Correction to: Fatty acid oxidation promotes reprogramming by enhancing oxidative phosphorylation and inhibiting protein kinase C

Chronic glucose infusion results in hyperinsulinemia and causes lipid accumulation and insulin resistance in rat muscle. To examine possible mechanisms for the insulin resistance, alterations in malonyl-CoA and long-chain acyl-CoA (LCA-CoA) concentration and the distribution of protein kinase C (PKC) isozymes, putative links between muscle lipids and insulin resistance, were determined. Cannulated rats were infused with glucose (40 mg ⋅ kg−1 ⋅ min−1) for 1 or 4 days. This increased red quadriceps muscle LCA-CoA content (sum of 6 species) by 1.3-fold at 1 day and 1.4-fold at 4 days vs. saline-infused controls (both P < 0.001 vs. control). The concentration of malonyl-CoA was also increased (1.7-fold at 1 day, P < 0.01, and 2.2-fold at 4 days, P < 0.001 vs. control), suggesting an even greater increase in cytosolic LCA-CoA. The ratio of membrane to cytosolic PKC-ε was increased twofold in the red gastrocnemius after both 1 and 4 days, suggesting chronic activation. No changes were observed for PKC-α, -δ, and -θ. We conclude that LCA-CoAs accumulate in muscle during chronic glucose infusion, consistent with a malonyl-CoA-induced inhibition of fatty acid oxidation (reverse glucose-fatty acid cycle). Accumulation of LCA-CoAs could play a role in the generation of muscle insulin resistance by glucose oversupply, either directly or via chronic activation of PKC-ε.

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Resolvin D1 Enhances Necroptotic Cell Clearance Through Promoting Macrophage Fatty Acid Oxidation and Oxidative Phosphorylation

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.315758 ◽

2021 ◽

Vol 41 (3) ◽

pp. 1062-1075

Author(s):

Zeinab Hosseini ◽

Michael Marinello ◽

Christa Decker ◽

Brian E. Sansbury ◽

Sudeshna Sadhu ◽

...

Keyword(s):

Fatty Acid ◽

Protein Kinase ◽

Oxidative Phosphorylation ◽

Fatty Acid Oxidation ◽

Therapeutic Strategy ◽

Acid Oxidation ◽

Resolvin D1 ◽

Cell Clearance ◽

Amp Activated Protein Kinase

Objective: Plaque necrosis is a key feature of defective resolution in atherosclerosis. Recent evidence suggests that necroptosis promotes plaque necrosis; therefore, we sought to determine how necroptotic cells (NCs) impact resolution programs in plaques. Approach and Results: To investigate the role(s) of necroptosis in advanced atherosclerosis, we used mice deficient of Mlkl , an effector of necroptosis. Mlkl −/− mice that were injected with a gain-of-function mutant PCSK9 (AAV8-gof-PCSK9) and fed a Western diet for 16 weeks, showed significantly less plaque necrosis, increased fibrous caps and improved efferocytosis compared with AAV8-gof-PCSK9 injected wt controls. Additionally, hypercholesterolemic Mlkl −/− mice had a significant increase in proresolving mediators including resolvin D1 (RvD1) and a decrease in prostanoids including thromboxane in plaques and in vitro. We found that exuberant thromboxane released by NCs impaired the clearance of both apoptotic cells and NCs through disruption of oxidative phosphorylation in macrophages. Moreover, we found that NCs did not readily synthesize RvD1 and that exogenous administration of RvD1 to macrophages rescued NC-induced defective efferocytosis. RvD1 also enhanced the uptake of NCs via the activation of p-AMPK (AMP-activated protein kinase), increased fatty acid oxidation, and enhanced oxidative phosphorylation in macrophages. Conclusions: These results suggest that NCs derange resolution by limiting key SPMs and impairing the efferocytic repertoire of macrophages. Moreover, these findings provide a molecular mechanism for RvD1 in directing proresolving metabolic programs in macrophages and further suggests RvD1 as a potential therapeutic strategy to limit NCs in tissues. Graphic Abstract: A graphic abstract is available for this article.

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