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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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VLDL secretion is increased in TSC22D4 deficient miceHepatic VLDL release in control or TSC22D4 shRNA-injected wild-type C57Bl/6 mice. Time after tyloxapol injection indicated (means ± SEM, n = 6). Statistical test: Two Way Repeated Measures ANOVA, Holm–Sidak post hoc.Apolipoprotein B protein expression is elevated in the livers of representative TSC22D4 shRNA adenovirus-injected C57Bl/6 mice. Western blots were performed 7 days after injection using ApoB and VCP antibodies.Hepatic VLDL release in empty control or TSC22D4 cDNA-injected wild-type C57Bl/6 mice fed a high fat diet (HFD) for 11 weeks. Time after tyloxapol injection indicated (means ± SEM, n = 4). Statistical test: Two Way Repeated Measures ANOVA, Holm–Sidak post hoc.White adipose tissue (WAT) lipoprotein lipase (LPL) activity in the same mice as in A. (student's t-test)Clearance of human ApoB from serum of control or TSC22D4 shRNA adenovirus–injected C57Bl/6 mice 7 days after virus injection. 20 µg of human VLDL were injected into each animal and serum samples were taken at the indicated time points. Human ApoB levels were determined by human-specific ELISA (means ± SEM, n = 6). Statistical test: Two Way Repeated Measures ANOVA, Holm–Sidak post hoc.
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fig06: VLDL secretion is increased in TSC22D4 deficient miceHepatic VLDL release in control or TSC22D4 shRNA-injected wild-type C57Bl/6 mice. Time after tyloxapol injection indicated (means ± SEM, n = 6). Statistical test: Two Way Repeated Measures ANOVA, Holm–Sidak post hoc.Apolipoprotein B protein expression is elevated in the livers of representative TSC22D4 shRNA adenovirus-injected C57Bl/6 mice. Western blots were performed 7 days after injection using ApoB and VCP antibodies.Hepatic VLDL release in empty control or TSC22D4 cDNA-injected wild-type C57Bl/6 mice fed a high fat diet (HFD) for 11 weeks. Time after tyloxapol injection indicated (means ± SEM, n = 4). Statistical test: Two Way Repeated Measures ANOVA, Holm–Sidak post hoc.White adipose tissue (WAT) lipoprotein lipase (LPL) activity in the same mice as in A. (student's t-test)Clearance of human ApoB from serum of control or TSC22D4 shRNA adenovirus–injected C57Bl/6 mice 7 days after virus injection. 20 µg of human VLDL were injected into each animal and serum samples were taken at the indicated time points. Human ApoB levels were determined by human-specific ELISA (means ± SEM, n = 6). Statistical test: Two Way Repeated Measures ANOVA, Holm–Sidak post hoc.

Mentions: To determine the mechanistic basis for TSC22D4 function in hepatic lipid handling, we measured hepatic VLDL production by experimental inhibition of peripheral VLDL clearance. Consistent with higher serum TG levels, mice deficient in hepatic TSC22D4 showed an increase in hepatic VLDL release as compared with controls (Fig 6A), correlating with enhanced levels of intra-hepatic ApoB as demonstrated by Western blot experiments (Fig 6B). In contrast, liver-specific overexpression of TSC22D4 significantly impaired hepatic VLDL release under high fat diet conditions (Fig 6C), overall suggesting that hepatic TSC22D4 controls systemic TG levels primarily through the control of liver lipid release. Indeed, adipose tissue LPL activity was not changed and VLDL transporter/receptor gene expression remained unaffected upon hepatic TSC22D4 deficiency (Fig 6D, Supporting Information Fig S5A). Hepatic VLDL uptake was actually slightly improved, perhaps as a compensatory response (Fig 6E).


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)

VLDL secretion is increased in TSC22D4 deficient miceHepatic VLDL release in control or TSC22D4 shRNA-injected wild-type C57Bl/6 mice. Time after tyloxapol injection indicated (means ± SEM, n = 6). Statistical test: Two Way Repeated Measures ANOVA, Holm–Sidak post hoc.Apolipoprotein B protein expression is elevated in the livers of representative TSC22D4 shRNA adenovirus-injected C57Bl/6 mice. Western blots were performed 7 days after injection using ApoB and VCP antibodies.Hepatic VLDL release in empty control or TSC22D4 cDNA-injected wild-type C57Bl/6 mice fed a high fat diet (HFD) for 11 weeks. Time after tyloxapol injection indicated (means ± SEM, n = 4). Statistical test: Two Way Repeated Measures ANOVA, Holm–Sidak post hoc.White adipose tissue (WAT) lipoprotein lipase (LPL) activity in the same mice as in A. (student's t-test)Clearance of human ApoB from serum of control or TSC22D4 shRNA adenovirus–injected C57Bl/6 mice 7 days after virus injection. 20 µg of human VLDL were injected into each animal and serum samples were taken at the indicated time points. Human ApoB levels were determined by human-specific ELISA (means ± SEM, n = 6). Statistical test: Two Way Repeated Measures ANOVA, Holm–Sidak post hoc.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3569644&req=5

fig06: VLDL secretion is increased in TSC22D4 deficient miceHepatic VLDL release in control or TSC22D4 shRNA-injected wild-type C57Bl/6 mice. Time after tyloxapol injection indicated (means ± SEM, n = 6). Statistical test: Two Way Repeated Measures ANOVA, Holm–Sidak post hoc.Apolipoprotein B protein expression is elevated in the livers of representative TSC22D4 shRNA adenovirus-injected C57Bl/6 mice. Western blots were performed 7 days after injection using ApoB and VCP antibodies.Hepatic VLDL release in empty control or TSC22D4 cDNA-injected wild-type C57Bl/6 mice fed a high fat diet (HFD) for 11 weeks. Time after tyloxapol injection indicated (means ± SEM, n = 4). Statistical test: Two Way Repeated Measures ANOVA, Holm–Sidak post hoc.White adipose tissue (WAT) lipoprotein lipase (LPL) activity in the same mice as in A. (student's t-test)Clearance of human ApoB from serum of control or TSC22D4 shRNA adenovirus–injected C57Bl/6 mice 7 days after virus injection. 20 µg of human VLDL were injected into each animal and serum samples were taken at the indicated time points. Human ApoB levels were determined by human-specific ELISA (means ± SEM, n = 6). Statistical test: Two Way Repeated Measures ANOVA, Holm–Sidak post hoc.
Mentions: To determine the mechanistic basis for TSC22D4 function in hepatic lipid handling, we measured hepatic VLDL production by experimental inhibition of peripheral VLDL clearance. Consistent with higher serum TG levels, mice deficient in hepatic TSC22D4 showed an increase in hepatic VLDL release as compared with controls (Fig 6A), correlating with enhanced levels of intra-hepatic ApoB as demonstrated by Western blot experiments (Fig 6B). In contrast, liver-specific overexpression of TSC22D4 significantly impaired hepatic VLDL release under high fat diet conditions (Fig 6C), overall suggesting that hepatic TSC22D4 controls systemic TG levels primarily through the control of liver lipid release. Indeed, adipose tissue LPL activity was not changed and VLDL transporter/receptor gene expression remained unaffected upon hepatic TSC22D4 deficiency (Fig 6D, Supporting Information Fig S5A). Hepatic VLDL uptake was actually slightly improved, perhaps as a compensatory response (Fig 6E).

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.

Show MeSH
Related in: MedlinePlus