Nadja Lehwald1, Guo-Zhong Tao2, Kyu Yun Jang3, Ioanna Papandreou4, Bowen Liu2, Bo Liu2, Marybeth A Pysz5, Jürgen K Willmann5, Wolfram T Knoefel6, Nicholas C Denko4, Karl G Sylvester7. 1. 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. 2. Department of Surgery, Divison of Pediatric Surgery, Stanford University School of Medicine, Stanford, California. 3. 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. 4. Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California. 5. Department of Radiology, Molecular Imaging Program, Stanford University School of Medicine, Stanford, California. 6. Department of General, Visceral, and Pediatric Surgery, School of Medicine, Heinrich Heine University, Duesseldorf, Germany. 7. 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.
Abstract
BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: 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.
Authors: J R Lynch; H Yi; D A Casolari; F Voli; E Gonzales-Aloy; T K Fung; B Liu; A Brown; T Liu; M Haber; M D Norris; I D Lewis; C W E So; R J D'Andrea; J Y Wang Journal: Leukemia Date: 2016-02-09 Impact factor: 11.528
Authors: Chiung-Kuei Huang; Tunan Yu; Suzanne M de la Monte; Jack R Wands; Zoltan Derdak; Miran Kim Journal: J Hepatol Date: 2015-02-24 Impact factor: 25.083
Authors: Gholamreza Bidkhori; Rui Benfeitas; Martina Klevstig; Cheng Zhang; Jens Nielsen; Mathias Uhlen; Jan Boren; Adil Mardinoglu Journal: Proc Natl Acad Sci U S A Date: 2018-11-27 Impact factor: 11.205