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TSC22D4 is a molecular output of hepatic wasting metabolism.

Jones A, Friedrich K, Rohm M, Schäfer M, Algire C, Kulozik P, Seibert O, Müller-Decker K, Sijmonsma T, Strzoda D, Sticht C, Gretz N, Dallinga-Thie GM, Leuchs B, Kögl M, Stremmel W, Diaz MB, Herzig S - EMBO Mol Med (2013)

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.

View Article: PubMed Central - PubMed

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.

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TSC22D4 expression correlates with the degree of body wastingCorrelation of TSC22D4 RNA expression and the degree of weight loss due to tumour implantation in Balb/C mice treated with PBS or 1.5 × 106 colon 26 (C26) cells over 3 weeks (means ± SEM, n ≥ 6, Pearson correlation coefficient, F-test to determine significance).Correlation of TSC22D4 RNA expression and VLDL-TG release in the same mice as in A. (Pearson correlation coefficient, F-test to determine significance)Quantitative PCR analysis of Acly, Scd1 and Fasn RNA levels in primary mouse hepatocytes treated with conditioned media from C26 cells for 24 h and control or TSC22D4 shRNA adenovirus for 48 h (means ± SEM, n = 3, Student's t-test for DMEM NC shRNA vs. C26 NC shRNA; C26 NC shRNA vs. C26 TSC22D4 shRNA).Quantitative PCR analysis of Acly, Scd1 and Fasn RNA levels in primary mouse hepatocytes treated with conditioned media from B16 cells for 24 h and control or TSC22D4 shRNA adenovirus for 48 h (means ± SEM, n = 3, Student's t-test for DMEM NC shRNA vs. B16 NC shRNA; B16 NC shRNA vs. B16 TSC22D4 shRNA).
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fig08: TSC22D4 expression correlates with the degree of body wastingCorrelation of TSC22D4 RNA expression and the degree of weight loss due to tumour implantation in Balb/C mice treated with PBS or 1.5 × 106 colon 26 (C26) cells over 3 weeks (means ± SEM, n ≥ 6, Pearson correlation coefficient, F-test to determine significance).Correlation of TSC22D4 RNA expression and VLDL-TG release in the same mice as in A. (Pearson correlation coefficient, F-test to determine significance)Quantitative PCR analysis of Acly, Scd1 and Fasn RNA levels in primary mouse hepatocytes treated with conditioned media from C26 cells for 24 h and control or TSC22D4 shRNA adenovirus for 48 h (means ± SEM, n = 3, Student's t-test for DMEM NC shRNA vs. C26 NC shRNA; C26 NC shRNA vs. C26 TSC22D4 shRNA).Quantitative PCR analysis of Acly, Scd1 and Fasn RNA levels in primary mouse hepatocytes treated with conditioned media from B16 cells for 24 h and control or TSC22D4 shRNA adenovirus for 48 h (means ± SEM, n = 3, Student's t-test for DMEM NC shRNA vs. B16 NC shRNA; B16 NC shRNA vs. B16 TSC22D4 shRNA).

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.


TSC22D4 is a molecular output of hepatic wasting metabolism.

Jones A, Friedrich K, Rohm M, Schäfer M, Algire C, Kulozik P, Seibert O, Müller-Decker K, Sijmonsma T, Strzoda D, Sticht C, Gretz N, Dallinga-Thie GM, Leuchs B, Kögl M, Stremmel W, Diaz MB, Herzig S - EMBO Mol Med (2013)

TSC22D4 expression correlates with the degree of body wastingCorrelation of TSC22D4 RNA expression and the degree of weight loss due to tumour implantation in Balb/C mice treated with PBS or 1.5 × 106 colon 26 (C26) cells over 3 weeks (means ± SEM, n ≥ 6, Pearson correlation coefficient, F-test to determine significance).Correlation of TSC22D4 RNA expression and VLDL-TG release in the same mice as in A. (Pearson correlation coefficient, F-test to determine significance)Quantitative PCR analysis of Acly, Scd1 and Fasn RNA levels in primary mouse hepatocytes treated with conditioned media from C26 cells for 24 h and control or TSC22D4 shRNA adenovirus for 48 h (means ± SEM, n = 3, Student's t-test for DMEM NC shRNA vs. C26 NC shRNA; C26 NC shRNA vs. C26 TSC22D4 shRNA).Quantitative PCR analysis of Acly, Scd1 and Fasn RNA levels in primary mouse hepatocytes treated with conditioned media from B16 cells for 24 h and control or TSC22D4 shRNA adenovirus for 48 h (means ± SEM, n = 3, Student's t-test for DMEM NC shRNA vs. B16 NC shRNA; B16 NC shRNA vs. B16 TSC22D4 shRNA).
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fig08: TSC22D4 expression correlates with the degree of body wastingCorrelation of TSC22D4 RNA expression and the degree of weight loss due to tumour implantation in Balb/C mice treated with PBS or 1.5 × 106 colon 26 (C26) cells over 3 weeks (means ± SEM, n ≥ 6, Pearson correlation coefficient, F-test to determine significance).Correlation of TSC22D4 RNA expression and VLDL-TG release in the same mice as in A. (Pearson correlation coefficient, F-test to determine significance)Quantitative PCR analysis of Acly, Scd1 and Fasn RNA levels in primary mouse hepatocytes treated with conditioned media from C26 cells for 24 h and control or TSC22D4 shRNA adenovirus for 48 h (means ± SEM, n = 3, Student's t-test for DMEM NC shRNA vs. C26 NC shRNA; C26 NC shRNA vs. C26 TSC22D4 shRNA).Quantitative PCR analysis of Acly, Scd1 and Fasn RNA levels in primary mouse hepatocytes treated with conditioned media from B16 cells for 24 h and control or TSC22D4 shRNA adenovirus for 48 h (means ± SEM, n = 3, Student's t-test for DMEM NC shRNA vs. B16 NC shRNA; B16 NC shRNA vs. B16 TSC22D4 shRNA).
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.

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.

View Article: PubMed Central - PubMed

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.

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Related in: MedlinePlus