Joseph (Yossi) Tam D.M.D., Ph.D.

The endocannabinoid (eCB) system is increasingly recognized as being of crucial importance in obesity-related metabolic abnormalities, one of which is liver injury and hepatic steatosis. eCBs, via activation of CB1 receptors in the liver, modulate hepatic lipogenesis and fatty acid oxidation. Yet, the underlying molecular mechanisms are largely unknown.

Our recent findings provide strong evidence for a functional role of the peroxisome proliferator-activated receptor-alpha (PPARα)/sirtuin 1(SIRT1) signaling pathway in potentially mediating the antisteatotic effect of peripherally restricted CB1 blockade. Therefore, the aim of this project is to delineate the key signaling factors involved in mediating the role of hepatic CB1 receptors in obesity-induced hepatic steatosis. Our general hypothesis is that activation of hepatic CB1 receptors by eCBs, decrease the expression and activity of SIRT1, which consequently impairs PPARα signaling, leading to the development of hepatic steatosis.

To achieve the objective of this project, we aim to: (i) verify the role of hepatic SIRT1 in the antisteatotic effect of peripheral CB1 blockade, (ii) examine the role of hepatic CB1 on SIRT1/PGC-1α/PPARα expression and activity, and (iii) determine the molecular signaling cascade by which CB1 modulates SIRT1 activity. As I have recently demonstrated the potential therapeutic value of selective blockade of peripheral CB1 receptors in animal models of obesity, further understanding of the regulation of hepatic steatosis by the CB1/eCB system has the potential to support the translation of our basic findings, and identify novel mechanisms that can be targeted for therapy, contributing directly to the fields of obesity and liver research.

Key words: Hepatic Steatosis, Liver injury, CB1 receptor blockade, PPAR alpha signaling, Sirt1, Obesity, Non-alcoholic fatty liver disease (NAFLD), Lipogenesis