The transcriptional regulator of the chaperone response HSF1 controls hepatic bioenergetics and protein homeostasis

Metabolic energy reprogramming facilitates adaptations to a variety of stress conditions and cellular dysfunction, but how the energetic demands are monitored and met in response to physiological stimuli remains elusive. Our data support a model demonstrating that heat shock factor 1 (HSF1), a master transcriptional regulator of the chaperone response, has been coopted from its role as a critical protein quality-control regulator to having a central role in systemic energy sensing and for metabolic adaptation to nutrient availability. We found that in the absence of HSF1, levels of NAD⁺ and ATP are not efficiently sustained in hepatic cells, largely because of transcriptional repression of nicotinamide phosphoribosyltransferase in the NAD⁺ salvage pathway. Mechanistically, the defect in NAD⁺ and ATP synthesis linked to a loss of NAD⁺-dependent deacetylase activity, increased protein acetylation, and impaired mitochondrial integrity. Remarkably, the drop in ATP level caused by HSF1 loss invoked an adaptive response featuring the inhibition of energetically demanding processes, including gluconeogenesis, translation, and lipid synthesis. Our work identifies HSF1 as a central regulator of cellular bioenergetics and protein homeostasis that benefits malignant cell progression and exacerbates development of metabolic diseases.