Distinct roles of specific fatty acids in cellular processes: implications for interpreting and reporting experiments

Watt, Matthew J.; Hoy, Andrew J.; Muoio, Deborah M.; Coleman, Rosalind A.

doi:10.1152/ajpendo.00418.2011

Cited by 51 publications

(51 citation statements)

References 17 publications

(16 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The concentration of lipids used for our experiments (200 M) is similar to previous reports (36) and is in the recommended range to simulate in vivo conditions (37). Importantly, the effects of lipids on PKA signaling were dose-dependent (data not shown) and did not decrease cell viability (rod-shaped cells after 18-h incubations).…”

Section: Discussionsupporting

confidence: 65%

cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart

Humphries

2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Diabetes mellitus causes cardiac dysfunction and heart failure that is associated with metabolic abnormalities and autonomic impairment. Autonomic control of ventricular function occurs through regulation of cAMP-dependent protein kinase (PKA). The diabetic heart has suppressed ␤-adrenergic responsiveness, partly attributable to receptor changes, yet little is known about how PKA signaling is directly affected. Control and streptozotocin-induced diabetic mice were therefore administered 8-bromo-cAMP (8Br-cAMP) acutely to activate PKA in a receptorindependent manner, and cardiac hemodynamic function and PKA signaling were evaluated. In response to 8Br-cAMP treatment, diabetic mice had impaired inotropic and lusitropic responses, thus demonstrating postreceptor defects. This impaired signaling was mediated by reduced PKA activity and PKA catalytic subunit content in the cytoplasm and myofilaments. Compartment-specific loss of PKA was reflected by reduced phosphorylation of discrete substrates. In response to 8Br-cAMP treatment, the glycolytic activator PFK-2 was robustly phosphorylated in control animals but not diabetics. Control adult cardiomyocytes cultured in lipid-supplemented media developed similar changes in PKA signaling, suggesting that lipotoxicity is a contributor to diabetes-induced ␤-adrenergic signaling dysfunction. This work demonstrates that PKA signaling is impaired in diabetes and suggests that treating hyperlipidemia is vital for proper cardiac signaling and function.Diabetes mellitus carries at least twice the risk of cardiovascular complications such as coronary artery disease, hypertension, and heart failure (1, 2). Diabetes can directly cause heart failure, in the case of diabetic cardiomyopathy, as well as exacerbate other comorbidities (3, 4). The reasons for this are multifaceted and involve both metabolic and mechanical cardiac stresses. Metabolic abnormalities include metabolic inflexibility caused by improper glucose uptake and oxidation and by lipotoxicity induced by lipid overload (5). Diabetes, in common with other forms of heart failure, has impairment of autonomic control and overstimulation of the sympathetic nervous system (6, 7). The etiology of chronic cardiac stimulation in diabetes is characterized by sympathetic enhancement and parasympathetic withdrawal (3, 8). Excess sympathetic stimulation over time causes extensive dysfunction to the ␤-adrenergic pathway, a process that is intimately tied with heart failure (9, 10).Normally, ligand binding to ␤ 1 -receptors activates G s proteins, which stimulate adenylate cyclase to produce cAMP. The primary target of cAMP is cAMP-dependent protein kinase (PKA), 2 a heterotetrameric protein comprised of two catalytic (PKA-C) and two regulatory subunits (either PKA-RI or PKA-RII isoforms). cAMP binds PKA-R subunits and induces the release of PKA-C, which then phosphorylates specific serines and threonines on protein targets in the cytoplasm, myofilaments, sarcoplasmic reticulum, sarcolemma, and nucleus to increase cardiac output, metab...

show abstract

Section: Discussionsupporting

confidence: 65%

cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart

Humphries

2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…However, most experiments have used supraphysiologic levels of FA, usually palmitate, which is toxic when given alone to cells (46,47). We show here that chronic exposure (72 h) at a physiologic level of the omega-6 PUFAs AA or linoleate to INS 832/13 cells reduces Acsl4 expression in a dose-dependent manner together with a reduction in GSIS.…”

