Prof. Song received his B.S. degree from Nanjing University in 1997, and Ph.D. diploma from Chinese Academy of Sciences in 2002. He joined the Brown-Goldstein lab at UT Southwestern Medical Center as a Postdoctoral Fellow. In 2005, he moved to Shanghai Institutes for Biological Sciences at Chinese Academy of Sciences as a Principle Investigator, and then he worked as a professor and was promoted to the Dean of College of Life Sciences, Wuhan University since 2014. He focuses on cholesterol metabolism and his major contributions are: 1) identifying a new cholesterol transport way through lysosome-peroxisome-ER membrane contacts; 2) elucidating the molecular pathway of intestinal cholesterol absorption; 3) revealing the mechanism of feedback regulation of cholesterol biosynthesis. 4) identifying that Smoothened (SMO) is a cholesterol-modified protein.
Cholesterol is an essential lipid and it costs lots of nutrients and energy to make such a molecule. Therefore, mammals increase cholesterol biosynthesis only after feeding and inhibit the process under fasting condition. However, the regulatory mechanisms of cholesterol biosynthesis at fasting-feeding transition are not fully understood. Here we show that the deubiquitylase USP20 stabilizes HMG-CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol biosynthetic pathway, at feeding state. The post-prandially increased insulin and glucose stimulate mTORC1 to phosphorylate USP20 at S132 and S134, which is further recruited to the HMGCR complex and antagonizes its degradation. The feeding-induced stabilization of HMGCR is abolished in the liver-specific Usp20 deficient mice and the Usp20-S132A/S134A knock-in mice. Genetic deletion or pharmacological inhibition of USP20 dramatically decreases diet-induced body weight gain, reduces lipid levels in the serum and liver, improves insulin sensitivity as well as increases energy expenditure. These metabolic improvements by USP20 inhibition are reversed by the constitutively stable HMGCR(K248R). This study reveals an unexpected regulatory axis from mTORC1 to HMGCR through USP20 phosphorylation and demonstrates USP20 inhibitor as a potential cholesterol-lowering drug to treat metabolic diseases including hyperlipidemia, liver steatosis, obesity and diabetes. I will also present our latest findings on cholesterol excretion.