Rolf Luft Award 2016

Their Prize Lectures "Scap: Cholesterol Sensor and Lipid Regulator" was held at The Rolf Luft Symposium on September 13, 2016.

Motivation

Michael Brown and Joe Goldstein have made seminal contributions to endocrinology and metabolism. Since winning the Nobel Prize, 1985, for establishing the pathologic mechanism responsible for Familial Hypercholesterolemia and identifying the LDL receptor, Brown and Goldstein have elucidated the components of a novel cholesterol sensing pathway in hepatocytes. At that time it was not clear how a cellular component as abundant as cholesterol could be sensed and in turn regulate cholesterol synthesis and metabolism. Brown and Goldstein first noted that expression of the LDL receptor gene was induced in cells deprived of cholesterol and set out to establish the transcriptional mechanism. This led to the identification of SREBP1a as a master regulator of a cluster of genes required for cholesterol synthesis, the observation that SREBP protein was expressed in the ER and that it was regulated by proteolytic cleavage. They then used a variety of approaches including studies of cholesterol auxotrophs to identify the cholesterol sensing protein SCAP, which regulates the first proteolytic cleavage of the SREBP precursor. After this cleavage, the SREBP precursor translocates to the Golgi where a second cleavage releases the mature transcription factor which then translocates to the nucleus. The identification of SCAP and the two proteases has established the regulatory mechanisms that control cholesterol production which is of general importance. In addition to these seminal studies Brown and Goldstein have contributed to other areas of endocrinology by identifying GOAT, the acyltransferase that octanoylates ghrelin,showing that ghrelin plays a critical role in the response to hypoglycemia and by showing that leptin is an effective therapy for lipodystrophy.