Non-alcoholic fatty liver (NAFL) and related syndromes affect one-third of the adultpopulation in industrialized and developing countries. Lifestyle and caloric oversupplyare the main causes of such array of disorders, but the molecular mechanismsunderlying their etiology remain elusive. Nuclear Protein 1 (NUPR1) expression increasesupon cell injury in all organs including liver. Recently, we reported NUPR1actively participates in the activation of the Unfolded Protein Response (UPR). TheUPR typically maintains protein homeostasis, but downstream mediators of the pathwayregulate metabolic functions including lipid metabolism. As increases in UPRand NUPR1 in obesity and liver disease have been well documented, the goal of thisstudy was to investigate the roles of NUPR1 in this context. To establish whetherNUPR1 is involved in these liver conditions we used patient-derived liver biopsiesand in vitro and in vivo NUPR1 loss of functions models. First, we analyzed NUPR1expression in a cohort of morbidly obese patients (MOPs), with simple fatty liver(NAFL) or more severe steatohepatitis (NASH). Next, we explored the metabolicroles of NUPR1 in wild-type (Nupr1+/+) or Nupr1 knockout mice (Nupr1−/−) fedwith a high-fat diet (HFD) for 15 weeks. Immunohistochemical and mRNA analysisrevealed NUPR1 expression is inversely correlated to hepatic steatosis progression.Mechanistically, we found NUPR1 participates in the activation of PPAR-α signalingvia UPR. As PPAR-α signaling is controlled by UPR, collectively, these findingssuggest a novel function for NUPR1 in protecting liver from metabolic distress bycontrolling lipid homeostasis, possibly through the UPR.
|Numero di pagine||19|
|Rivista||THE FASEB JOURNAL|
|Stato di pubblicazione||Published - 2021|