title: Growth Hormone Inhibits Hepatic De Novo Lipogenesis in Adult Mice.
abstract: Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have low growth hormone (GH) production and/or hepatic GH resistance. GH replacement can resolve the fatty liver condition in diet-induced obese rodents and in GH-deficient patients. However, it remains to be determined whether this inhibitory action of GH is due to direct regulation of hepatic lipid metabolism. Therefore, an adult-onset, hepatocyte-specific, GH receptor (GHR) knockdown (aLivGHRkd) mouse was developed to model hepatic GH resistance in humans that may occur after sexual maturation. Just 7 days after aLivGHRkd, hepatic de novo lipogenesis (DNL) was increased in male and female chow-fed mice, compared with GHR-intact littermate controls. However, hepatosteatosis developed only in male and ovariectomized female aLivGHRkd mice. The increase in DNL observed in aLivGHRkd mice was not associated with hyperactivation of the pathway by which insulin is classically considered to regulate DNL. However, glucokinase mRNA and protein levels as well as fructose-2,6-bisphosphate levels were increased in aLivGHRkd mice, suggesting that enhanced glycolysis drives DNL in the GH-resistant liver. These results demonstrate that hepatic GH actions normally serve to inhibit DNL, where loss of this inhibitory signal may explain, in part, the inappropriate increase in hepatic DNL observed in NAFLD patients.
authors.affiliation: Research and Development Division, Jesse Brown VA Medical Center, Chicago, IL Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL.
authors.forename: Jose
authors.initials: J
authors.lastname: Cordoba-Chacon
authors.affiliation: Research and Development Division, Jesse Brown VA Medical Center, Chicago, IL Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL.
authors.forename: Neena
authors.initials: N
authors.lastname: Majumdar
authors.affiliation: Edison Biotechnology Institute, Ohio University, Athens, OH Department of Specialty Medicine, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH.
authors.forename: Edward O
authors.initials: EO
authors.lastname: List
authors.affiliation: Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD.
authors.forename: Alberto
authors.initials: A
authors.lastname: Diaz-Ruiz
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL Endocrinology Section Medical Service, Birmingham VA Medical Center, Birmingham, AL.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Frank
authors.affiliation: Department of Physiological Sciences, University of Barcelona, L'Hospitalet, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Manzano
authors.affiliation: Department of Physiological Sciences, University of Barcelona, L'Hospitalet, Barcelona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Bartrons
authors.affiliation: Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Michelle
authors.initials: M
authors.lastname: Puchowicz
authors.affiliation: Edison Biotechnology Institute, Ohio University, Athens, OH Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH.
authors.forename: John J
authors.initials: JJ
authors.lastname: Kopchick
authors.affiliation: Research and Development Division, Jesse Brown VA Medical Center, Chicago, IL Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL kineman@uic.edu.
authors.forename: Rhonda D
authors.initials: RD
authors.lastname: Kineman
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005635:Fructosediphosphates; D055785:Gene Knockdown Techniques; D005941:Glucokinase / Q000235:genetics* / Q000378:metabolism; D006019:Glycolysis; D013006:Growth Hormone / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D050155:Lipogenesis / Q000235:genetics* / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000378:metabolism; D010052:Ovariectomy; D012333:RNA, Messenger / Q000378:metabolism*; D011986:Receptors, Somatotropin / Q000235:genetics* / Q000378:metabolism
chemical_list: D005635:Fructosediphosphates; D007328:Insulin; D012333:RNA, Messenger; D011986:Receptors, Somatotropin; C027652:fructose 2,6-diphosphate; D013006:Growth Hormone; D005941:Glucokinase