β-Catenin regulates hepatic mitochondrial function and energy balance in mice.
OBJECTIVE
Wnt signaling regulates hepatic function and nutrient homeostasis. However, little is known about the roles of β-catenin in cellular respiration or mitochondria of hepatocytes.


METHODS
We investigated β-catenin's role in the metabolic function of hepatocytes under homeostatic conditions and in response to metabolic stress using mice with hepatocyte-specific deletion of β-catenin and their wild-type littermates, given either saline (sham) or ethanol (as a model of binge drinking and acute ethanol intoxication).


RESULTS
Under homeostatic conditions, β-catenin-deficient hepatocytes demonstrated mitochondrial dysfunctions that included impairments to the tricarboxylic acid cycle and oxidative phosphorylation (OXPHOS) and decreased production of adenosine triphosphate (ATP). There was no evidence for redox imbalance or oxidative cellular injury in the absence of metabolic stress. In mice with β-catenin-deficient hepatocytes, ethanol intoxication led to significant redox imbalance in the hepatocytes and further deterioration in mitochondrial function that included reduced OXPHOS, fatty acid oxidation (FAO), and ATP production. Ethanol feeding significantly increased liver steatosis and oxidative damage, compared with wild-type mice, and disrupted the ratio of nicotinamide adenine dinucleotide. β-catenin-deficient hepatocytes also had showed disrupted signaling of Sirt1/peroxisome proliferator-activated receptor-α signaling.


CONCLUSIONS
β-catenin has an important role in the maintenance of mitochondrial homeostasis, regulating ATP production via the tricarboxylic acid cycle, OXPHOS, and fatty acid oxidation; β-catenin function in these systems is compromised under conditions of nutrient oxidative stress. Reagents that alter Wnt-β-catenin signaling might be developed as a useful new therapeutic strategy for treatment of liver disease.
Department of Surgery, Divison of Pediatric Surgery, Stanford University School of Medicine, Stanford, California; Department of General, Visceral, and Pediatric Surgery, School of Medicine, Heinrich Heine University, Duesseldorf, Germany.
Nadja
N
Lehwald
Department of Surgery, Divison of Pediatric Surgery, Stanford University School of Medicine, Stanford, California.
Guo-Zhong
GZ
Tao
Department of Surgery, Divison of Pediatric Surgery, Stanford University School of Medicine, Stanford, California; Department of Pathology and Research Institute of Clinical Medicine, Chonbuk National University Medical School, South Korea.
Kyu Yun
KY
Jang
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
Ioanna
I
Papandreou
Department of Surgery, Divison of Pediatric Surgery, Stanford University School of Medicine, Stanford, California.
Bowen
B
Liu
Department of Surgery, Divison of Pediatric Surgery, Stanford University School of Medicine, Stanford, California.
Bo
B
Liu
Department of Radiology, Molecular Imaging Program, Stanford University School of Medicine, Stanford, California.
Marybeth A
MA
Pysz
Department of Radiology, Molecular Imaging Program, Stanford University School of Medicine, Stanford, California.
Jürgen K
JK
Willmann
Department of General, Visceral, and Pediatric Surgery, School of Medicine, Heinrich Heine University, Duesseldorf, Germany.
Wolfram T
WT
Knoefel
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
Nicholas C
NC
Denko
Department of Surgery, Divison of Pediatric Surgery, Stanford University School of Medicine, Stanford, California; The Lucile Packard Children's Hospital, Stanford, California. Electronic address: sylvester@stanford.edu.
Karl G
KG
Sylvester
D000255:Adenosine Triphosphate; D000818:Animals; D002952:Citric Acid Cycle; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D000431:Ethanol / Q000633:toxicity; D005227:Fatty Acids / Q000378:metabolism; D005235:Fatty Liver, Alcoholic / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis; D015227:Lipid Peroxidation; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D013997:Time Factors; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C495267:CTNNB1 protein, mouse; D005227:Fatty Acids; D051176:beta Catenin; D000431:Ethanol; D000255:Adenosine Triphosphate