β-catenin links hepatic metabolic zonation with lipid metabolism and diet-induced obesity in mice.

Abstract

β-catenin regulates the establishment of hepatic metabolic zonation. To elucidate the functional significance of liver metabolic zonation in the chronically overfed state in vivo, we fed a high-fat diet (HFD) to hepatocyte-specific β-catenin transgenic (TG) and knockout (KO) mice. Chow-fed TG and KO mice had normal liver histologic findings and body weight. However, HFD-fed TG mice developed prominent perivenous steatosis with periportal sparing. In contrast, HFD-fed KO mice had increased lobular inflammation and hepatocyte apoptosis. HFD-fed TG mice rapidly developed diet-induced obesity and systemic insulin resistance, but KO mice were resistant to diet-induced obesity. However, β-catenin did not directly affect hepatic insulin signaling, suggesting that the metabolic effects of β-catenin occurred via a parallel pathway. Hepatic expression of key glycolytic and lipogenic genes was higher in HFD-fed TG and lower in KO mice compared with wild-type mice. KO mice also exhibited defective hepatic fatty acid oxidation and fasting ketogenesis. Hepatic levels of hypoxia inducible factor-1α, an oxygen-sensitive transcriptional regulator of glycolysis and a known β-catenin binding partner, were higher in HFD-fed TG and lower in KO mice. KO mice had attenuated perivenous hypoxia, suggesting disruption of the normal sinusoidal oxygen gradient, a major determinant of liver carbohydrate and liver metabolism. Canonical Wnt signaling in hepatocytes is essential for the development of diet-induced fatty liver and obesity.

• Authors: Jaideep Behari, Huanan Li, Shiguang Liu, Maja Stefanovic-Racic, Laura Alonso, Christopher P O'Donnell, Sruti Shiva, Srikanth Singamsetty, Yoshio Watanabe, Vijay P Singh, Qing Liu
• Journal: The American journal of pathology (Am J Pathol) Vol. 184 Issue 12 Pg. 3284-98 (Dec 2014) ISSN: 1525-2191 [Electronic] United States
• PMID: 25300578 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• CTNNB1 protein, mouse
• Fatty Acids
• Insulin
• beta Catenin
• Oxygen

Topics

• Animals
• Apoptosis
• Body Weight
• Diet, High-Fat
• Fatty Acids (chemistry)
• Fatty Liver (metabolism)
• Glycolysis
• Hepatocytes (metabolism)
• Hypoxia (metabolism)
• Immunohistochemistry
• Inflammation
• Insulin (metabolism)
• Insulin Resistance
• Lipid Metabolism
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondria (metabolism)
• Obesity (metabolism)
• Oxygen (chemistry)
• Signal Transduction
• beta Catenin (metabolism)