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Nuclear Receptors Based Modulation of Hepatic Lipid and Glucose Metabolism

Deepak Nagrath1, Yoko Tanimura1, Hongzhi Xu1, Francois Berthiaume2, and Martin L. Yarmush3. (1) Massachusetts General Hospital/Shriners Burn Hospital/Harvard Medical School, 51 Blossom Street, Boston, MA 02114, (2) Center for Engineering in Medicine, Harvard Medical School, 51 Blossom St, Boston, MA 02114, (3) Harvard Medical School, Center for Engineering in Medicine, Massachusetts General Hospital, 51 Blossom Street, Boston, MA 02114

Nuclear Hormone Receptors are ligand activated transcription factors which are activated by binding to lipophilic ligands. The activated nuclear transcription factors have emerged as important regulators of lipid and glucose metabolism. These activated receptors, although pleitropic in nature, have been found to regulate the expression of genes involved in lipid and glucose metabolism and homeostasis. The modulation of these receptors provides a suitable therapeutic strategy for the management of various diseases ranging from diabetes to obesity. The current work investigates two different invitro (lean hepatocytes; fatty-hepatocytes made fatty invitro using a high fat diet and) and invivo (choline methionine deficient diet induced steatosis and Zucker rats)systems.

Using various ligands for these receptors we have developed strategies for regulating lipid and glucose metabolism and, increasing hepatic functions in cultured hepatocytes for bioartificial liver. First, hepatocytes were made fatty invitro using unsaturated fatty acids and later defatting kinetics and hepatic function was measured using various nuclear receptor ligands. Few nuclear receptor agonists selected from invitro experiments were then used for exvivo liver defatting.

Importantly, our results suggest a new mechanism to differentially regulate/promote fatty oxidation and limit lipid esterification and storage in hepatocytes using various agonists and antagonists of these nuclear receptors.