Aquaporin 7: the glycerol aquaeductus in the heart.

Deprivation of available energy has been postulated to play a major role in the genesis of heart failure, and accumulating evidence points to the premise that changes in gene expression that alter energy metabolism weaken the heart muscle, reinforcing the logic of ameliorating energy substrates, and/or metabolism as a heart failure therapeutic. Reduced cardiac energy levels, in turn, influence a plethora of cardiac events, including free radical defense mechanisms which lower cardiomyocyte survivability, cardiac contractility, adverse remodelling and arrhythmogenic susceptibility. The heart is able to produce energy from a wide range of substrates and shifts continuously between sources, according to supply availability as controlled by exercise, nutritional status, or pathophysiological conditions. Therefore, the immediate cardiac capacity to produce energy and to adapt its metabolism to requirement changes is a crucial cardiac functional parameter. ATP is the direct source of energy for all energy-consuming reactions in the heart (pump function, Ca2þ re-uptake into the sarcoplasmic reticulum and maintenance of the sarcolemmal ion gradients). In the healthy adult heart, more than 70% of the energy required is covered by fatty acid oxidation in mitochondria, with the remaining 30% being accounted for by carbohydrate oxidation, mainly using glucose and ketone bodies as exogenous substrates. Under conditions of high ATP demand relative to ATP availability, the myocyte is able to recruit additional pathways or depend more heavily on alternative pathways for ATP synthesis (e.g. glycolysis and phosphotransferase reactions). The efficiency of ATP generation differs depending on the oxidized substrates, with fatty acid oxidation generating more ATP, on a molar basis, than glucose utilization. Accumulating evidence indicates that glycerol could be an as of yet largely overlooked metabolic cardiac substrate. In cardiomyocytes, glycerol controls several steps of lipid metabolism by forming a backbone for complex lipid synthesis (phospholipids and triacylglycerols). In cultured rat cardiac cells, glycerol was shown to be phosphorylated to yield glycerol-3-phosphate, contributing dosedependently to energy production through oxidation, to membrane homeostasis via phospholipid synthesis, and to lipid storage as triacylglycerol, and thus regulating energy balance. Further, glycerol metabolism in the heart seems to be regulated by energy demand. This has been addressed in a model of isolated working rat heart where both glycerol supply and energy demand levels resulted in increased glycerol uptake and suppressed fatty acid oxidation. At low glycerol levels, higher energy demand by increased heart rate did not affect glycerol uptake; however, this was augmented once the available glycerol concentrations were also elevated. Furthermore, increasing energy demand requires higher amounts of phospholipids and thus improved phospholipid turnover, which may be dependent on the available concentrations of glycerol in the cell. Although the metabolic pathways for ATP production from glycerol do theoretically exist in the heart, their functionality has not been elucidated thus far. The study by Hibuse et al. in this issue of the journal opens a novel perspective by demonstrating that glycerol, as an energetic substrate, is dispensable under physiological conditions but becomes important in the stressed heart. Under pressure and/or volume overload-induced cardiac stress situations, a reduction in fatty acid oxidation, caused in part by downregulation of fatty acid oxidation enzyme expression, is paralleled by a shift to higher dependency on glucose oxidation. Glucose entry in myocytes is followed either by its storage as glycogen or by glycolysis, which converts it into pyruvate, which is converted into acetyl CoA by pyruvate dehydrogenase in the mitochondria. Similarly, myocyte glycerol uptake also leads to pyruvate formation. Hibuse et al. now demonstrate that under low fatty acid oxidation conditions, the heart favours glycerol over glucose consumption, which points to a compensatory effect of glycerol metabolism under adverse cardiac conditions. On its own, this groundbreaking finding forces us to drastically revise our conceptualization of cardiac energy metabolism. The authors then go further to identify aquaporin 7 (AQP7) as the main cardiac glycerol uptake channel. Although first identified as water uptake facilitators that increase The opinions expressed in this article are not necessarily those of the Editors of the Cardiovascular Research or of the European Society of Cardiology. * Corresponding author. Tel: þ31 30 253 8900; fax: þ31 30 253 9036. E-mail address: [email protected]