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

Yogi Umbarawan,Noriyo Hayakawa,Hiroki Matsui,Hiroaki Sunaga,Masahiko Kurabayashi,Norimichi Koitabashi,Mas Syamsunarno,Ryo Kawakami,Hirofumi Hanaoka,Hideru Obinata,Takako Hishiki,Aiko Yamaguchi,Tatsuya Iso

doi:10.3390/metabo11120881

Abstract

Cardiac dysfunction is induced by multifactorial mechanisms in diabetes. Deranged fatty acid (FA) utilization, known as lipotoxicity, has long been postulated as one of the upstream events in the development of diabetic cardiomyopathy. CD36, a transmembrane glycoprotein, plays a major role in FA uptake in the heart. CD36 knockout (CD36KO) hearts exhibit reduced rates of FA transport with marked enhancement of glucose use. In this study, we explore whether reduced FA use by CD36 ablation suppresses the development of streptozotocin (STZ)-induced diabetic cardiomyopathy. We found that cardiac contractile dysfunction had deteriorated 16 weeks after STZ treatment in CD36KO mice. Although accelerated glucose uptake was not reduced in CD36KO-STZ hearts, the total energy supply, estimated by the pool size in the TCA cycle, was significantly reduced. The isotopomer analysis with 13C6-glucose revealed that accelerated glycolysis, estimated by enrichment of 13C2-citrate and 13C2-malate, was markedly suppressed in CD36KO-STZ hearts. Levels of ceramides, which are cardiotoxic lipids, were not elevated in CD36KO-STZ hearts compared to wild-type-STZ ones. Furthermore, increased energy demand by transverse aortic constriction resulted in synergistic exacerbation of contractile dysfunction in CD36KO-STZ mice. These findings suggest that CD36KO-STZ hearts are energetically compromised by reduced FA use and suppressed glycolysis; therefore, the limitation of FA utilization is detrimental to cardiac energetics in this model of diabetic cardiomyopathy.

Highlights

Diabetes is an independent risk factor for the development of heart failure
6B).supply, These findings suggest by thatthe energy insufficiency due to STZ cycle, treatment becomes more prominent due to the elevation of energy demand by TAC, which diminished by reduced fatty acid (FA) uptake and suppressed glycolysis in CD36 knockout (CD36KO) h could lead to the synergistic exacerbation of contractile dysfunction by STZ and TAC in can result in deterioration of the contractile dysfunction by energy insufficien
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Summary

Introduction

Diabetes is an independent risk factor for the development of heart failure. Diabetic cardiomyopathy is likely to be induced by multifactorial mechanisms, lipotoxicity is suggested to play a significant role [1–5]. Deranged FA utilization in the heart has been shown to occur in diabetes in humans and animals. Excessive FA is converted into lipid intermediates such as triacylglycerol (TG) and others with lipotoxic effects (e.g., diacylglycerol and ceramides). Increased ceramide levels can activate inflammatory signaling pathways and increase the production of reactive oxygen species, which, in turn, results in impairment of mitochondrial energy production. Reduced cardiac efficiency (cardiac work/oxygen consumption) by deranged FA use is suggested to be causative of diabetic cardiomyopathy. The lipotoxicity hypothesis prevails as one of most upstream events to trigger cardiac dysfunction in diabetes [1–5]

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Conclusion