Thyroid hormone upregulates zinc-α2-glycoprotein production in the liver but not in adipose tissue.
Overproduction of zinc-α2-glycoprotein by adipose tissue is crucial in accounting for the lipolysis occurring in cancer cachexia of certain malignant tumors. The main aim of this study was to explore whether thyroid hormone could enhance zinc-α2-glycoprotein production in adipose tissue. In addition, the regulation of zinc-α2-glycoprotein by thyroid hormone in the liver was investigated. We performed in vitro (HepG2 cells and primary human adipocytes) and in vivo (C57BL6/mice) experiments addressed to examine the effect of thyroid hormone on zinc-α2-glycoprotein production (mRNA and protein levels) in liver and visceral adipose tissue. We also measured the zinc-α2-glycoprotein serum levels in a cohort of patients before and after controlling their hyperthyroidism. Our results showed that thyroid hormone up-regulates zinc-α2-glycoprotein production in HepG2 cells in a dose-dependent manner. In addition, the zinc-α2-glycoprotein proximal promoter contains functional thyroid hormone receptor binding sites that respond to thyroid hormone treatment in luciferase reporter gene assays in HepG2 cells. Furthermore, zinc-α2-glycoprotein induced lipolysis in HepG2 in a dose-dependent manner. Our in vivo experiments in mice confirmed the up-regulation of zinc-α2-glycoprotein induced by thyroid hormone in the liver, thus leading to a significant increase in zinc-α2-glycoprotein circulating levels. However, thyroid hormone did not regulate zinc-α2-glycoprotein production in either human or mouse adipocytes. Finally, in patients with hyperthyroidism a significant reduction of zinc-α2-glycoprotein serum levels was detected after treatment but was unrelated to body weight changes. We conclude that thyroid hormone up-regulates the production of zinc-α2-glycoprotein in the liver but not in the adipose tissue. The neutral effect of thyroid hormones on zinc-α2-glycoprotein expression in adipose tissue could be the reason why zinc-α2-glycoprotein is not related to weight loss in hyperthyroidism.
Diabetes and Metabolism Research Unit, Institut de Recerca Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona and CIBERDEM (ISCIII), Barcelona, Spain.
Rafael
R
Simó
Diabetes and Metabolism Research Unit, Institut de Recerca Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona and CIBERDEM (ISCIII), Barcelona, Spain.
Cristina
C
Hernández
Diabetes and Metabolism Research Unit, Institut de Recerca Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona and CIBERDEM (ISCIII), Barcelona, Spain.
Cristina
C
Sáez-López
Service of Endocrinology and Nutrition, Department of Medicine, Germans Trias i Pujol Health Sciences Reseach Institute and Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
Berta
B
Soldevila
Service of Endocrinology and Nutrition, Department of Medicine, Germans Trias i Pujol Health Sciences Reseach Institute and Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
Manel
M
Puig-Domingo
Diabetes and Metabolism Research Unit, Institut de Recerca Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona and CIBERDEM (ISCIII), Barcelona, Spain.
David M
DM
Selva
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001835:Body Weight / Q000187:drug effects; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D006980:Hyperthyroidism / Q000097:blood / Q000503:physiopathology; D008066:Lipolysis / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D029589:Seminal Plasma Proteins / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics / Q000378:metabolism; D013960:Thyroid Function Tests; D014284:Triiodothyronine / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*; D000090203:Zn-Alpha-2-Glycoprotein
D029589:Seminal Plasma Proteins; D000090203:Zn-Alpha-2-Glycoprotein; D014284:Triiodothyronine