Cholesterol, a vital nutrient, plays many roles both within the cell and systemically, such as regulating cell-membrane fluidity and cell signaling and acting as a chemical precursor to steroid hormones.Emerging evidence indicates that cholesterol has a critical function in regulating growth and thereby plays a crucial role in health and disease. Dysregulation of cholesterol homeostasis and signaling pathways is associated with a variety of metabolic disorders and cancers. However, how cholesterol is sensed and drives growth is not fully understood.

Using intact Drosophila melanogaster larvae and tissues as well as human cell culture, we in this research show that cholesterol is sensed through the highly conserved Target of Rapamycin (TOR) pathway. This pathway is a well-known nutrient-responsive pathway that integrates numerousindicators of environmental favorability and regulates cellular and systemic growth in response.Increasing intracellular cholesterol levels either by dietary supplementation or through knockdown of the lysosomal cholesterol exporter Niemann-Pick Type C-1a (Npc1a) increases TOR activity, leading to increased cell growth. Mechanisms underlying TOR activation by lysosomal cholesterol have been reported in other systems, but those mechanisms are not entirely conserved across taxa. Sterol trafficking and TOR signaling are evolutionarily ancient (they likely arose in an early eukaryote before animals, plants, and fungi diverged), but any conserved upstream cholesterol sensor that regulates TOR activity remains unidentified. The Drosophila nuclear receptor HR3 acts as a regulator of cellautonomous growth through modulation of the TOR pathway, and in humans its closest ortholog, retinoid-related orphan receptor alpha (RORα) binds cholesterol and has been suggested to be a regulator of TOR activity. We have found that HR3 is indeed activated by cholesterol and alters TOR activity – feeding Drosophila larvae cholesterol-containing food induces TOR activation in a HR3dependent manner.

Using intact Drosophila melanogaster larvae and tissues as well as human cell culture, we in this research show that cholesterol is sensed through the highly conserved Target of Rapamycin (TOR) pathway. This pathway is a well-known nutrient-responsive pathway that integrates numerousindicators of environmental favorability and regulates cellular and systemic growth in response.Increasing intracellular cholesterol levels either by dietary supplementation or through knockdown of the lysosomal cholesterol exporter Niemann-Pick Type C-1a (Npc1a) increases TOR activity, leading to increased cell growth. Mechanisms underlying TOR activation by lysosomal cholesterol have been reported in other systems, but those mechanisms are not entirely conserved across taxa. Sterol trafficking and TOR signaling are evolutionarily ancient (they likely arose in an early eukaryote before animals, plants, and fungi diverged), but any conserved upstream cholesterol sensor that regulates TOR activity remains unidentified. The Drosophila nuclear receptor HR3 acts as a regulator of cellautonomous growth through modulation of the TOR pathway, and in humans its closest ortholog, retinoid-related orphan receptor alpha (RORα) binds cholesterol and has been suggested to be a regulator of TOR activity. We have found that HR3 is indeed activated by cholesterol and alters TOR activity – feeding Drosophila larvae cholesterol-containing food induces TOR activation in a HR3dependent manner.