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

Jaideep Behari, Huanan Li, Shiguang Liu, Maja Stefanovic-Racic, Laura Alonso, Christopher P. O'Donnell, Sruti Shiva, Srikanth Singamsetty, Yoshio Watanabe, Vijay Prem Singh, Qing Liu

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3284-3298
Number of pages15
JournalAmerican Journal of Pathology
Volume184
Issue number12
DOIs
StatePublished - Dec 1 2014

Fingerprint

Catenins
Lipid Metabolism
Knockout Mice
Obesity
High Fat Diet
Diet
Liver
Transgenic Mice
Hepatocytes
Oxygen
Hypoxia-Inducible Factor 1
Carbohydrate Metabolism
Glycolysis
Fatty Liver
Insulin Resistance
Fasting
Fatty Acids
Body Weight
Insulin
Apoptosis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Behari, J., Li, H., Liu, S., Stefanovic-Racic, M., Alonso, L., O'Donnell, C. P., ... Liu, Q. (2014). β-catenin links hepatic metabolic zonation with lipid metabolism and diet-induced obesity in mice. American Journal of Pathology, 184(12), 3284-3298. https://doi.org/10.1016/j.ajpath.2014.08.022

β-catenin links hepatic metabolic zonation with lipid metabolism and diet-induced obesity in mice. / Behari, Jaideep; Li, Huanan; Liu, Shiguang; Stefanovic-Racic, Maja; Alonso, Laura; O'Donnell, Christopher P.; Shiva, Sruti; Singamsetty, Srikanth; Watanabe, Yoshio; Singh, Vijay Prem; Liu, Qing.

In: American Journal of Pathology, Vol. 184, No. 12, 01.12.2014, p. 3284-3298.

Research output: Contribution to journalArticle

Behari, J, Li, H, Liu, S, Stefanovic-Racic, M, Alonso, L, O'Donnell, CP, Shiva, S, Singamsetty, S, Watanabe, Y, Singh, VP & Liu, Q 2014, 'β-catenin links hepatic metabolic zonation with lipid metabolism and diet-induced obesity in mice', American Journal of Pathology, vol. 184, no. 12, pp. 3284-3298. https://doi.org/10.1016/j.ajpath.2014.08.022
Behari, Jaideep ; Li, Huanan ; Liu, Shiguang ; Stefanovic-Racic, Maja ; Alonso, Laura ; O'Donnell, Christopher P. ; Shiva, Sruti ; Singamsetty, Srikanth ; Watanabe, Yoshio ; Singh, Vijay Prem ; Liu, Qing. / β-catenin links hepatic metabolic zonation with lipid metabolism and diet-induced obesity in mice. In: American Journal of Pathology. 2014 ; Vol. 184, No. 12. pp. 3284-3298.
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