Cholesterol plays a critical role in regulating embryonic development and membrane functions. But a high level of circulating cholesterol causes cardiovascular disease. Hedgehog (Hh) has been known as the only cholesterol-modified morphogen playing pivotal roles in development and tumorigenesis. A major unsolved question is how Hh signaling regulates the activity of Smoothened (SMO). The speaker performed an unbiased biochemical screen and identified that SMO was covalently modified by cholesterol on the Asp95 (D95) residue through an ester bond. This modification was inhibited by Patched-1 (Ptch1) but enhanced by Hh. The SMO(D95N) mutation, which could not be cholesterol modified, was refractory to Hh-stimulated ciliary localization and failed to activate downstream signaling. Furthermore, homozygous SmoD99N/D99N (the equivalent residue in mouse) knockin mice were embryonic lethal with severe cardiac defects, phenocopying the Smo-/- mice. Together, the results of his study suggest that Hh signaling transduces to SMO through modulating its cholesterylation. A high concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease. He identified a rare frameshift variant in the LIMA1 (also known as EPLIN or SREBP3) gene from a Chinese family of Kazakh ethnicity with inherited low LDL-C and reduced cholesterol absorption. In a mouse model, LIMA1 was mainly expressed in the small intestine and localized on the brush border membrane. LIMA1 bridged NPC1L1, an essential protein for cholesterol absorption, to a transportation complex containing myosin Vb and facilitated cholesterol uptake. Similar to the human phenotype, Lima1-deficient mice displayed reduced cholesterol absorption and were resistant to diet-induced hypercholesterolemia. In this lecture, the speaker will also present some recent progresses of his study.
About the speaker
Prof. Song Bao-Liang received his BS in Biology from Nanjing University in 1997 ad his PhD from Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences in 2002. He joined the University of Texas Southwestern Medical Center as a Postdoctoral Research Fellow, and in 2005, he returned to Shanghai Institutes for Biological Sciences to serve as a Principal Investigator. He was appointed the Professor of Biochemistry and Dean of Life Sciences at Wuhan University in 2014.
Prof. Song’s research focuses on cholesterol homeostasis that is closely related to cardiovascular disease. His group has dissected the molecular pathway of intestinal cholesterol absorption and identified most of the proteins in this process. He has uncovered the mechanism of sterol-regulated degradation of HMG-CoA reductase, which is a major feed-back regulation of de novo cholesterol biosynthesis. His group also identified betulin, a small molecule, which can decrease both cholesterol and fatty acid levels by inhibiting SREBP pathway.
