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Direct link between metabolic regulation and the heat-shock response through the transcriptional regulator PGC-1α

Significance In recent years an extensive effort has been made to elucidate the molecular pathways involved in metabolic signaling. Our study shows, surprisingly, a direct link between metabolic regulation and the heat-shock response, a highly conserved transcriptional program that is activated in the presence of various environmental stresses. Specifically, we demonstrate that peroxisome proliferator-activated receptor γ coactivator 1α, a critical and well-established inducible transcriptional coactivator of metabolic genes, acts as a direct transcriptional repressor of heat-shock factor 1, a key regulator of the heat-shock/stress response and a factor more recently demonstrated to be necessary for cancer initiation and survival. Thus, our findings have possible implications both for our understanding of the full scope of metabolically regulated target genes in vivo and, conceivably, for therapeutics. In recent years an extensive effort has been made to elucidate the molecular pathways involved in metabolic signaling in health and disease. Here we show, surprisingly, that metabolic regulation and the heat-shock/stress response are directly linked. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a critical transcriptional coactivator of metabolic genes, acts as a direct transcriptional repressor of heat-shock factor 1 (HSF1), a key regulator of the heat-shock/stress response. Our findings reveal that heat-shock protein (HSP) gene expression is suppressed during fasting in mouse liver and in primary hepatocytes dependent on PGC-1α. HSF1 and PGC-1α associate physically and are colocalized on several HSP promoters. These observations are extended to several cancer cell lines in which PGC-1α is shown to repress the ability of HSF1 to activate gene-expression programs necessary for cancer survival. Our study reveals a surprising direct link between two major cellular transcriptional networks, highlighting a previously unrecognized facet of the activity of the central metabolic regulator PGC-1α beyond its well-established ability to boost metabolic genes via its interactions with nuclear hormone receptors and nuclear respiratory factors. Our data point to PGC-1α as a critical repressor of HSF1-mediated transcriptional programs, a finding with possible implications both for our understanding of the full scope of metabolically regulated target genes in vivo and, conceivably, for therapeutics.