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: Given the substantial upregulation of TSC22D4 under conditions of energy wasting (Fig 3B and F), we next sought to test the effects of TSC22D4 overexpression (Fig 5A) on systemic lipid handling. To this end, we employed wild-type mice with adenovirus-mediated liver-specific overexpression of TSC22D4 in a fasting-feeding regimen. In line with the results from TSC22D4 loss-of-function experiments (Fig. 4), overexpression of TSC22D4 led to a substantial reduction of VLDL-associated serum TG levels, particularly under fasting conditions (Fig 5B), leaving other metabolic parameters mostly unaltered (Supporting Information Fig S4A–F). To next explore whether TSC22D4 over-activation could potentially even counteract hyper-triglyceridemia as associated with energy surplus, mice were placed on a high-fat diet (60% calories from fat vs. 10% calories from fat) for 12 weeks and then injected with an adenovirus carrying the TSC22D4 cDNA. Consistent with the results from acute TSC22D4 loss- and gain-of-function data, overexpression of TSC22D4 (Supporting Information Fig S4G) was sufficient to substantially reduce serum levels of VLDL-associated TG (Fig 5C) and tended to induce hepatic lipid accumulation (Fig 5D), even in livers of overweight mice, while leaving other metabolic parameters generally unaltered (Supporting Information Fig S4H–L). Together, these data underline the notion that hepatic TSC22D4 fulfils a critical and specific checkpoint function for the regulation of circulating VLDL-TG and hepatic TG load, and that high TSC22D4 levels induce serum TG depletion and hypobetalipoproteinemia under both normal and high caloric intake conditions.
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.