Crossroads between drug and energy metabolism : role of constitutive androstane receptor and AMP-activated kinase

Phenobarbital (PB) is a prototype inducer of genes encoding drug metabolizing enzymes
including the cytochromes P450 (CYPs). Additionally, phenobarbital was found to
repress genes that encode enzymes involved in gluconeogenesis such as
phosphoenolpyruvate carboxykinase (PEPCK). Constitutive androstane receptor (CAR)
is known to play a fundamental role in the phenobarbital-mediated regulation of
cytochromes P450 and in gluconegenesis in the liver. Phenobarbital was recently shown
in our laboratory to activate a known inhibitor of hepatic glucose production, the energy
sensor AMP-activated kinase (AMPK). In the present thesis, we investigated the role of
AMPK in the phenobarbital-mediated inhibition of gluconeogenesis. Our experiments
reveal that both CAR and AMPK are necessary to mediate the PB inhibitory effect on
PEPCK mRNA expression. Furthermore, our study indicates that AMPK and CAR
physically interact in this process. We speculate that once activated by PB, the CARAMPK
complex may prevent coactivators such as PGC-1α to interact with partners at the
PEPCK promoter. However, overexpression of exogenous CAR dose-dependently
increased PEPCK mRNA expression and its promoter activity in a human hepatoma cell
line. The co-transfection of CAR with PGC-1α, a master regulator of PEPCK, clearly
increases PEPCK promoter activity. Moreover, we show that the cotransfection of CAR
and protein kinase A (PKA), a well established inducer of gluconeogenic pathways, dose
dependently activates PEPCK.
Our results also indicate that similarily to PEPCK, CAR mRNA expression is induced
during fasting and in the absence of glucose. CAR also induces genes that encode for
glucose transport during fasting. On the other hand, insulin represses CAR mRNA
expression suggesting that CAR plays a significant role in the fasting-feeding transition.
Finally, we demonstrate that CAR regulates the expression of genes encoding for of
acetyl-CoA carboxylase (ACC), an enzyme known to be involved in the control of
lipogenesis and beta oxidation of fatty acids. Altogether, these studies indicate that CAR is involved in the regulation of glucose and lipid metabolism and the regulation of its
activity may be crucial to understand the molecular mechanisms that link drug
metabolism to energy metabolism.