Diabetes mellitus is a group of metabolic diseases that are caused by elevated blood glucose levels. Individuals with diabetes have an increased risk of cardiovascular complications that include diabetic cardiomyopathy, hypertension, and coronary artery disease. Research has shown that hyperglycemia causes metabolic abnormalities in the heart such that cardiomyocytes are unable to utilize glucose for energy production due to reduced glucose intake, instead they solely depend on fatty acid oxidation for energy. Eventually, fatty acids accumulate and cause cardiac lipotoxicity, a presumed factor in the development of diabetic cardiomyopathy. Carnitine Pamitoyl Transferease 2 (CPT2) is one of the enzymes responsible for the transport of long-chain fatty acids into the mitochondria for fatty acid oxidation and energy production. CPT2 activity is elevated in diabetic hearts by mechanisms that are unclear. CPT2 is composed of 5 exons; the largest, exon 4 contains the transferase domain and is alternatively spliced in diabetes. In normal hearts, half of the CPT2 transcripts include exon 4 representing the active form of the enzyme. Through RNA sequencing analysis assay, we discovered that CPT2 is mis-spliced in diabetic hearts in a way that 70% of total CPT2 transcripts include the functional domain exon 4. The splicing change in CPT2 results in increased expression of the active CPT2 isoform in diabetic hearts. In summary, we identified a functionally important alternative splicing event in the CPT2 gene that may contribute to increased fatty acid oxidation and lipotoxicity in the diabetic heart.
Fatty Acid Oxidation Disorder with Secondary Mitochondrial Energy Production Defect: A Case Report
