[Show abstract][Hide abstract] ABSTRACT: The aberrant accumulation of lipids in the liver ("fatty liver") is tightly associated with several components of the metabolic syndrome, including type 2 diabetes, coronary heart disease, and atherosclerosis. Here we show that the impaired hepatic expression of transcriptional cofactor transducin beta-like (TBL) 1 represents a common feature of mono- and multigenic fatty liver mouse models. Indeed, the liver-specific ablation of TBL1 gene expression in healthy mice promoted hypertriglyceridemia and hepatic steatosis under both normal and high-fat dietary conditions. TBL1 deficiency resulted in inhibition of fatty acid oxidation due to impaired functional cooperation with its heterodimerization partner TBL-related (TBLR) 1 and the nuclear receptor peroxisome proliferator-activated receptor (PPAR) α. As TBL1 expression levels were found to also inversely correlate with liver fat content in human patients, the lack of hepatic TBL1/TBLR1 cofactor activity may represent a molecular rationale for hepatic steatosis in subjects with obesity and the metabolic syndrome.
[Show abstract][Hide abstract] ABSTRACT: 1 Purpose This RFC proposes a standard for the quantitative characterization of miRNA binding sites (miRNA-BS) in mammalian cells. The miMeasure standard introduces a ready-to-use standard measurement plasmid (pSMB_miMeasure, BBa_K337049) enabling rapid experimental characterization of any miRNA-BS of choice. We recommend a new standard unit, RKDU (relative knock-down unit) to describe the knock-down efficiency of a miRNA-BS in a specific cell type. pSMB_miMeasure allows for an easy and fast measurement of RKDU while providing effective normalization against variance stemming from differences in transfection efficiency and from other sources. 2 Relation to other RFCs This RFC represents an extension of the idea of ensuring measurement comparability via in vivo reference standards introduced in RFC 19 by JR Kelly and D Endy. The unit RKDU is closely related to the REU standard unit proposed for the characterization of promoters in mammalian cells (RFC 41).
[Show abstract][Hide abstract] ABSTRACT: The purpose of this RFC is to introduce a modular expression tuning kit for use in mammalian cells. The kit enables the regulation of the gene expression of any gene of interest (GOI) based on synthetic microRNAs, endogenous microRNAs or a combination of both. 2 Relation to other RFCs All parts provided in the miTuner Kit are constructed in BB-2 standard (RFC 12, RFC 45). Some parts (microRNA binding site patterns) were constructed by the RA-PCR method described in RFC 42. RFC 73 provides complementary measurement instructions for the applications described in this RFC. 3 Copyright Notice Copyright (C) The BioBricks Foundation (2010).
[Show abstract][Hide abstract] ABSTRACT: Based on its role as an energy storage compartment and endocrine organ, white adipose tissue (WAT) fulfills a critical function in the maintenance of whole-body energy homeostasis. Indeed, WAT dysfunction is connected to obesity-related type 2 diabetes triggered at least partly by an inflammatory response in adipocytes. The pseudokinase tribbles (TRB) 3 has been identified by us and others as a critical regulator of hepatic glucose homeostasis in type 2 diabetes and WAT lipid homeostasis. Therefore, this study aimed to test the hypothesis that the TRB gene family fulfills broader functions in the integration of metabolic and inflammatory pathways in various tissues.
To determine the role of TRB family members for WAT function, we profiled the expression patterns of TRB13 under healthy and metabolic stress conditions. The differentially expressed TRB1 was functionally characterized in loss-of-function animal and primary adipocyte models.
Here, we show that the expression of TRB1 was specifically upregulated during acute and chronic inflammation in WAT of mice. Deficiency of TRB1 was found to impair cytokine gene expression in white adipocytes and to protect against high-fat diet-induced obesity. In adipocytes, TRB1 served as a nuclear transcriptional coactivator for the nuclear factor kappaB subunit RelA, thereby promoting the induction of proinflammatory cytokines in these cells.
As inflammation is typically seen in sepsis, insulin resistance, and obesity-related type 2 diabetes, the dual role of TRB1 as both a target and a (co) activator of inflammatory signaling might provide a molecular rationale for the amplification of proinflammatory responses in WAT in these subjects.