The metabolic “switch” AMPK regulates cardiac heparin-releasable lipoprotein lipase

Ding, An; Pulinilkunnil, Thomas; Qi, Dake; Ghosh, Sanjoy; Abrahani, Ashraf; Rodrigues, Brian

doi:10.1152/ajpendo.00211.2004

Cited by 86 publications

(63 citation statements)

References 46 publications

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“…Moreover, AMPK activation by AICAR and metformin increased intralipid clearance and increased heparin-releasable LPL activity in rat hearts without causing any change in LPL mRNA (31,32). Furthermore, AICAR and metformin enhanced LPL activity in rat L6 muscle cells (33).…”

Section: Discussionmentioning

confidence: 93%

Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise

Catoire

Alex

Paraskevopulos

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

123

165

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Physical activity increases energy metabolism in exercising muscle. Whether acute exercise elicits metabolic changes in nonexercising muscles remains unclear. We show that one of the few genes that is more highly induced in nonexercising muscle than in exercising human muscle during acute exercise encodes angiopoietin-like 4 (ANGPTL4), an inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. Using a combination of human, animal, and in vitro data, we show that induction of ANGPTL4 in nonexercising muscle is mediated by elevated plasma free fatty acids via peroxisome proliferator-activated receptor-δ, presumably leading to reduced local uptake of plasma triglyceride-derived fatty acids and their sparing for use by exercising muscle. In contrast, the induction of ANGPTL4 in exercising muscle likely is counteracted via AMP-activated protein kinase (AMPK)-mediated down-regulation, promoting the use of plasma triglycerides as fuel for active muscles. Our data suggest that nonexercising muscle and the local regulation of ANGPTL4 via AMPK and free fatty acids have key roles in governing lipid homeostasis during exercise.

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Section: Discussionmentioning

confidence: 93%

Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise

Catoire

Alex

Paraskevopulos

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

123

165

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“…Once activated, AMPK switches off energy-consuming processes such as protein synthesis, whereas ATP-generating mechanisms, such as fatty acid oxidation and glycolysis, are turned on (20). Additionally, results from our laboratory have demonstrated a strong correlation between activation of AMPK and increases in LPL activity (21). The objective of the present study was to determine the mechanisms by which AMPK augments cardiac LPL.…”

mentioning

confidence: 90%

Acute Diabetes Moderates Trafficking of Cardiac Lipoprotein Lipase Through p38 Mitogen-Activated Protein Kinase–Dependent Actin Cytoskeleton Organization

et al. 2008

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OBJECTIVE-Heart disease is a leading cause of death in diabetes and could occur because of excessive use of fatty acid for energy generation. Our objective was to determine the mechanisms by which AMP-activated protein kinase (AMPK) augments cardiac lipoprotein lipase (LPL), the enzyme that provides the heart with the majority of its fatty acid.RESEARCH DESIGN AND METHODS-We used diazoxide in rats to induce hyperglycemia or used 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR) and thrombin to directly stimulate AMPK and p38 mitogen-activated protein kinase (MAPK), respectively, in cardiomyocytes.RESULTS-There was a substantial increase in LPL at the coronary lumen following 4 h of diazoxide. In these diabetic animals, phosphorylation of AMPK, p38 MAPK, and heat shock protein (Hsp)25 produced actin cytoskeleton rearrangement to facilitate LPL translocation to the myocyte surface and, eventually, the vascular lumen. AICAR activated AMPK, p38 MAPK, and Hsp25 in a pattern similar to that seen with diabetes. AICAR also appreciably enhanced LPL, an effect reduced by preincubation with the p38 MAPK inhibitor SB202190 or by cytochalasin D, which inhibits actin polymerization. Thrombin activated p38 MAPK in the absence of AMPK phosphorylation. Comparable with diabetes, activation of p38 MAPK and, subsequently, Hsp25 phosphorylation and F-actin polymerization corresponded with an enhanced LPL activity. SB202190 and silencing of p38 MAPK also prevented these effects induced by thrombin and AICAR, respectively. CONCLUSIONS-We propose that AMPK recruitment of LPL to the cardiomyocyte surface (which embraces p38 MAPK activation and actin cytoskeleton polymerization) represents an immediate compensatory response by the heart to guarantee fatty acid supply when glucose utilization is compromised. Diabetes 57: 64-76, 2008

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“…Western blot was carried out as described previously [19]. Briefly, 50 mg of heart tissue was ground under liquid nitrogen, and homogenised.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Once activated, AMPK stimulates glucose uptake and subsequent glycolysis through translocation of glucose transporter 4 (GLUT4) and activation of 6-phosphofructo-2-kinase (PFK2) [14][15][16]. Moreover, through its control of lipoprotein lipase, CD36, and acetyl-CoA carboxylase (ACC), AMPK facilitates fatty acid delivery and oxidation [17][18][19]. In addition to its effect on substrate metabolism, metformin is also known to regulate endothelial cell death [20].…”

Section: Introductionmentioning

confidence: 99%

Metformin influences cardiomyocyte cell death by pathways that are dependent and independent of caspase-3

et al. 2006

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Aims/hypothesis Metformin has been shown to increase fatty acid oxidation, an effect mediated by AMP activated protein kinase (AMPK). We hypothesised that metformin could prevent both caspase-3 activation and apoptosis when induced by palmitic acid. Materials and methods Cardiomyocytes were incubated with 1 mmol/l palmitic acid, in the absence or presence of metformin (1-5 mmol/l). Following 1 to 16 h, cell damage was evaluated by measuring lactate dehydrogenase released into the incubation medium, and Hoechst staining. To investigate the mechanism of metformin's effect on cardiomyocytes, substrate utilisation and phosphorylation of AMPK and acetyl-CoA carboxylase were measured. Intracellular mediators of apoptosis were also evaluated. Results Incubation of myocytes with palmitic acid for 16 h increased apoptosis, an effect that was partly blunted by 1 and 2 mmol/l metformin. This beneficial effect of metformin was associated with increased AMPK phosphorylation, palmitic acid oxidation and suppression of high-fat-induced increases in (1) long chain base biosynthesis protein 1 levels, (2) ceramide levels, and (3) caspase-3 activity. Unexpectedly, 5 mmol/l metformin dramatically increased apoptosis in myocytes incubated with high fat. This effect was associated with a robust increase in glycolysis, lactate accumulation, and a significant drop of pH in the myocyte incubation medium. Conclusions/interpretation Our study demonstrates that metformin reduces high-fat-induced cardiac cell death, probably through inhibition of ceramide synthesis. However, at high concentrations, metformin causes proton and lactate accumulation, leading to cell damage that is independent of caspase-3.

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The metabolic “switch” AMPK regulates cardiac heparin-releasable lipoprotein lipase

Cited by 86 publications

References 46 publications

Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise

Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise

Acute Diabetes Moderates Trafficking of Cardiac Lipoprotein Lipase Through p38 Mitogen-Activated Protein Kinase–Dependent Actin Cytoskeleton Organization

Metformin influences cardiomyocyte cell death by pathways that are dependent and independent of caspase-3

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