Extracellular glycerol regulates the cardiac energy balance in a working rat heart model

Abstract

We reported previously that glycerol is a substrate for energy production in cardiomyocytes. Increasing glycerol availability results in increased glycerol uptake and its involvement in complex lipid biosynthesis and energy production. This study evaluated the relationship between glycerol supply, energy demand, and intermediary metabolism leading to energy production. The work was performed on isolated rat heart perfused in the working mode. Glycerol concentrations modeled the fasting (0.33 mM) and fed (3.33 mM) states. Cardiac energy demand was modeled by increasing heart rate from 350 to 450 beats/min (bpm). Increasing glycerol supply increased glycerol uptake from 1.4 (350 bpm) to 3.8 (450 bpm) and from 9.7 (350 bpm) to 34.2 (450 bpm) micro mol glycerol/heart in 30 min at 0.33 and 3.33 mM glycerol, respectively. At low glycerol supply, increasing heart rate did not influence the complex lipid synthesis. Conversely, high glycerol concentration increased the complex lipid synthesis by 5- and 30-fold at 350 and 450 bpm, respectively. Increasing glycerol supply and heart rate significantly increased glycerol oxidation rate. Moreover, increasing glycerol supply did not affect glucose oxidation but increased palmitate uptake and significantly decreased its beta-oxidation. Physiological concentrations of glycerol contribute to the cardiac intermediary metabolism, both for energy production and glycerolipid synthesis. Increasing energy demand enhances the requirement and use of glycerol. Glycerol contributes to the regulation of cardiac metabolism and energy balance, mainly by decreasing the contribution of fatty acid oxidation, and may thus represent a new factor in cardiac protection through the reduction of oxygen demand.

Evidence for Transaldolase Activity in the Isolated Heart Supplied with [U-13C3]Glycerol

“…The distribution of 2 H in glucose, after the administration of 2 H 2 O, is commonly used to measure the relative activity of gluconeogenesis and glycogenolysis in hepatic glucose production. In principle, 2 H labeling should occur in three-carbon units derived from either glycerol or the citric acid cycle at the level of TPI. The hydrogen destined to become the H5 of glucose exchanges with any 2 H in tissue water and thus reports the fraction of glucose derived from the sum of glycerol plus the citric acid cycle contribution, assuming equilibration in the TPI reaction.…”

“…First, 2 H incorporation at the level of mannose 6-phosphate isomerase (F6P 7 mannose 6-phosphate) can lead to 2 H enrichment of H1 position of glucose (33). The other possibility is intramolecular exchange of 1 H in position 1 of F6P with 2 H in position 2 of G6P (34).…”

“…Quite unexpectedly, 13 C from [U- 13 Free fatty acids, lactate and glucose are primary substrates for cardiac energy production, but the heart has the capacity to oxidize a wide variety of alternative compounds. In mammalian heart tissue, 14 C-enriched glycerol was readily oxidized to 14 CO 2 even in the presence of glucose or long chain fatty acids (1,2). Glycerol is phosphorylated by glycerol kinase to form glycerol 3-phosphate, and this intermediate is then converted to dihydroxyacetone phosphate (DHAP) 2 which is rearranged to D-glyceraldehyde 3-phosphate (GA3P) via triose phosphate isomerase (TPI; EC 5.3.1.1).…”

“…In mammalian heart tissue, 14 C-enriched glycerol was readily oxidized to 14 CO 2 even in the presence of glucose or long chain fatty acids (1,2). Glycerol is phosphorylated by glycerol kinase to form glycerol 3-phosphate, and this intermediate is then converted to dihydroxyacetone phosphate (DHAP) 2 which is rearranged to D-glyceraldehyde 3-phosphate (GA3P) via triose phosphate isomerase (TPI; EC 5.3.1.1). GA3P may be further metabolized to pyruvate and enter the citric acid cycle via pyruvate dehydrogenase, or pyruvate may supply carbon to the cycle via pyruvate carboxylase without net oxidation (3).…”

“…GA3P may be further metabolized to pyruvate and enter the citric acid cycle via pyruvate dehydrogenase, or pyruvate may supply carbon to the cycle via pyruvate carboxylase without net oxidation (3). Another metabolic fate of glycerol after phosphorylation is that it is readily utilized in the synthesis of triglycerides and phospholipids in the mammalian heart (2). Although the heart is not a glyconeogenic organ, the enzymes necessary to convert glycerol to glucose 1-phosphate (G1P) and glycogen are all present, and conversion of 14 C-enriched glycerol to glycogen in isolated heart tissue of nonmammalian species has been reported (4).…”