IL-6: A Potential Role in Cardiac Metabolic Homeostasis

Figures

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  Figure 1. Schematic diagram of metabolism in cardiac myocyte. (A) Metabolism in normal cardiomyocytes. Under well-oxygenated conditions, cardiac energy requirement is largely met by fatty acid oxidation (~60%). Only a minor proportion (around 40%) is generated by glucose metabolism; and (B) Consequences of cardiac lipotoxicity. The precise balance between fatty acid uptake and oxidation is upset by metabolic disorders (i.e., HFD). Under these circumstances, excessive fatty acid is accumulated in cardiomyocytes and leads to cellular injury (e.g., mitochondria dysfunction, ER stress) and lipotoxicity, thereby predisposing to cardiac diseases (e.g., heart failure and arrhythmia). Dashed arrow: multistep processes; Solid arrow: direct effects. FA, fatty acid; TAG, triacylglyceride; GLUT-4, Glucose transporter type 4; TCA cycle, tricarboxylic acid cycle; HFD, high-fat diet; CD-36, cluster of differentiation 36 (also known as fatty acid translocase).

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  Figure 2. The role of IL-6 deficiency in intramyocardial fatty acid accumulation. IL-6 deficiency upregulates CD36 which is the key protein carrier of fatty acid across plasma membrane, thereby enhancing myocardial fatty acid uptake and accumulation. Moreover, IL-6 deficiency inhibits CPT1 which is involved in fatty acid translocation into mitochondria, thereby exacerbating fatty acid excess. Due to the limited storage capacity, fatty acid deposits are converted into toxic lipid metabolites (e.g., DAG and ceramide) which result in cardiac insulin resistance and cellular apoptosis. Taken together, fatty acid per se and its metabolites lead to myocardial lipotoxicity. Black arrows: direct stimulatory effects or consequences of upstream factors; Red dashed arrows: multistep inhibitory effects; Red solid arrows: direct inhibition. FA, fatty acid; HFD, high-fat diet; DAG, diacylglycerol; CPT-1, Carnitine palmitoyltransferase I; IR, insulin receptor; IRS-1, insulin receptor substrate 1.

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  Figure 3. The role of IL-6 deficiency in mitochondria dysfunction. IL-6 deficiency negatively regulates PPARα, which results in downregulation of proteins involved in mitochondria biogenesis (e.g., PGC-1α, MTFA, and EndoG) and enzymes of fatty acid oxidation. Furthermore, IL-6 deficiency inhibits expression of cytochrome c, which is involved in the electron transport chain, thereby resulting in cardiac ATP deficiency. Taken together, IL-6 deficiency impairs mitochondria biogenesis as well as fatty acid oxidation, which leads to cardiac energy deficit. Red arrows indicate inhibitory effects of IL-6 deficiency and black arrows represent stimulatory effects or consequences of upstream factors. FA, fatty acid; RXR, retinoid X receptor; PPAR, Peroxisome Proliferator-activated Receptor; PGC-1α, PPARγ coactivator 1α; MTFA, mitochondrial transcription factor A; EndoG, Endonuclease G; Cyto C, cytochrome C; ETC, electron transport chain.

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  Figure 4. The role of IL-6 deficiency in the AMPK/ACC axis. IL-6 deficiency inhibits FA oxidation and mitochondria biogenesis through multistep pathways, thereby resulting in cardiac ATP depletion. Consequently, reduced [AMP]/[ATP] ratio activates AMPK and subsequently stimulates ACC which in turn catalyzes the conversion of acetyl CoA to malonyl CoA. As this reaction is the rate-limiting step in FA de novo synthesis, activation of ACC promotes TG pool expansion and lipotoxicity. Moreover, malonyl CoA inhibits CPT1 which is responsible for translocation of activated FA into mitochondria for oxidation, thereby exacerbating lipid accumulation and lipotoxicity. Black arrows denote stimulatory or consequential effects of upstream factors and red arrows indicate inhibitory effects. FA, fatty acid; CPT1, carnitine palmitoyltransferase-1 (CPT-1); AMPK, AMP-activated protein kinase; ACC, acetyl-CoA carboxylase; TG, triglycerides.