The Website of Mengwei Zang’s Laboratory

Research Summary

The main goal of Dr. Zang’s laboratory is to investigate the physiological regulation of novel signaling molecules important in energy homeostasis and their impact in diabetes and cardiovascular complications. Better understanding of these molecular mechanisms will provide a great opportunity for the development of novel therapeutic strategies for metabolic syndrome and cardiovascular disease. A major focus is to determine how protein kinases or signal transduction pathways modulate glucose and lipid metabolism in hepatocytes by their effects on phosphorylation, protein-protein interactions and gene expression, and their implication for pathological dysregulation in insulin resistance and diabetes. Recent studies focus on the role of key energy sensors, such as AMP-activated protein kinase (AMPK) and the NAD-dependent deacetylase (SIRT1), in the regulation of cell metabolism and diabetes. These studies have demonstrated that AMPK is required for metformin, one of the most widely prescribed type 2 diabetes drugs in the world, to prevent hepatocyte lipid accumulation caused by high glucose. Importantly, she has identified AMPK activation as a molecular mechanism for the beneficial effects of nature products, such as polyphenols including resveratrol, present in red wine, on hepatic lipid accumulation, hyperlipidemia and atherogenesis in type 1 and type 2 diabetic LDL receptor deficient mice. She and her colleagues have also defined SIRT1 as an upstream effector responsible for activating the LKB1/AMPK signaling pathway that explains the ability of polyphenols to inhibit high glucose-induced hepatocyte lipid accumulation. Our findings point to SIRT1 and AMPK as sharing a common pathway and functional consequence, providing major therapeutic targets for the treatment of diabetes. Parallel studies are being performed using in vitro cultured cell models and in vivo genetically-modified mice, to dissect the relationship between the cell signaling and alteration in cell metabolism that can be assessed from molecular and cellular levels that are integrated in diabetic mouse models. Current research is attempting to elucidate how these critical signaling pathways influence disease states, including fatty liver, dyslipidemia, and atherosclerosis in obesity, insulin resistance and type 2 diabetes. The ultimate goal is to provide new insight into the mechanism of insulin resistance and diabetes and to identify potential therapeutic interventions.

Key words: phosphorylation, signal transduction, AMP-activated protein kinase, NAD-dependent deacetylase (SIRT1), hepatocytes, lipid metabolism, insulin resistance and diabetes.