MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability

Abstract

Fat is stored or mobilized according to food availability. Malfunction of the mechanisms that ensure this coordination underlie metabolic diseases in humans. In mammals, lysosomal and autophagic function is required for normal fat storage and mobilization in the presence or absence of food. Autophagy is tightly linked to nutrients. However, if and how lysosomal lipolysis is coupled to nutritional status remains to be determined. Here we identify MXL-3 and HLH-30 as transcriptional switches coupling lysosomal lipolysis and autophagy to nutrient availability and controlling fat storage and ageing in Caenorhabditis elegans. Transcriptional coupling of lysosomal lipolysis and autophagy to nutrients is also observed in mammals. Thus, MXL-3 and HLH-30 orchestrate an adaptive and conserved cellular response to nutritional status and regulate lifespan.

NHR‐49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

“…hif‐1 RNAi did not prevent tBOOH‐induced expression of fmo‐2p::gfp (data not shown). However, reminiscent of its activation following fasting (O'Rourke & Ruvkun, 2013), we observed a transient increase in nuclear levels of a HLH‐30::GFP fusion protein in response to tBOOH (Figure S3a). Thus, we examined whether hlh‐30 and nhr‐49 might function in the same stress response pathway.…”

“…The intestinal induction of fmo‐ 2 by fasting or hypoxia requires the transcription factors hlh‐30/TFEB and hif‐1/HIF (Leiser et al., 2015), master regulators of C. elegans autophagy, and hypoxia gene programs, respectively (Lapierre et al., 2013; O'Rourke & Ruvkun, 2013; Powell‐Coffman, 2010). Moreover, hlh‐30 is required for the long lifespan of glp‐1 ( e2141 ) mutants (Nakamura et al., 2016).…”

Autophagy at the crossroads of catabolism and anabolism

“…The importance of acidic lipases in lipophagy is further supported by recent studies in Caenorhabditis elegans, in which the transcriptional upregulation of the lysosomal lipases LIPL-1 and LIPL-3 was observed in response to starvation. Two transcription factors, MXL-3 and HLH-30, compete for binding to the promoter region of lipl-1 and lipl-3 genes; during nutrient starvation, HLH-30 overrides the transcriptional repressor MXL-3 to promote lipase expression 71 . Importantly, HLH-30 is the worm orthologue of the mammalian nutrient-sensitive transcription factor EB (TFEB), which simultaneously induces both autophagy and lysosomal genes during starvation 72 .…”

The role of protein clearance mechanisms in organismal ageing and age-related diseases

“…TFEB/HLH-30 induces many autophagy and lysosomal-related genes 150 . However, the longevity phenotype induced by TFEB/HLH-30 is caused by increased lysosomal lipolysis and might be independent of proteostasis 149,151 .…”