ATF6 modulates SREBP2-mediated lipogenesis

Activating transcription factor 6 (ATF6) and sterol regulatory element‐binding proteins (SREBPs) are activated by proteolytic cleavage. The ensuing nuclear translocation of their N‐termini (i.e., ATF6(N) and SREBP(N)) activates the respective target genes involved in unfolded protein response and lipogenesis. Here, we report that glucose deprivation activated ATF6 but suppressed the SREBP2‐regulated transcription. Overexpression of ATF6(N) had similar inhibitory effects on SREBP2‐targeted genes. The blockade of ATF6 cleavage by BiP/grp78 reversed this inhibitory effect. GST pull‐down and immunoprecipitation assays revealed that ATF6(N) bound to SREBP2(N). Deletion analysis of the various functional domains of ATF6 indicated that the interaction was through its leucine‐zipper domain. Chromatin immunoprecipitation assays revealed that ATF6(N) formed a complex with the SRE‐bound SREBP2(N). The attenuated transcriptional activity of SREBP2 was due, in part, to the recruitment of HDAC1 to the ATF6–SREBP2 complex. As a functional consequence, the lipogenic effect of SREBP2(N) in liver cells was suppressed by ATF6(N). Our results provide a novel mechanism by which ATF6 antagonizes SREBP2 to regulate the homeostasis of lipid and glucose.