Foam Cell Induction Activates AMPK But Uncouples Its Regulation of Autophagy and Lysosomal Homeostasis

LeBlond, Nicholas D.; Smith, Tyler; O’Dwyer, Conor; Robichaud, Sabrina; Gadde, Suresh; Côté, Marceline; Kemp, Bruce E.; Ouimet, Mireille; Fullerton, Morgan D.

doi:10.3390/ijms21239033

Cited by 7 publications

(6 citation statements)

References 52 publications

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“…Calmodulin-dependent protein kinase-2 (CaMKK2)mediated AMPK signaling is activated in macrophages with imbalanced lipid metabolism. 129 CD36 shows a regulatory effect on AMPK in macrophages as well as in hepatocytes. 130 Therefore, we speculate that the same or similar Ca 2+ signaling pathways controlling lipid metabolism may exist in macrophages as in hepatocytes.…”

Section: Mcu Complex In Metabolic Syndrome-associated Heart Diseasementioning

confidence: 95%

“…In this process, AMPK acts as a downstream signaling molecule regulating fatty acid oxidation. Calmodulin‐dependent protein kinase‐2 (CaMKK2)‐mediated AMPK signaling is activated in macrophages with imbalanced lipid metabolism 129 . CD36 shows a regulatory effect on AMPK in macrophages as well as in hepatocytes 130 .…”

Section: Pathological Role Of Mcu Complex In Metabolic Diseasesmentioning

confidence: 99%

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Implications of MCU complex in metabolic diseases

Li,

Sun,

Zhang

et al. 2023

The FASEB Journal

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Metabolic diseases are considered the primary culprit for physical and mental health of individuals. Although the diagnosis of these diseases is relatively easy, more effective and convenient potent drugs are still being explored. Ca 2+ across the inner mitochondrial membrane is a vital intracellular messenger that regulates energy metabolism and cellular Ca 2+ homeostasis and is involved in cell death. Mitochondria rely on a selective mitochondrial Ca 2+ unidirectional transport complex (MCU complex) in their inner membrane for Ca 2+ uptake. We found that the channel contains several subunits and undergoes dramatic transformations in various pathological processes, especially in metabolic diseases. In this way, we believe that the MCU complex becomes a target with significant potential for these diseases. However, there is no review linking the two factors, thus hindering the possibility of new drug production. Here, we highlight the connection between MCU complex-related Ca 2+ transport and the pathophysiology of metabolic diseases, adding understanding and insight at the molecular level to provide new insights for targeting MCU to reverse metabolism-related diseases.

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Section: Mcu Complex In Metabolic Syndrome-associated Heart Diseasementioning

confidence: 95%

Section: Pathological Role Of Mcu Complex In Metabolic Diseasesmentioning

confidence: 99%

Implications of MCU complex in metabolic diseases

Li,

Sun,

Zhang

et al. 2023

The FASEB Journal

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“…This pathway inhibits the phosphorylation of mammalian target of rapamycin (mTOR)and ULK1 through activation of AMPK and enhances LC-3II accumulation and P62 degradation. AMPK directly activates ULK1 and suppresses the inhibitory effects of mTORC1 on ULK1, thereby enhancing macrophage autophagy [ 72 , 92 ]. This function of AMPK is critical for handling metabolic substrates and removing damaged or senescent organelles.…”

Section: Role Of Ampk In Macrophage-related Diseasesmentioning

confidence: 99%

The role of AMPK in macrophage metabolism, function and polarisation

Cui,

Chen,

Zhang

et al. 2023

J Transl Med

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AMP-activated protein kinase (AMPK) is a ubiquitous sensor of energy and nutritional status in eukaryotic cells. It plays a key role in regulating cellular energy homeostasis and multiple aspects of cell metabolism. During macrophage polarisation, AMPK not only guides the metabolic programming of macrophages, but also counter-regulates the inflammatory function of macrophages and promotes their polarisation toward the anti-inflammatory phenotype. AMPK is located at the intersection of macrophage metabolism and inflammation. The metabolic characteristics of macrophages are closely related to immune-related diseases, infectious diseases, cancer progression and immunotherapy. This review discusses the structure of AMPK and its role in the metabolism, function and polarisation of macrophages. In addition, it summarises the important role of the AMPK pathway and AMPK activators in the development of macrophage-related diseases.

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“…Modified LDL loading in macrophages has been previously shown to induce autophagy flux. 3,31 Therefore, we surmised that the failure of metformin to further induce cholesterol efflux from agLDL-loaded macrophages might be explained by the fact that autophagy was already maximally induced by lipid-loading in these cells. Indeed, we observed a significant induction of cholesterol efflux in BMDMs when incubated with radiolabeled cholesterol incorporated into modified LDL acetylated LDL as compared with that delivered in a free form (nonloaded; Figure 5F).…”

Section: Autophagy Activation In Vsmc But Not Macrophage Foam Cells P...mentioning

confidence: 99%

Autophagy Is Differentially Regulated in Leukocyte and Nonleukocyte Foam Cells During Atherosclerosis

Robichaud¹,

Rasheed²,

Pietrangelo³

et al. 2022

Circulation Research

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Rationale: Atherosclerosis is characterized by an accumulation of foam cells within the arterial wall, resulting from excess cholesterol uptake and buildup of cytosolic lipid droplets (LDs). Autophagy promotes LD clearance by freeing stored cholesterol for efflux, a process that has been shown to be atheroprotective. While the role of autophagy in LD catabolism has been studied in macrophage-derived foam cells, this has remained unexplored in vascular smooth muscle cell (VSMC)-derived foam cells that constitute a large fraction of foam cells within atherosclerotic lesions. Objective: We performed a comparative analysis of autophagy flux in lipid-rich aortic intimal populations to determine whether VSMC-derived foam cells metabolize LDs similarly to their macrophage counterparts. Methods and Results: Atherosclerosis was induced in GFP-LC3 transgenic mice by PCSK9 (proprotein convertase subtilisin/kexin type 9)-adeno-associated viral injection and Western diet feeding. Using flow cytometry of aortic digests, we observed a significant increase in dysfunctional autophagy of VSMC-derived foam cells during atherogenesis relative to macrophage-derived foam cells. Using cell culture models of lipid-loaded VSMC and macrophage, we show that autophagy-mediated cholesterol efflux from VSMC foam cells was poor relative to macrophage foam cells, and largely occurs when HDL (high-density lipoprotein) is used as a cholesterol acceptor, as opposed to apoA-1 (apolipoproteinA-1). This was associated with the predominant expression of ABCG1 in VSMC foam cells. Using metformin, an autophagy activator, cholesterol efflux to HDL was significantly increased in VSMC, but not in macrophage, foam cells. Conclusions: These data demonstrate that VSMC and macrophage foam cells perform cholesterol efflux by distinct mechanisms, and that autophagy flux is highly impaired in VSMC foam cells, but can be induced by pharmacological means. Further investigation is warranted into targeting autophagy specifically in VSMC foam cells, the predominant foam cell subtype of advanced atherosclerotic plaques, to promote reverse cholesterol transport and resolution of the atherosclerotic plaque.

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Foam Cell Induction Activates AMPK But Uncouples Its Regulation of Autophagy and Lysosomal Homeostasis

Cited by 7 publications

References 52 publications

Implications of MCU complex in metabolic diseases

Implications of MCU complex in metabolic diseases

The role of AMPK in macrophage metabolism, function and polarisation

Autophagy Is Differentially Regulated in Leukocyte and Nonleukocyte Foam Cells During Atherosclerosis

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