title: TSC22D4 is a molecular output of hepatic wasting metabolism.
abstract: In mammals, proper storage and distribution of lipids in and between tissues is essential for the maintenance of energy homeostasis. Here, we show that tumour growth triggers hepatic metabolic dysfunction as part of the cancer cachectic phenotype, particularly by reduced hepatic very-low-density-lipoprotein (VLDL) secretion and hypobetalipoproteinemia. As a molecular cachexia output pathway, hepatic levels of the transcription factor transforming growth factor beta 1-stimulated clone (TSC) 22 D4 were increased in cancer cachexia. Mimicking high cachectic levels of TSC22D4 in healthy livers led to the inhibition of hepatic VLDL release and lipogenic genes, and diminished systemic VLDL levels under both normal and high fat dietary conditions. Liver-specific ablation of TSC22D4 triggered hypertriglyceridemia through the induction of hepatic VLDL secretion. Furthermore, hepatic TSC22D4 expression levels were correlated with the degree of body weight loss and VLDL hypo-secretion in cancer cachexia, and TSC22D4 deficiency rescued tumour cell-induced metabolic dysfunction in hepatocytes. Therefore, hepatic TSC22D4 activity may represent a molecular rationale for peripheral energy deprivation in subjects with metabolic wasting diseases, including cancer cachexia.
authors: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, Heidelberg, Germany.
authors: Allan
authors: A
authors: Jones
authors: Kilian
authors: K
authors: Friedrich
authors: Maria
authors: M
authors: Rohm
authors: Michaela
authors: M
authors: Schäfer
authors: Carolyn
authors: C
authors: Algire
authors: Philipp
authors: P
authors: Kulozik
authors: Oksana
authors: O
authors: Seibert
authors: Karin
authors: K
authors: Müller-Decker
authors: Tjeerd
authors: T
authors: Sijmonsma
authors: Daniela
authors: D
authors: Strzoda
authors: Carsten
authors: C
authors: Sticht
authors: Norbert
authors: N
authors: Gretz
authors: Geesje M
authors: GM
authors: Dallinga-Thie
authors: Barbara
authors: B
authors: Leuchs
authors: Manfred
authors: M
authors: Kögl
authors: Wolfgang
authors: W
authors: Stremmel
authors: Mauricio Berriel
authors: MB
authors: Diaz
authors: Stephan
authors: S
authors: Herzig
mesh_terms: D000818:Animals; D002100:Cachexia / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000150:complications* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D008079:Lipoproteins, VLDL; C582288:TSC22D4 protein, human; C443111:Spacdr protein, mouse; D014157:Transcription Factors; D014280:Triglycerides