Lipotoxic cardiomyopathy heart failure is strongly correlated with obesity and mortality. Incidence of obesity has grown to alarming proportions around the globe, increasing evidence suggests parents’ nutritional status may predispose offspring to lipotoxic cardiomyopathy with the underlying mechanisms of intergenerational heart disease remaining to be elucidated.
According to the team their results provide evidence of cardiac dysfunction induced by high fats diets persists for 2 subsequent generations in Drosophila and is associated with reduced expression of 2 key metabolic regulators: transcriptional cofactor PGC-1, and adipose triglyceride lipase; targeted expression of ATGL/bmm in offspring of high fat diet fed parents protects them and the subsequent generation from cardio-lipotoxicity. Intergenerational inheritance of lipotoxic cardiomyopathy was found to correlate with elevated systemic H3K27 trimethylation; lowering H3K27 trimethylation genetically or pharmacologically in offspring of HFD fed parents prevents cardiac pathology, suggesting metabolic homeostasis is epigenetically regulated across generations.
Rolf Bodmer, PhD suggests their findings reveal an inheritance mechanism behind heart failure fueled by high fat diets; and uncovered an epigenetic factor as well as genetic targets that can be explored to protect individuals from effects of their parents or grandparents poor diets; as well as proof of concept results needed to embark on further studies.
80% of genes that cause disease in humans are also found in the Drosophila, their tube shaped heart consists of only 80 cardiomyocytes; their similarity to humans, simplicity and short life cycle makes them excellent models for studying genes that contribute to human heart health.
Fruit flies were fed coconut oil rich diets for 5 days; they became overweight and developed traits that mimic human lipotoxic heart disease, dysfunction, and lead to heart failure; offspring and grandchildren also had heart dysfunction, even when fed normal diets. Comparing generations born from parents with normal diets and inherited epigenetic marker trimethylated lysine 27 in histone 3 was identified, reducing its level throughout the fruit fly protected the two subsequent generations from heart dysfunction. Genes PGC-1 and mbb which are involved in metabolism were also identified that were turned down in the next 2 generations; revving up the flies’ metabolism by overexpressing these genes protected the hearts of the next 2 generations of flies that ate HFD, protection lasted even if subsequent generations consumed coconut oil.
The team wants to determine how and when these genetic and epigenetic changes are inherited, to which parental extent they arise from to determine what the inherited primary changed are and at which point changes are implemented to cause metabolic imbalance and lipotoxic heart disease, and to learn how to intervene and stop these changes from passing to the next generations.
