Disturbances in Cardiac Glutathione Augments Cardiac Lipotoxicity in Mice with Diet‐Induced Obesity

Abstract

Cardiac lipid accumulation is a key feature of obesity‐related cardiomyopathy. The role of the antioxidant glutathione (GSH) in cardiolipotoxicity is unclear. Cystathionine‐β‐synthase(Cbs) provides 50% of total cysteine required for GSH biosynthesis in the liver. We studied the effect of diet‐induced obesity in mice heterozygous for targeted deletion of Cbs(+/−) and C57BL6/J (+/+) mice fed a high fat (60% energy) diet (HF) or a control diet (C) from weaning for 12 weeks. HF+/− and HF+/+ mice had higher body weight (P<0.001) and adipose tissue accumulation (P<0.001) than C+/− and C+/+ mice. Total GSH and reduced GSH levels in heart were lower in +/− mice (P<0.01) than in +/+ mice and where further reduced in +/− mice fed the HF diet. This was accompanied by higher levels of triglyceride and higher levels of nitrotyrosine in heart form HF+/− mice. Expression of genes (mRNA) related to fatty acid oxidation (Acox1, Ppara) and mitochondrial function (Pgc1a, Nrf1, Rela) were higher (P<0.01) in heart from +/− mice than in +/+ mice. Feeding the HF diet had no effect on gene expression in the +/+ mice but reduced levels of mRNA in +/− mice. This study demonstrates a potential role between Cbs, heart GSH levels, and triglyceride accumulation in heart during diet‐induced obesity.