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: Thus, we first aimed at mimicking a TSC22D4-deficient metabolic status by liver-specific genetic manipulation. To this end, we disrupted the activity of TSC22D4 in livers of lean wild-type mice by delivering an adenovirus expressing a TSC22D4-specific or a non-specific control shRNA via tail vein injection. TSC22D4 shRNA treatment significantly reduced hepatic TSC22D4 protein levels as compared with control shRNA-injected littermates (Fig 4A). At day 7 after injection, acute knockdown of TSC22D4 caused no major differences in body-, liver-, total fat- and lean weight (Supporting Information Fig S3A–D), serum and hepatic cholesterol levels (Supporting Information Fig S3F and G), circulating and hepatic NEFA (Supporting Information Fig S3H and I), and serum insulin levels (Supporting Information Fig S3J), compared with controls. In contrast, loss of hepatic TSC22D4 resulted in a significant decrease in liver TG levels, which was evident upon both feeding and fasting conditions (Fig 4B), and a more than 2-fold elevation of total and (VLDL)-associated serum TG levels in the fed state (Fig 4C and D), indicating that TSC22D4 controls hepatic and systemic lipid handling in healthy wild-type animals.
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.