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: As tissue-specific target gene networks of TSC22D4 have not been investigated to date, we next sought to explore the molecular basis for TSC22D4 function in hepatic lipid homeostasis in vivo. In congruence with a stimulatory function of TSC22D4 deficiency for hepatic VLDL release, high throughput gene expression profiling revealed that TSC22D4 knockdown in wild-type mice induced the expression of key genes in the lipogenic pathway, including fatty acid synthase (FAS), ATP citrate lyase (ACLY) and sterol regulatory element binding protein (SREBP)-1c, as well as LIPIN1, a gene involved in hepatic VLDL production (Fig 7A). Bile acid synthesis, lipid transporter, as well as LPL inhibitor gene expression were however left unaltered as compared to controls (Supporting Information Fig S5B and C). Indeed, inactivation of TSC22D4 in primary mouse hepatocytes by shRNA-mediated gene knockdown resulted in a significant induction of genes in the fatty acid biosynthesis and biosynthesis of unsaturated fatty acids KEGG pathways (Fig 7B; Supporting Information Table 1), confirming the regulatory impact of TSC22D4 on lipid-generating gene networks in a cell autonomous manner.
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.