Professor Sheng-Cai Lin is the winner of the 2025 FAOBMB Award for Research Excellence
Professor Sheng-Cai Lin
School of Life Sciences, Xiamen University, China
Dr. Sheng-Cai Lin obtained his bachelor’s degree in biology from Xiamen University, China in 1984, and earned his PhD degree in biochemistry from the University of Texas Southwestern Medical Center at Dallas in 1991. He went on to finish his post-doctoral training with Dr. Michael Geoff Rosenfeld at the Howard Hughes Medical Institute, University of California at San Diego. In 1995, he was recruited by the Institute of Molecular and Cell Biology of Singapore as a Principal Investigator. Six years later, he moved to the Department of Biochemistry of Hong Kong University Science and Technology, where he became an Associate Professor with tenure. In 2006 Xiamen University recruited him as a Professor at its School of Life Sciences.
Over the last 15 years, Dr. Sheng-Cai Lin and his team have been studying how nutrients regulate cellular activities to affect physiological functions. As a molecular biologist and a biochemist, Dr. Lin is interested in how physiologically normal fluctuations of glucose are sensed and transmitted to manifest biological functions. He and his team have discovered a molecular pathway, referred to as the lysosomal glucose-sensing-AMPK pathway, which senses low glucose, activates the lysosomally localized pool of AMPK, and concomitantly inhibits mTORC1. They have also shown that the glucose sensing pathway is shared by metformin and lithocholic acid. Through testing in animal models, including nematodes, flies, and mice, they have demonstrated that the glucose sensing pathway plays critical roles in health and longevity of metazoans.
In more specific terms, Dr. Lin and his team discovered that LKB1, as an upstream kinase, binds to AXIN and requires this scaffold protein to phosphorylate and consequentially activate AMPK, which is a serine/threonine kinase that acts as a master regulator of metabolism. This demonstrates that AMPK activation by LKB1 needs a scaffold. They further found that the AXIN-mediated activation of AMPK by LKB1 takes place at the lysosome, with the lysosomal proton pump v-ATPase as a key anchor for AXIN in cells undergoing glucose starvation. Along the course of delineating the mechanism for the low glucose-triggered activation of AMPK, they realized that such activated AMPK is in fact lysosomally localized. A major breakthrough for understanding glucose sensing was made when they later found that the glycolytic enzyme aldolase, associated with the v-ATPase complex, is the sensor for the intermediary metabolite of glucose, namely fructose-1,6-bisphosphate (FBP). In low glucose, cellular levels of FBP were also lower and aldolase became unoccupied with FBP. This leads to inhibition of v-ATPase, allowing AXIN in complex with LKB1 to translocate onto the lysosome through binding to the inhibited v-ATPase along with other proteins. This lysosomal translocation of AXIN brings LKB1 to the vicinity of the lysosomal AMPK; thereby, AMPK is phosphorylated by LKB1 and becomes active, with a concomitant inhibition of mTORC1, a kinase complex with opposite function to that of AMPK.
What has helped reinforce the significance of the discovery of the glucose sensing-AMPK pathway was that Dr. Lin and his team uncovered that metformin signals through PEN2, which intersects the glucose sensing pathway via v-ATPase. Moreover, they found that lithocholic acid, accumulated in the blood of mice under calorie restriction, on its own generates likewise the benefits of calorie restriction. In addition, they have found that lithocholic acid also utilizes the glucose sensing-AMPK pathway to elicit rejuvenating and anti-ageing effects. The discovery of the glucose sensing-AMPK pathway has enabled them to identify a family of chemicals of low molecular weight, members of which can act as mimetics of glucose starvation. One of them is a drug lead, aldometanib, which has been shown effective in animal models for the treatment of type 2 diabetes, non-alcoholic fatty liver disease, obesity, liver cancer and in extending healthspan and lifespan.
In summary, Dr. Lin has shown that metazoan cells possess a specialized pathway that enables the cells to sense oscillating glucose levels and convert these signals to the activation of either AMPK or mTORC1 to promote catabolism or anabolism depending on the supply of glucose. This discovery hints at a profound metaphysical significance: glucose is not just a simple fuel but it also acts as a dynamic messenger orchestrating the “intricate dance” of metabolic homeostasis. The implications are exciting and will open new frontiers in our understanding of metabolism. Dr. Lin served as Vice-President of the Chinese Society of Biochemistry and Molecular Biology from 2014-23. He was elected a Member of the Chinese Academy of Sciences in 2021. He has been invited to present work at prestigious conferences including the Cold Spring Harbor Symposia, FASEB meetings, and various congresses of the Chinese biological societies. He has received various awards, including the Ho Leung Ho Lee Award (2023), and the Research Excellence Award from the Chinese Society of Cell Biology (2022).