Reduced fatty acid uptake aggravates cardiac contractile dysfunction in streptozotocin-induced diabetic cardiomyopathy

Abstract

Diabetes is an independent risk factor for the development of heart failure. Increased fatty acid (FA) uptake and deranged utilization leads to reduced cardiac efficiency and accumulation of cardiotoxic lipids, which is suggested to facilitate diabetic cardiomyopathy. We studied whether reduced FA uptake in the heart is protective against streptozotocin (STZ)-induced diabetic cardiomyopathy by using mice doubly deficient in fatty acid binding protein 4 (FABP4) and FABP5 (DKO mice). Cardiac contractile dysfunction was aggravated 8 weeks after STZ treatment in DKO mice. Although compensatory glucose uptake was not reduced in DKO-STZ hearts, total energy supply, estimated by the pool size in the TCA cycle, was significantly reduced. Tracer analysis with 13C6-glucose revealed that accelerated glycolysis in DKO hearts was strongly suppressed by STZ treatment. Levels of ceramides, cardiotoxic lipids, were similarly elevated by STZ treatment. These findings suggest that a reduction in total energy supply by reduced FA uptake and suppressed glycolysis could account for exacerbated contractile dysfunction in DKO-STZ hearts. Thus, enhanced FA uptake in diabetic hearts seems to be a compensatory response to reduced energy supply from glucose, and therefore, limited FA use could be detrimental to cardiac contractile dysfunction due to energy insufficiency.

Single-cell RNA Sequencing Reveals the Temporal Diversity and Dynamics of Cardiac Immunity after Myocardial Infarction

“…Additionally, these cells showed differential expression of fatty acid (FA) binding protein 5 (Fabp5) (Figure 2B), which is vital for FA transport from the circulation to the heart, providing cardiac protection via an energy metabolism pathway. [14] Similarly, this set was highly amplified, showing approximately 15-fold expansion from days 0 to 3 (Figure 2D). Therefore, this set was also a postinfarction cluster with superimposed characteristics.…”

Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in Mice

“…We have reported that cardiac contraction is reduced when the energy supply does not meet the energy demand in mice with genetic deletion of genes associated with FA uptake, including CD36KO and fatty acid binding protein 4 (FABP4)/FABP5 double-KO mice [9,14,26]. The concept of association between cardiac contraction and contractile function is summarized below.…”

“…The concept of association between cardiac contraction and contractile function is summarized below. Despite a significant decrease in the total energy supply, contractile function is preserved in CD36KO and FABP4/5 double-KO mice [9,14,26], because the required energy expenditure is also small at rest [27]. Cardiac contraction is reduced when they are subjected to the following situations: (1) increased workload by TAC and (2) reduced energy supply by STZ-induced diabetes.…”

“…However, in CD36KO and FABP4/5 double-KO mice, the compensatory energy use for the increased afterload fails because of a reduction in FA uptake and loss of compensatory increase in the glycolytic flux into the TCA cycle [27]. In the case of STZ-induced diabetes, reduced FA uptake and suppressed glycolysis cause energetically compromised hearts [26,27]. When the energy demand is elevated by TAC in such energetically compromised hearts, the cardiac energetics further deteriorate, leading to severe suppression of cardiac contraction, as shown in this study.…”

“…For the type-1 diabetic model, 10-12-week-old male mice were treated with i.p. STZ in 0.1 M sodium citrate (pH 4.5) at a dose of 50 mg/kg for five days [26]. Four weeks after STZ treatment, pressure overload was produced by TAC as described previously [9,14].…”