Phospholipid homeostasis and lipotoxic cardiomyopathy: a matter of balance

Abstract

Obesity has reached pandemic proportions globally and is often associated with lipotoxic heart diseases. In the obese state, caloric surplus is accommodated in the adipocytes as triglycerides. As the storage capacity of adipocytes is exceeded or malfunctioning, lipids begin to infiltrate and accumulate in non-adipose tissues, including the myocardium of the heart, leading to organ dysfunction. While the disruption of caloric homeostasis has been widely viewed as a principal mechanism in contributing to peripheral tissue steatosis and lipotoxicity, our recent studies in Drosophila have led to the novel finding that deregulation of phospholipid homeostasis may also significantly contribute to the pathogenesis of lipotoxic cardiomyopathy. Fly mutants that bear perturbations in phosphatidylethanolamine (PE) biosynthesis, such as the easily-shocked (eas) mutants defective in ethanolamine kinase, incurred aberrant activation of the sterol regulatory element binding protein (SREBP) pathway, thereby causing chronic lipogenesis and cardiac steatosis that culminates in the development of lipotoxic cardiomyopathy. Here, we describe the potential relationship between SREBP and other eas-associated phenotypes, such as neuronal excitability defects. We will further discuss the additional implications presented by our work toward the effects of altered lipid metabolism on cellular growth and/or proliferation in response to defective phospholipid homeostasis.

Figure 1

Changes in body weight of eas² mutant flies. Female flies, 7- to 10-days old and reared under same growth conditions, were weighed with a precision scale (range 0.001–10 mg; Mettler ME 30). Compared to wild-type (w¹¹¹⁸), eas² mutant and eas²;Arm-Gal4 (driver only) flies display a significant reduction in average body weight. Upon re-expression of a wild-type Eas⁺ transgene in the eas² mutant background using Armadillo-Gal4 (eas²; Arm-G4>Eas⁺), the eas² body weight loss is partially reversed. eas² flies lacking one functional copy of dSREBP fully regain normal weights. Partial loss of ACC function seems to have a lesser capacity to restore normal body weight of the eas² fly. ACC, Acetyl-coA carboxylase, is a transcriptional target of the lipogenic activity of SREBP. p-values (*p < 0.01, **p = 0.06) were calculated using the Student's t-test. Error bars indicate Standard Deviation. n = number of flies measured.