Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms

Pinkosky, Stephen L.; Scott, John W.; Desjardins, Eric M.; Smith, Brennan K.; Day, Emily; Ford, Rebecca J.; Langendorf, Christopher G.; Ling, Naomi X.Y.; Nero, Tracy L.; Loh, Kim; Galić, Sandra; Hoque, Ashfaqul; Smiles, William J.; Ngoei, Kevin R.W.; Parker, Michael W.; Yan, Yan; Melcher, Karsten; Kemp, Bruce E.; Oakhill, Jonathan S.; Steinberg, Gregory R.

doi:10.1038/s42255-020-0245-2

Cited by 92 publications

(83 citation statements)

References 56 publications

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“…To our knowledge, our studies are the first to investigate AMPK signaling in response to model (acLDL) and physiological (oxLDL/agLDL) atherogenic stimuli in BMDM. We first focused on a potential mechanism to explain how exposure to these modified lipoproteins could lead to AMPK activation, which can occur in response to glucose deprivation (lysosomal activation), adenine nucleotide fluctuations (AMP/ADP binding to the γ subunit of AMPK), intracellular calcium release (via CaMKK2) and most recently binding of long chain acyl-CoA 44 . Since it has been shown that oxLDL is capable of triggering ER stress, a process linked to alterations in cytosolic calcium flux 3,35,36 , we reasoned that calcium-stimulated CaMKK2 may be responsible.…”

Section: Discussionmentioning

confidence: 99%

Foam cell induction activates AMPK but uncouples its regulation of autophagy and lysosomal homeostasis

LeBlond

Smith

Robichaud

et al. 2020

Preprint

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The dysregulation of macrophage lipid metabolism drives atherosclerosis. AMP-activated protein kinase (AMPK) is a master regulator of cellular energetics and plays essential roles regulating macrophage lipid dynamics. Here, we investigated the consequences of atherogenic lipoprotein-induced foam cell formation on downstream immunometabolic signaling in primary mouse macrophages. A variety of atherogenic low-density lipoproteins (acetylated, oxidized and aggregated forms) activated AMPK signaling in a manner that was in part, due to CD36 and calcium-related signaling. In quiescent macrophages, basal AMPK signaling was crucial for maintaining markers of lysosomal homeostasis, as well as levels of key components in the lysosomal expression and regulation network. Moreover, AMPK activation resulted in targeted up-regulation of members of this network via transcription factor EB. However, in lipid-induced macrophage foam cells, neither basal AMPK signaling nor its activation affected lysosomal-associated programs. These results suggest that while the sum of AMPK signaling in cultured macrophages may be anti-atherogenic, atherosclerotic input dampens the regulatory capacity of AMPK signaling.

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Section: Discussionmentioning

confidence: 99%

Foam cell induction activates AMPK but uncouples its regulation of autophagy and lysosomal homeostasis

LeBlond

Smith

Robichaud

et al. 2020

Preprint

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“…Immediately following the NTD is a conserved carbohydrate binding module (CBM; β1: 68–163; β2: 67–163), that forms an interface with the N-lobe of the α kinase domain creating a hydrophobic cleft termed the allosteric drug and metabolite (ADaM) site [ 105 ]. The ADaM site binds synthetic compounds (e.g., A769662, SC4 and MK8722) [ 13 , 21 , 28 ] and endogenous long chain fatty acyl-CoAs (e.g., palmitoyl-CoA) [ 106 ], which are able to allosterically activate AMPK complexes. While MK8722 activates all 12 AMPK complexes [ 21 ], A769662 and palmitoyl-CoA are β1-selective [ 106 , 107 ].…”

Section: Regulation By Phosphorylationmentioning

confidence: 99%

Post-Translational Modifications of the Energy Guardian AMP-Activated Protein Kinase

Ovens

Scott

Langendorf

et al. 2021

IJMS

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Physical exercise elicits physiological metabolic perturbations such as energetic and oxidative stress; however, a diverse range of cellular processes are stimulated in response to combat these challenges and maintain cellular energy homeostasis. AMP-activated protein kinase (AMPK) is a highly conserved enzyme that acts as a metabolic fuel sensor and is central to this adaptive response to exercise. The complexity of AMPK’s role in modulating a range of cellular signalling cascades is well documented, yet aside from its well-characterised regulation by activation loop phosphorylation, AMPK is further subject to a multitude of additional regulatory stimuli. Therefore, in this review we comprehensively outline current knowledge around the post-translational modifications of AMPK, including novel phosphorylation sites, as well as underappreciated roles for ubiquitination, sumoylation, acetylation, methylation and oxidation. We provide insight into the physiological ramifications of these AMPK modifications, which not only affect its activity, but also subcellular localisation, nutrient interactions and protein stability. Lastly, we highlight the current knowledge gaps in this area of AMPK research and provide perspectives on how the field can apply greater rigour to the characterisation of novel AMPK regulatory modifications.

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“…Recently, it has been suggested by Pinkosky et al [ 129 ] that the natural ligands that activate AMPK by binding to the ADaM site may be long-chain fatty acyl-CoA esters (LCFA-CoAs). Ironically, this brings the story of regulation of AMPK full circle, as one of the first papers to define AMPK and demonstrate its sensitivity to AMP also noted that its activation by an upstream kinase (at that time unidentified) was enhanced by palmitoyl-CoA [ 130 ].…”

Section: Pharmacological Activation and Inhibition Of Ampkmentioning

confidence: 99%

“…In this latest paper [ 129 ], the structural basis for the regulation of AMPK by LCFAs has been addressed. It was found that micromolar concentrations of LCFA-CoAs containing saturated or mono-unsaturated fatty acids of 12 carbons or more activated AMPK, whereas the corresponding free acids or carnitine esters did not.…”

Section: Pharmacological Activation and Inhibition Of Ampkmentioning

confidence: 99%

AMP-Activated Protein Kinase: Do We Need Activators or Inhibitors to Treat or Prevent Cancer?

Russell

Hardie

2020

IJMS

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AMP-activated protein kinase (AMPK) is a key regulator of cellular energy balance. In response to metabolic stress, it acts to redress energy imbalance through promotion of ATP-generating catabolic processes and inhibition of ATP-consuming processes, including cell growth and proliferation. While findings that AMPK was a downstream effector of the tumour suppressor LKB1 indicated that it might act to repress tumourigenesis, more recent evidence suggests that AMPK can either suppress or promote cancer, depending on the context. Prior to tumourigenesis AMPK may indeed restrain aberrant growth, but once a cancer has arisen, AMPK may instead support survival of the cancer cells by adjusting their rate of growth to match their energy supply, as well as promoting genome stability. The two isoforms of the AMPK catalytic subunit may have distinct functions in human cancers, with the AMPK-α1 gene often being amplified, while the AMPK-α2 gene is more often mutated. The prevalence of metabolic disorders, such as obesity and Type 2 diabetes, has led to the development of a wide range of AMPK-activating drugs. While these might be useful as preventative therapeutics in individuals predisposed to cancer, it seems more likely that AMPK inhibitors, whose development has lagged behind that of activators, would be efficacious for the treatment of pre-existing cancers.

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Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms

Cited by 92 publications

References 56 publications

Foam cell induction activates AMPK but uncouples its regulation of autophagy and lysosomal homeostasis

Foam cell induction activates AMPK but uncouples its regulation of autophagy and lysosomal homeostasis

Post-Translational Modifications of the Energy Guardian AMP-Activated Protein Kinase

AMP-Activated Protein Kinase: Do We Need Activators or Inhibitors to Treat or Prevent Cancer?

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