View Program - 63rd Annual Drosophila Research Conference

Growth control is fundamentally important for normal biological development, with nutrient availability being a key factor regulating cellular and systemic growth and maturation timing (including mammalian puberty and insect metamorphosis). Cholesterol is an essential lipid used as substrate for steroidogenesis and as a structural component of cellular membranes. Diet is a major source of cholesterol, and adipose tissue is a main cholesterol storage depot, especially in obesity. Emerging evidence indicates that cholesterol is an important regulator of cell growth and thereby plays a critical role in health and disease. In fact, cholesterol has recently been identified as a promoter of the occurrence, metastasis, and mortality of cancers such as breast and prostate cancer and glioblastoma, and this lipid has therefore become a clinically important therapeutic target. Despite this importance, the mechanism by which cholesterol regulates both normal cell growth and cancer development remains poorly understood. Since growth control is a fundamental process during development, the signaling pathways that regulate growth have been conserved between flies and humans. We have found that cholesterol’s influence on systemic and cellular growth in Drosophila larva arises primarily through effects on the conserved intracellular nutrient sensor Target of Rapamycin (TOR) and the superimposed insulin-like signaling system, the main hormonal system controlling systemic growth. Increasing intracellular cholesterol levels either by dietary supplementation or through knockdown of the lysosomal cholesterol transporter Niemann-Pick Type C-1a (NPC1a) increases TOR activity, leading to increased cell growth. These effects in the cells of the fat body and glia of the blood-brain barrier lead to increased insulin production, release and signaling, whereas in the prothoracic gland, cholesterol-driven TOR activity promotes endoreduplication and thus appears to alter or bypass the “critical weight” checkpoint. Cholesterol induced TOR activity appears to be tightly regulated and exhibits temporal dynamics that differ from those seen in amino acid-induced TOR activity. Dysregulation of the TOR and insulin/IGF signaling systems are frequently linked with cancers, and thus these findings may further our understanding of the links between cholesterol, hormonal signaling, and growth control in cancer development, as well as and the connection between childhood obesity and early puberty.

Mechanisms of Systemic and Cellular Growth Control by Cholesterol