scholarly journals AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target

1999 ◽  
Vol 338 (3) ◽  
pp. 783-791 ◽  
Author(s):  
Deborah M. MUOIO ◽  
Kimberly SEEFELD ◽  
Lee A. WITTERS ◽  
Rosalind A. COLEMAN
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Rat Hepatocytes ◽  
C2c12 Myotubes ◽  
Acid Oxidation ◽  
Dependent Manner ◽  
Triacylglycerol Synthesis ◽  
Skeletal Muscle Lipid ◽  
Novel Target

AMP-activated kinase (AMPK) is activated in response to metabolic stresses that deplete cellular ATP, and in both liver and skeletal muscle, activated AMPK stimulates fatty acid oxidation. To determine whether AMPK might reciprocally regulate glycerolipid synthesis, we studied liver and skeletal-muscle lipid metabolism in the presence of 5-amino-4-imidazolecarboxamide (AICA) riboside, a cell-permeable compound whose phosphorylated metabolite activates AMPK. Adding AICA riboside to cultured rat hepatocytes for 3 h decreased [14C]oleate and [3H]glycerol incorporation into triacylglycerol (TAG) by 50% and 38% respectively, and decreased oleate labelling of diacylglycerol by 60%. In isolated mouse soleus, a highly oxidative muscle, incubation with AICA riboside for 90 min decreased [14C]oleate incorporation into TAG by 37% and increased 14CO2 production by 48%. When insulin was present, [14C]oleate oxidation was 49% lower and [14C]oleate incorporation into TAG was 62% higher than under basal conditions. AICA riboside blocked insulin's antioxidative and lipogenic effects, increasing fatty acid oxidation by 78% and decreasing labelled TAG 43%. Similar results on fatty acid oxidation and acylglycerol synthesis were observed in C2C12 myoblasts, and in differentiated C2C12 myotubes, AICA riboside also inhibited the hydrolysis of intracellular TAG. These data suggest that AICA riboside might inhibit sn-glycerol-3-phosphate acyltransferase (GPAT), which catalyses the committed step in the pathway of glycerolipid biosynthesis. Incubating rat hepatocytes with AICA riboside for both 15 and 30 min decreased mitochondrial GPAT activity 22–34% without affecting microsomal GPAT, diacylglycerol acyltransferase or acyl-CoA synthetase activities. Finally, purified recombinant AMPKα1 and AMPKα2 inhibited hepatic mitochondrial GPAT in a time-and ATP-dependent manner. These data show that AMPK reciprocally regulates acyl-CoA channelling towards β-oxidation and away from glycerolipid biosynthesis, and provide strong evidence that AMPK phosphorylates and inhibits mitochondrial GPAT.

scholarly journals Effect of starvation and diabetes on the sensitivity of carnitine palmitoyltransferase I to inhibition by 4-hydroxyphenylglyoxylate

1987 ◽  
Vol 243 (2) ◽  
pp. 405-412 ◽  
Author(s):  
T W Stephens ◽  
R A Harris
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Rat Hepatocytes ◽  
Isolated Hepatocytes ◽  
Carnitine Palmitoyltransferase ◽  
Time Dependent ◽  
Acid Oxidation ◽  
Moderate Increase ◽  
Dependent Manner ◽  
Carnitine Palmitoyltransferase I

