Apc Tumor Suppressor Gene Is the “Zonation-Keeper” of Mouse Liver

Abstract

The molecular mechanisms by which liver genes are differentially expressed along a portocentral axis, allowing for metabolic zonation, are poorly understood. We provide here compelling evidence that the Wnt/beta-catenin pathway plays a key role in liver zonation. First, we show the complementary localization of activated beta-catenin in the perivenous area and the negative regulator Apc in periportal hepatocytes. We then analyzed the immediate consequences of either a liver-inducible Apc disruption or a blockade of Wnt signaling after infection with an adenovirus encoding Dkk1, and we show that Wnt/beta-catenin signaling inversely controls the perivenous and periportal genetic programs. Finally, we show that genes involved in the periportal urea cycle and the perivenous glutamine synthesis systems are critical targets of beta-catenin signaling, and that perturbations to ammonia metabolism are likely responsible for the death of mice with liver-targeted Apc loss. From our results, we propose that Apc is the liver "zonation-keeper" gene.

Endothelial Wnts regulate β‐catenin signaling in murine liver zonation and regeneration: A sequel to the Wnt–Wnt situation

“…The limited movement of Wnts, in general owing to their hydrophobicity secondary to acylation, which is essential for their biological activity, likely restricts β‐catenin activation to a few hepatocyte layers around the central vein. Further, high antigen‐presenting cell (APC) expression in hepatocytes in the periportal region also deters basal β‐catenin activity in that region 3. The basis of constitutive Wnt2 and Wnt9b release from ECs lining central veins remains unknown.…”

“…Mice with liver‐specific β‐catenin knockout (β‐catenin‐LKO) have been instrumental in discerning its many roles in hepatic physiology. These mice showed absence of pericentral gene expression validating pathway target genes, such as glutamine synthetase (GS), cytochrome P450 2E1 (Cyp2e1), and Cyp1a2 3, 4, 5, 6. A follow‐up study showed that dual KO of Wnt coreceptors LRP5 and LRP6 in the liver (LRP5‐6‐LDKO) also led to absent metabolic zonation 7.…”

Wnt/?-Catenin Signalling during Liver Metabolism, Chronic Liver Disease and Hepatocarcinogenesis

“…Benhamouche and colleagues established that the Wnt/β-catenin pathway is a major control switch pathway for metabolic zonation by demonstrating that blocking of β-catenin in hepatocytes by infection with an adenovirus encoding the Wnt signalling antagonist Dickkopf-1 (Dkk-1) resulted in expansion of the periportal transcriptome and downregulation of perivenous genes. Conversely, constitutive activation of β-catenin through liver-induced disruption of the negative regulator APC reversed this gene expression profile and induced the perivenous gene expression programme (48).…”

From hepatoprotection models to new therapeutic modalities for treating liver diseases: a personal perspective

“…The functional consequence of this change in enzyme localization is not currently known. However, CYP2E1 is a bona fide target of β-catenin, which is critical for liver zonation 27 and is also involved in liver regeneration after APAP overdose 9, 10 . It is intriguing and worth noting that a similar shift in localization of flavin-containing monooxygenase-3 (FMO3) was also noted in livers of our APAP autoprotection model 13 .…”