Section: Discussionmentioning

confidence: 67%

Diminished Acyl-CoA Synthetase Isoform 4 Activity in INS 832/13 Cells Reduces Cellular Epoxyeicosatrienoic Acid Levels and Results in Impaired Glucose-stimulated Insulin Secretion

Klett

Chen

Edin

et al. 2013

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background:The role of intracellular lipid metabolism as it relates to nutrient-coupled glucose-stimulated insulin secretion has not been fully elucidated. Results: Knockdown of acyl-CoA synthetase isoform 4 impairs glucose-stimulated insulin secretion caused by decreased cellular epoxyeicosatrienoic acids. Conclusion: Acyl-CoA synthetase 4 is required for optimal glucose-stimulated insulin secretion. Significance: Understanding the role of beta-cell lipid metabolism is needed to develop novel strategies to enhance insulin secretion.

show abstract

“…Therefore, we examined 14 C-oleate oxidation after a 24-h pulse with 500 mmol/L oleate (in the absence of carnitine to label the endogenous lipid pool). Oleate was chosen instead of palmitate because of the lipotoxic effects of palmitate on myotubes (28,29). Confirming the lower 14 C-palmitate incorporation into TAG, incorporation of 14 C-oleate into the total lipid pool after 24 h was significantly lower (1.7-fold) in myotubes from individuals with T2D (controls: 16.3 6 2.40 nmol/mg protein; T2D: 9.5 6 0.78 nmol/mg protein; P = 0.02) (Fig.…”

Section: Endogenous Fa Metabolismmentioning

confidence: 99%

Reduced Incorporation of Fatty Acids Into Triacylglycerol in Myotubes From Obese Individuals With Type 2 Diabetes

et al. 2014

View full text Add to dashboard Cite

Altered skeletal muscle lipid metabolism is a hallmark feature of type 2 diabetes (T2D). We investigated muscle lipid turnover in T2D versus BMI-matched control subjects (controls) and examined whether putative in vivo differences would be preserved in the myotubes. Male obese T2D individuals (n = 6) and BMI-matched controls (n = 6) underwent a hyperinsulinemic-euglycemic clamp, VO 2 max test, dual-energy X-ray absorptiometry scan, underwater weighing, and muscle biopsy of the vastus lateralis.14 C-palmitate and 14 C-oleate oxidation rates and incorporation into lipids were measured in muscle tissue as well as in primary myotubes. Palmitate oxidation (controls: 0.99 6 0.17 nmol/mg protein; T2D: 0.53 6 0.07 nmol/mg protein; P = 0.03) and incorporation of fatty acids (FAs) into triacylglycerol (TAG) (controls: 0.45 6 0.13 nmol/mg protein; T2D: 0.11 6 0.02 nmol/mg protein; P = 0.047) were significantly reduced in muscle homogenates of T2D. These reductions were not retained for palmitate oxidation in primary myotubes (P = 0.38); however, incorporation of FAs into TAG was lower in T2D (P = 0.03 for oleate and P = 0.11 for palmitate), with a strong correlation of TAG incorporation between muscle tissue and primary myotubes (r = 0.848, P = 0.008). The data indicate that the ability to incorporate FAs into TAG is an intrinsic feature of human muscle cells that is reduced in individuals with T2D.

show abstract

Distinct roles of specific fatty acids in cellular processes: implications for interpreting and reporting experiments

Cited by 51 publications

References 17 publications

cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart

cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart

Diminished Acyl-CoA Synthetase Isoform 4 Activity in INS 832/13 Cells Reduces Cellular Epoxyeicosatrienoic Acid Levels and Results in Impaired Glucose-stimulated Insulin Secretion

Reduced Incorporation of Fatty Acids Into Triacylglycerol in Myotubes From Obese Individuals With Type 2 Diabetes

Contact Info

Product

Resources

About