TSC22D4 is a molecular output of hepatic wasting metabolism.
Bottom Line: In mammals, proper storage and distribution of lipids in and between tissues is essential for the maintenance of energy homeostasis.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.Therefore, hepatic TSC22D4 activity may represent a molecular rationale for peripheral energy deprivation in subjects with metabolic wasting diseases, including cancer cachexia.
Affiliation: 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.Show MeSH
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Mentions: The induction of TSC22D4 expression in cancer cachexia (Fig 3B) and its regulatory impact on hepatic lipid handling finally prompted us to correlate the hepatic expression levels of various transcriptional regulators, including TSC22D4, with either the degree of cachexia or hepatic VLDL release in tumour-bearing and healthy control animals. While these studies revealed a correlation between the expression levels of PGC-1alpha and TBL1 and wasting, PGC-1beta, SRC-1, SRC-3 and CBP mRNA levels did not correlate with tumour-induced body weight loss (Supporting Information Fig S6A and B). In contrast, TSC22D4 mRNA levels positively correlated with the degree of body weight loss and negatively correlated with hepatic VLDL secretion in tumour bearing versus control animals (Fig 8A and B). In line with the assumption that TSC22D4 mediates parts of the metabolic liver phenotype during cancer cachexia, inhibition of lipogenic gene expression in primary hepatocytes by cachexia-inducing conditioned C26 or B16 melanoma tumour cell supernatants was rescued by TSC22D4 knockdown (Fig 8C and D). These data overall indicated that TSC22D4 expression levels may serve as a specific molecular indicator of the hepatic lipid handling status particularly under conditions of energy deficiency, including tumour-induced cachexia.
Affiliation: 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.