Abstract
We have explored the role of Tm7sf2 gene, which codifies for 3β-hydroxysterol Δ14-reductase, an endoplasmic reticulum resident protein, in the sensitivity to endoplasmic reticulum stress and in the resulting inflammatory response. We used mouse embryonic fibroblasts, derived from Tm7sf2+/+ and Tm7sf2−/− mice, to determine the in vitro effects of thapsigargin on NF-κB activation. Our results show that the Tm7sf2 gene controls the launch of the unfolded protein response and presides an anti-inflammatory loop thus its absence correlates with NF-κB activation and TNFα up-regulation. Our data also show that Tm7sf2 gene regulates liver X receptor activation and its absence inhibits LXR signalling. By expressing the hTm7sf2 gene in KO MEFs and observing a reduced NF-κB activation, we have confirmed that Tm7sf2 gene is linked to NF-κB activation. Finally we used genetically modified mice in an in vivo model of ER stress and of inflammation. Our results show a significant increase in renal TNFα expression after tunicamycin exposure and in the oedematogenic response in Tm7sf2−/− mice. In conclusion, we have shown that the Tm7sf2 gene, to date involved only in cholesterol biosynthesis, also controls an anti-inflammatory loop thereby confirming the existence of cross talk between metabolic pathways and inflammatory response.
Highlights
Cholesterol is an extremely important biological molecule because of its dual character: a friend as an essential component of cell membranes and a precursor for the synthesis of steroid hormones, bile acids and vitamin D; a foe as a predisposing factor for various diseases [1]
We propose that the C14SR, encoded by Tm7sf2, besides actively participating in cholesterol biosynthesis, is linked to the cellular response to endoplasmic reticulum (ER) stressors
Since cholesterol biosynthesis is tightly regulated by cholesterol levels, we first verified the induction of Tm7sf2 under sterol starving conditions
Summary
Cholesterol is an extremely important biological molecule because of its dual character: a friend as an essential component of cell membranes and a precursor for the synthesis of steroid hormones, bile acids and vitamin D; a foe as a predisposing factor for various diseases [1]. UPR, an important signalling pathway evolved in the ER to cope with stress, includes an increase in the folding capacity of the ER through the induction of ER resident molecular chaperones and protein foldases, a decrease in the folding demand on the ER by up-regulation of ER associated degradation (ERAD), an attenuation of general translation, and a stimulation of ER synthesis to dilute the unfolded protein load. PERK promotes the translation of certain mRNAs, such as the activating transcription factor 4 (ATF4) mRNA [5,7,14], whose downstream target genes are involved in amino acid metabolism, glutathione biosynthesis, resistance to oxidative stress and protein secretion. We investigated whether the Tm7sf gene, involved in cholesterol biosynthesis, is involved in controlling a common adaptive mechanism for cellular responses against inflammation and ER stress
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