Title | β-catenin links hepatic metabolic zonation with lipid metabolism and diet-induced obesity in mice. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Behari J, Li H, Liu S, Stefanovic-Racic M, Alonso L, O'Donnell CP, Shiva S, Singamsetty S, Watanabe Y, Singh VP, Liu Q |
Journal | Am J Pathol |
Volume | 184 |
Issue | 12 |
Pagination | 3284-98 |
Date Published | 2014 Dec |
ISSN | 1525-2191 |
Keywords | Animals, Apoptosis, beta Catenin, Body Weight, Diet, High-Fat, Fatty Acids, Fatty Liver, Glycolysis, Hepatocytes, Hypoxia, Immunohistochemistry, Inflammation, Insulin, Insulin Resistance, Lipid Metabolism, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Obesity, Oxygen, Signal Transduction |
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. |
DOI | 10.1016/j.ajpath.2014.08.022 |
Alternate Journal | Am. J. Pathol. |
PubMed ID | 25300578 |
PubMed Central ID | PMC4258504 |
Grant List | K08 AA017622 / AA / NIAAA NIH HHS / United States R01 DK095140 / DK / NIDDK NIH HHS / United States |