-/- mice have normal lifespan higher rate accumulate less fat. Mutant fed high-fat/high-carbohydrate diets weighed than their WT cohorts, accumulated fat, maintained levels insulin glucose, whereas became type-2 diabetic with hyperglycemic hyperinsulinemic status. Fatty rates soleus muscle...

Acetyl-CoA carboxylase 2 (ACC)2 is a key regulator of mitochondrial fat oxidation. To examine the impact ACC2 deletion on whole-body energy metabolism, we measured changes in substrate oxidation and total expenditure Acc2(-/-) WT control mice fed either regular or high-fat diets. determine insulin action vivo, also insulin-stimulated liver muscle glucose metabolism during hyperinsulinemic-euglycemic clamp diet. Contrary to previous studies that have suggested increased might result lower...

In animals, liver and white adipose are the main sites for de novo fatty acid synthesis. Deletion of synthase or acetyl-CoA carboxylase (ACC) 1 in mice resulted embryonic lethality, indicating that synthesis is essential development. To understand importance role ACC1-produced malonyl-CoA adult mouse tissues, we generated liver-specific ACC1 knockout (LACC1KO) mice. LACC1KO have no obvious health problem under normal feeding conditions. Total ACC activity levels were approximately 70-75%...

Acetyl-CoA carboxylases (ACC1 and ACC2) catalyze the carboxylation of acetyl-CoA to form malonyl-CoA, an intermediate metabolite that plays a pivotal role in regulation fatty acid metabolism. We previously reported ACC2 null mice are viable, important oxidation through inhibition carnitine palmitoyltransferase I, mitochondrial component fatty-acyl shuttle system. Herein, we used gene targeting knock out ACC1 gene. The heterozygous mutant (Acc1(+/-)) had normal fertility lifespans maintained...

Constitutive androstane receptor CAR (NR1I3) has been identified as a central mediator of coordinate responses to xenobiotic and endobiotic stress. Here we use leptin-deficient mice (ob/ob) ob/ob, CAR(-/-) double mutant identify metabolic role in type 2 diabetes. Activation significantly reduces serum glucose levels improves tolerance insulin sensitivity. Gene expression analyses hyperinsulinemic euglycemic clamp results suggest that activation ameliorates hyperglycemia by suppressing...

In animals, including humans, the source of long-chain saturated fatty acids is de novo synthesis, which mediated by acid synthase (FAS), ingested food, or both. To understand importance we generated FAS knockout mice. The heterozygous mutants (Fasn+/-) are ostensibly normal. Fasn+/- mice levels mRNA and activity approximately 50% 35% lower, respectively, than those WT mice; hence, affected gene dosage. When mutant were interbred, Fasn-/- not produced; thus, essential during embryonic...

Fatty acid synthase (FAS; EC 2.3.1.85) was purified to near homogeneity from a human hepatoma cell line, HepG2. The HepG2 FAS has specific activity of 600 nmol NADPH oxidized per min mg, which is about half that chicken liver FAS. All the partial activities are comparable those other animal FASs, except for beta-ketoacyl synthase, whose significantly lower attributable low 4'-phosphopantetheine content We cloned brain cDNA. cDNA sequence an open reading frame 7512 bp encodes 2504 amino acids...

We have cloned and sequenced the cDNA coding for human HepG2 acetyl-CoA carboxylase (ACC; EC 6.4.1.2). The sequence has an open reading frame of 7038 bp that encode 2346 amino acids (M(r), 264,737). C-terminal 2.6-kb is very different from recently reported ACC (Ha, J., Daniel, S., Kong, I.-S., Park, C.-K., Tae, H.-J. & Kim, K.-H. [1994] Eur. J. Biochem. 219, 297-306). Northern blot analysis revealed mRNA approximately 10 kb in size its level varies among tissues tested. Evidence...

Acc2 -/- mutant mice, when fed a high-fat/high-carbohydrate (HF/HC) diet, were protected against diet-induced obesity and diabetes. To investigate the role of acetyl-CoA carboxylase 2 (ACC2) in regulation energy metabolism adipose tissues, we studied fatty acid glucose oxidation primary cultures adipocytes isolated from wild-type mice either normal chow or HF/HC diet. When chow, [ 14 C]palmitate was ≈80% higher than WT it remained significantly presence insulin. Interestingly, addition to...

Hepatic fat accumulation resulting from increased de novo fatty acid synthesis leads to hepatic steatosis and insulin resistance. We have shown previously that acetyl-CoA carboxylase 2 (Acc2(-/-)) mutant mice, when fed a high-fat (HF) or high-fat, high-carbohydrate (HFHC) diet, are protected against diet-induced obesity maintained whole body sensitivity. To determine the effect of an ACC2 deletion on metabolism, we studied regulation enzymes involved in lipogenic pathway under Western HFHC...

Fatostatin, a recently discovered small molecule that inhibits activation of sterol regulatory element-binding protein (SREBP), blocks biosynthesis and accumulation fat in obese mice. We synthesized evaluated series fatostatin derivatives. Our structure-activity relationships led to the identification N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenyl)methanesulfonamide (24, FGH10019) as most potent druglike among analogues tested. Compound 24 has high aqueous solubility membrane permeability...

The cardiac-enriched isoform of acetyl-CoA carboxylase (ACC2) is a key regulator mitochondrial fatty acid (FA) uptake via carnitine palmitoyltransferase 1 (CPT1). To test the hypothesis that oxidative metabolism upregulated in hearts from animals lacking ACC2 (employing transgenic Acc2-mutant mouse), we assessed cardiac function vivo and determined rates myocardial substrate oxidation ex vivo. When examined by echocardiography, there was no difference systolic function, but left ventricular...

Understanding the mechanisms of CD4 memory T cell (Tmem) differentiation in malaria is critical for vaccine development. However, metabolic regulation Tmem not clear, particularly persistent infections. In this study, we investigated role fatty acid synthesis (FAS) development Plasmodium chabaudi chronic mouse infection. We show that cell-specific deletion and early pharmaceutical inhibition acetyl CoA carboxylase 1, rate limiting step FAS, inhibit generation precursor effector cells (MPEC)....

DL-alpha-Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, prevented the increases in putrescine and spermidine, but not spermine, human erythrocytes infected with malarial parasite Plasmodium falciparum. The addition to these polyamine-depleted cultures restored normal concentrations whereas that even exceeded control cultures. DFMO also inhibited incorporation radioactive amino acids into proteins parasitized erythrocytes. Electrophoresis on...

Malonic acid (MA), methylmalonic (MMA), and ethylmalonic (EMA) metabolites are implicated in various non-cancer disorders that associated with inborn-error metabolism. In this study, we have slightly modified the published 3-nitrophenylhydrazine (3NPH) derivatization method applied it to derivatize MA, MMA, EMA their hydrazone derivatives, which were amenable for liquid chromatography- mass spectrometry (LC-MS) quantitation. 3NPH was used EMA, multiple reaction monitoring (MRM) transitions...

DNA polymerase from the malarial parasite Plasmodium falciparum required Mg2+ for activity, Putrescine (1 mM) caused a twofold increase in enzyme activity presence of suboptimal concentration MgCl2 (2 mM). Spermidine (1.5-2.0 or spermine (0.1-0.3 increased polymerase, 2 mM MgCl2, by factors 6 and 3-5, respectively. The calf thymus NIH 3T3 cells transformed ras oncogene were not stimulated these polyamines to same extent. These findings suggest that malaria-infected erythrocytes, polyamines,...