The ins and outs of triglyceride metabolism in yeast: implications for lipid‐associated disorders

Lipotoxicity is the pathological consequence of lipid overflow in non‐adipose tissue, mediated through reactive lipid moieties which may lead to lipid‐induced cell death (lipoapoptosis). This derailment of cellular and organismal fat homeostasis contributes substantially to the pathogenesis of insulin resistance, type 2 diabetes mellitus and cardiovascular disease. The metabolic and regulatory processes relevant to establishing cellular energy and lipid homeostasis are remarkably conserved in yeast. Yeast mutants which are unable to detoxify excess fatty acids in the form of triglycerides are highly sensitive to supplementation with unsaturated fatty acids, which are then incorporated into phospholipids. As a consequence, the unfolded protein response is up‐regulated and vesicular trafficking from the endoplasmic reticulum is blocked, leading to rapid loss of viability. Similarly, viability of mutant cells expressing a hyperactive allele of acetyl‐CoA carboxylase Acc1, key enzyme of fatty acid synthesis, is severely compromised in the absence of triglyceride formation. Our recent discovery that triglyceride homeostasis is regulated in coordination with the cell division cycle underscores the importance of maintaining a strictly balanced flux of fatty acids into and out of triglycerides, to support growth and viability.