Liver-specific loss of beta-catenin blocks glutamine synthesis pathway activity and cytochrome p450 expression in mice.
There is accumulating evidence that Wnt/beta-catenin signaling is involved in the regulation of liver development and physiology. The presence of genetic alterations resulting in constitutive beta-catenin stabilization in human and murine liver tumors also implicates this pathway in hepatocyte proliferation. In the present study, we generated hepatocyte-specific beta-catenin knockout mice to explore the role of beta-catenin in liver function. Conditional knockout mice were born at the expected Mendelian ratio and developed normally to adulthood, indicating beta-catenin is dispensable for essential liver function under normal breeding conditions. However, the liver mass of knockout mice was 20% less than those of mice in the control groups. Expression analysis revealed loss of genes required for glutamine synthesis in knockout mice. Loss of the liver glutamine synthesis pathway did not affect the blood ammonia level in mice fed a standard diet, yet, knockout mice showed significantly elevated blood ammonia levels with high-protein dietary feeding. Furthermore, the expression of two cytochrome P450 enzymes, CYP1A2 and CYP2E1, was almost completely abolished in livers from hepatocyte-specific beta-catenin knockout mice. Consequently, these mice were resistant to acetaminophen challenge, confirming the requirement of these cytochrome P450 enzymes for metabolism of xenobiotic substances. In conclusion, in addition to regulating hepatocyte proliferation, beta-catenin may also control multiple aspects of normal liver function.
Department of Medicine, Diabetes Center, University of California--San Francisco, San Francisco, CA 94143-0573, USA.
Shigeki
S
Sekine
Billy Yu-Ang
BY
Lan
Melanie
M
Bedolli
Sandy
S
Feng
Matthias
M
Hebrok
D000082:Acetaminophen / Q000494:pharmacology; D000641:Ammonia / Q000097:blood; D000818:Animals; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004044:Dietary Proteins / Q000008:administration & dosage; D004351:Drug Resistance; D005786:Gene Expression Regulation; D005973:Glutamine / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051176:beta Catenin / Q000172:deficiency* / Q000378:metabolism
D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004044:Dietary Proteins; D051176:beta Catenin; D005973:Glutamine; D000082:Acetaminophen; D000641:Ammonia