The sensitivity of carnitine palmitoyltransferase I to inhibition by 4-hydroxyphenylglyoxylate was decreased markedly in liver mitochondria isolated from either 48 h-starved or streptozotocin-diabetic rats. These treatments of the rat also decreased the sensitivity of fatty acid oxidation by isolated hepatocytes to inhibition by this compound. Furthermore, incubation of hepatocytes prepared from fed rats with N6O2′-dibutyryl cyclic AMP also decreased the sensitivity, whereas incubation of hepatocytes prepared from starved rats with lactate plus pyruvate had the opposite effect on 4-hydroxyphenylglyoxylate inhibition of fatty acid oxidation. The sensitivity of carnitine palmitoyltransferase I of mitochondria to 4-hydroxyphenylglyoxylate increased in a time-dependent manner, as previously reported for malonyl-CoA. Likewise, oleoyl-CoA activated carnitine palmitoyltransferase I in a time-dependent manner and prevented the sensitization by 4-hydroxyphenylglyoxylate. Increased exogenous carnitine caused a moderate increase in fatty acid oxidation by hepatocytes under some conditions and a decreased 4-hydroxyphenylglyoxylate inhibition of fatty acid oxidation at low oleate concentration, without decreasing the difference in 4-hydroxyphenylglyoxylate inhibition between fed- and starved-rat hepatocytes. Time-dependent changes in the conformation of carnitine palmitoyltransferase I or the membrane environment may be involved in differences among nutritional states in 4-hydroxyphenylglyoxylate-sensitivity of carnitine palmitoyltransferase I.

Skeletal muscle lipid metabolism with obesity

2003 ◽  
Vol 284 (4) ◽  
pp. E741-E747 ◽  
Author(s):  
Matthew W. Hulver ◽  
Jason R. Berggren ◽  
Ronald N. Cortright ◽  
Ronald W. Dudek ◽  
R. Peter Thompson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fatty Acyl ◽  
Normal Weight ◽  
Acid Oxidation ◽  
Palmitate Oxidation ◽  
Lower Fatty Acid ◽  
Skeletal Muscle Lipid ◽  
Long Chain

The objectives of this study were to 1) examine skeletal muscle fatty acid oxidation in individuals with varying degrees of adiposity and 2) determine the relationship between skeletal muscle fatty acid oxidation and the accumulation of long-chain fatty acyl-CoAs. Muscle was obtained from normal-weight [ n = 8; body mass index (BMI) 23.8 ± 0.58 kg/m2], overweight/obese ( n = 8; BMI 30.2 ± 0.81 kg/m2), and extremely obese ( n = 8; BMI 53.8 ± 3.5 kg/m2) females undergoing abdominal surgery. Skeletal muscle fatty acid oxidation was assessed in intact muscle strips. Long-chain fatty acyl-CoA concentrations were measured in a separate portion of the same muscle tissue in which fatty acid oxidation was determined. Palmitate oxidation was 58 and 83% lower in skeletal muscle from extremely obese (44.9 ± 5.2 nmol · g−1 · h−1) patients compared with normal-weight (71.0 ± 5.0 nmol · g−1 · h−1) and overweight/obese (82.2 ± 8.7 nmol · g−1 · h−1) patients, respectively. Palmitate oxidation was negatively ( R = −0.44, P = 0.003) associated with BMI. Long-chain fatty acyl-CoA content was higher in both the overweight/obese and extremely obese patients compared with normal-weight patients, despite significantly lower fatty acid oxidation only in the extremely obese. No associations were observed between long-chain fatty acyl-CoA content and palmitate oxidation. These data suggest that there is a defect in skeletal muscle fatty acid oxidation with extreme obesity but not overweight/obesity and that the accumulation of intramyocellular long-chain fatty acyl-CoAs is not solely a result of reduced fatty acid oxidation.

Contribution of FAT/CD36 to the regulation of skeletal muscle fatty acid oxidation: an overview

2008 ◽  
Vol 194 (4) ◽  
pp. 293-309 ◽  
Author(s):  
G. P. Holloway ◽  
J. J. F. P. Luiken ◽  
J. F. C. Glatz ◽  
L. L. Spriet ◽  
A. Bonen
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation

scholarly journals Overexpression of Long-Chain Acyl-CoA Synthetase 5 Increases Fatty Acid Oxidation and Free Radical Formation While Attenuating Insulin Signaling in Primary Human Skeletal Myotubes

