title: 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.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: beharij@upmc.edu.
authors.forename: Jaideep
authors.initials: J
authors.lastname: Behari
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Huanan
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Shiguang
authors.initials: S
authors.lastname: Liu
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Maja
authors.initials: M
authors.lastname: Stefanovic-Racic
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Laura
authors.initials: L
authors.lastname: Alonso
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: O'Donnell
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Singamsetty
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Vijay P
authors.initials: VP
authors.lastname: Singh
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D059305:Diet, High-Fat; D005227:Fatty Acids / Q000737:chemistry; D005234:Fatty Liver / Q000378:metabolism; D006019:Glycolysis; D022781:Hepatocytes / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D010100:Oxygen / Q000737:chemistry; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D005227:Fatty Acids; D007328:Insulin; D051176:beta Catenin; D010100:Oxygen