NUPR1 protects liver from lipotoxic injury by improving the endoplasmic reticulum stress response
Authors: Borrello Maria Teresa , Emma Maria Rita , Listi Angela , Rubis Marion , Coslet Sergiu , Augello Giuseppa , Cusimano Antonella , Cabibi Daniela , Porcasi Rossana , Giannitrapani Lydia , Soresi Maurizio , Pantuso Gianni , Blyth Karen , Montalto Giuseppe , Pin Christopher , Cervello Melchiorre , Iovanna Juan 
Published: October 2020

Background and Aims

Non-alcoholic fatty liver disease and related hepatic syndromes affect up to one third of the adult population. The molecular mechanisms underlying NAFL etiology remain elusive. Nuclear Protein 1 (NUPR1) expression increases upon cell injury in all organs and recently we report its active participation in the activation of the Unfolded Protein Response (UPR). The UPR typically maintains protein homeostasis, but downstream mediators of the pathway regulate metabolic functions, including lipid metabolism. NUPR1 and UPR increase have been reported in obesity and liver pathologies and the goal of this study was to investigate the roles of NUPR1 in this context.

Methods

We used patient-derived liver biopsies andin vitroandin vivoNUPR1 loss of functions models. First, we analysed NUPR1 expression in a cohort of morbidly obese patients (MOPs), with either simple fatty liver (NAFL) or more severe steatohepatitis (NASH). Next, we explored the metabolic roles of NUPR1 in wild type (Nupr1+/+) orNupr1knockout mice (Nupr1-/-) fedad libitumwith a high fat diet (HFD) for up to 15 weeks.

Results

NUPR1 expression is inversely correlated to hepatic steatosis progression. We found that NUPR1 participates in the activation of PPAR-α signalling via UPR. PPAR-α signalling, is involved in the maintenance of fat metabolism and proper lipid homeostasis and energy balance. As PPAR-α signalling is controlled by UPR, collectively, these findings suggest a novel function for NUPR1 in protecting liver from metabolic distress by controlling lipid homeostasis, possibly through the UPR.

Objective

Non-alcoholic fatty liver (NAFL) disease and related hepatic syndromes affect up to one third of the adult population in industrialised and developing countries. However, the molecular mechanisms underlying NAFL etiology remain elusive. Nuclear Protein 1 (NUPR1) expression increases upon cell injury in all organs including the liver. Recently, we report NUPR1 actively participates in activation of the Unfolded Protein Response (UPR). The UPR typically maintains protein homeostasis, but downstream mediators of the pathway regulate metabolic functions, including lipid metabolism. NUPR1 and UPR increase have been reported in obesity and liver pathologies and the goal of this study was to investigate the roles of NUPR1 in this context.

Design

We used patient-derived liver biopsies andin vitroandin vivoNUPR1 loss of functions models. First, we analysed NUPR1 expression in a cohort of morbidly obese patients (MOPs), with either simple fatty liver (NAFL) or more severe steatohepatitis (NASH). Next, we explored the metabolic roles of NUPR1 in wild type (Nupr1+/+) orNupr1knockout mice (Nupr1-/-) fedad libitumwith a high fat diet (HFD) for up to 15 weeks.

Results

NUPR1 expression is inversely correlated to hepatic steatosis progression. Mechanistically, we found NUPR1 participates in the activation of PPAR-α signalling via UPR. PPAR-α signalling, is involved in the maintenance of fat metabolism and proper lipid homeostasis and energy balance. As PPAR-α signalling is controlled by UPR, collectively, these findings suggest a novel function for NUPR1 in protecting liver from metabolic distress by controlling lipid homeostasis, possibly through the UPR.

Conclusions

As PPAR-α signalling is controlled by UPR, collectively, these findings suggest a novel function for NUPR1 in protecting liver from metabolic distress by controlling lipid homeostasis, possibly through the UPR.

Lay summary

NUPR1 is activated during high caloric intake in both mice and patients. Decrease in expression or inhibition of NUPR1 worsens lipid deposition and hepatic damage.

Graphical abstract

Highlights

NUPR1 protects liver from high caloric intake hepatic damage

The function of NUPR1 in this context is to control the lipid homeostasis through the UPR and more specifically through PPAR-α signalling.

NUPR1 could be used as a predictive marker for the gravity of NAFL progression. Moreover, as clinical interest is being raised around NUPR1 inhibitors to treat liver and pancreatic cancer, care should be taken in monitoring lipotoxic parameters.