2019 ◽  
Vol 16 (7) ◽  
pp. 1157 ◽  
Author(s):  
Hyo-Bum Kwak ◽  
Tracey Woodlief ◽  
Thomas Green ◽  
Julie Cox ◽  
Robert Hickner ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Free Radical ◽  
Fatty Acid Oxidation ◽  
Insulin Signaling ◽  
Human Skeletal Muscle ◽  
Acid Oxidation ◽  
Protein Levels ◽  
Human Skeletal Muscle Cells ◽  
Mitochondrial Fatty Acid

In rodent skeletal muscle, acyl-coenzyme A (CoA) synthetase 5 (ACSL-5) is suggested to localize to the mitochondria but its precise function in human skeletal muscle is unknown. The purpose of these studies was to define the role of ACSL-5 in mitochondrial fatty acid metabolism and the potential effects on insulin action in human skeletal muscle cells (HSKMC). Primary myoblasts isolated from vastus lateralis (obese women (body mass index (BMI) = 34.7 ± 3.1 kg/m2)) were transfected with ACSL-5 plasmid DNA or green fluorescent protein (GFP) vector (control), differentiated into myotubes, and harvested (7 days). HSKMC were assayed for complete and incomplete fatty acid oxidation ([1-14C] palmitate) or permeabilized to determine mitochondrial respiratory capacity (basal (non-ADP stimulated state 4), maximal uncoupled (carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP)-linked) respiration, and free radical (superoxide) emitting potential). Protein levels of ACSL-5 were 2-fold higher in ACSL-5 overexpressed HSKMC. Both complete and incomplete fatty acid oxidation increased by 2-fold (p < 0.05). In permeabilized HSKMC, ACSL-5 overexpression significantly increased basal and maximal uncoupled respiration (p < 0.05). Unexpectedly, however, elevated ACSL-5 expression increased mitochondrial superoxide production (+30%), which was associated with a significant reduction (p < 0.05) in insulin-stimulated p-Akt and p-AS160 protein levels. We concluded that ACSL-5 in human skeletal muscle functions to increase mitochondrial fatty acid oxidation, but contrary to conventional wisdom, is associated with increased free radical production and reduced insulin signaling.

Effect of phosphorylation by AMP-activated protein kinase on palmitoyl-CoA inhibition of skeletal muscle acetyl-CoA carboxylase

2005 ◽  
Vol 98 (4) ◽  
pp. 1221-1227 ◽  
Author(s):  
D. S. Rubink ◽  
W. W. Winder
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Oxidation Rates ◽  
Malonyl Coa ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) has previously been demonstrated to phosphorylate and inactivate skeletal muscle acetyl-CoA carboxylase (ACC), the enzyme responsible for synthesis of malonyl-CoA, an inhibitor of carnitine palmitoyltransferase 1 and fatty acid oxidation. Contraction-induced activation of AMPK with subsequent phosphorylation/inactivation of ACC has been postulated to be responsible in part for the increase in fatty acid oxidation that occurs in muscle during exercise. These studies were designed to answer the question: Does phosphorylation of ACC by AMPK make palmitoyl-CoA a more effective inhibitor of ACC? Purified rat muscle ACC was subjected to phosphorylation by AMPK. Activity was determined on nonphosphorylated and phosphorylated ACC preparations at acetyl-CoA concentrations ranging from 2 to 500 μM and at palmitoyl-CoA concentrations ranging from 0 to 100 μM. Phosphorylation resulted in a significant decline in the substrate saturation curve at all palmitoyl-CoA concentrations. The inhibitor constant for palmitoyl-CoA inhibition of ACC was reduced from 1.7 ± 0.25 to 0.85 ± 0.13 μM as a consequence of phosphorylation. At 0.5 mM citrate, ACC activity was reduced to 13% of control values in response to the combination of phosphorylation and 10 μM palmitoyl-CoA. Skeletal muscle ACC is more potently inhibited by palmitoyl-CoA after having been phosphorylated by AMPK. This may contribute to low-muscle malonyl-CoA values and increasing fatty acid oxidation rates during long-term exercise when plasma fatty acid concentrations are elevated.

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