26 Remarkably,

26 Remarkably, EPZ-6438 nmr when HCC patients were classified

into low- and high-survival groups on the basis of global gene expression profiling of their liver samples,27 high Gal-1 expression was associated with low survival. Thus, in inflammation-mediated hepatocarcinogenesis, Gal-1 may act as a protective anti-inflammatory agent during early stages of chronic liver pathology but as a protumorigenic agent during the late stages of the disease. On the basis of our finding that endogenous Gal-1 protects the liver against ConA-induced hepatitis in the B6 strain but not in the FVB strain (Fig. 7), we hypothesize that the increased inflammation (and aberrant regulation of multiple immune/inflammatory genes) in the Mdr2-KO/FVB strain can be explained in part by the impaired anti-inflammatory activity of Gal-1. This hypothesis is supported by the up-regulation of other anti-inflammatory genes (e.g., Slpi) specifically in the Mdr2-KO/FVB strain (Supporting Table 2), more robust Gal-1 induction in the Mdr2-KO/B6 liver versus the Mdr2-KO/FVB liver at the age of 1 month (Fig. 6C,D), and the induction of proinflammatory Epigenetics inhibitor Tnfa, Il2, and Cxcl2 as well as anti-inflammatory Slpi after ConA challenge in Gal-1–KO/B6 mice (Fig. 7E,F). Several genes that were differentially expressed only in the Mdr2-KO/B6 strain are involved in the regulation of NF-κB signaling: trefoil factor 3 (Tff3)

and TRAF-interacting protein with forkhead-associated domain (Tifa), which were up-regulated, and hexamethylene bisacetamide inducible 1 (Hexim1), which was down-regulated (Supporting Table 2). Tff3 may transiently activate NF-κB,28 and Tifa also activates NF-κB,29 whereas Hexim1 inhibits NF-κB–mediated transcription.30 These examples indicate differential regulation of the NF-κB signaling pathway between the two Mdr2-KO

strains. Among genes up-regulated in the Mdr2-KO/FVB mice but down-regulated in the Mdr2-KO/B6 mice (Supporting Table 2), Angptl4, Lpin1, and Lpin2 encode regulators of lipid metabolism, and Por encodes cytochrome P450 reductase. In line with reduced chronic inflammation in Mdr2-KO/B6 mice, many genes involved in response to oxidative stress were up-regulated in the Mdr2-KO/FVB Oxalosuccinic acid strain but not in the Mdr2-KO/B6 strain. This effect of the Mdr2-KO/B6 liver could be caused in part by down-regulation of the Por and Lipin-1 proteins. Por may be a source of endogenous oxidative DNA damage and genetic instability,31 and Lipin-1 promotes fatty acid oxidation.12 Importantly, the gene Aif1, encoding Aif1, was up-regulated in the Mdr2-KO/FVB liver4 but not in the Mdr2-KO/B6 liver (Fig. 4C). Aif1 is a crucial mediator in the inflammatory response, which may enhance NF-κB transcriptional activity and facilitate tumor growth,32 and thus serves as a central node in coexpression networks connecting obesity-associated genes in the liver and other tissues.

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