NUPR1 protects liver from lipotoxic injury by improving the endoplasmic reticulum stress response

Autor: Maria Rita Emma, Antonella Cusimano, Karen Blyth, Maurizio Soresi, Melchiorre Cervello, Angela Listi, Daniela Cabibi, Christopher L. Pin, Sergiu Coslet, Rossana Porcasi, Gianni Pantuso, Marion Rubis, Giuseppa Augello, Juan L. Iovanna, Maria Teresa Borrello, Lydia Giannitrapani, Giuseppe Montalto
Přispěvatelé: Borrello MT, Emma MR, Listi A, Rubis M, Coslet S, Augello G, Cusimano A, Cabibi D, Porcasi R, Giannitrapani L, Soresi M, Pantuso G, Blyth K, Montalto G, Pin C, Cervello M, Iovanna J
Rok vydání: 2021
Předmět:
0301 basic medicine
medicine.medical_specialty
Settore MED/09 - Medicina Interna
PPAR-a signalling
UPR
Peroxisome proliferator-activated receptor
Context (language use)
UPR
Diet
High-Fat
Biochemistry
03 medical and health sciences
Liver disease
Mice
0302 clinical medicine
Internal medicine
Cell Line
Tumor
Genetics
medicine
Basic Helix-Loop-Helix Transcription Factors
Animals
Homeostasis
Humans
Molecular Biology
chemistry.chemical_classification
business.industry
Endoplasmic reticulum
Fatty liver
NASH
Lipid metabolism
lipotoxicity
medicine.disease
Endoplasmic Reticulum Stress
Lipid Metabolism
Neoplasm Proteins
030104 developmental biology
Endocrinology
chemistry
Lipotoxicity
Liver
NAFL
Knockout mouse
Unfolded protein response
Unfolded Protein Response
PPAR-a signalling
Steatosis
Steatohepatitis
business
030217 neurology & neurosurgery
NUPR1
Biotechnology
Zdroj: Paediatrics Publications
The FASEB journal (Online) 35 (2021): e21395. doi:10.1096/fj.202002413RR
info:cnr-pdr/source/autori:Teresa Borrello M; Rita Emma M; Listi A; Rubis M; Coslet S; Augello G; Cusimano A; Cabibi D; Porcasi R; Giannitrapani L; Soresi M; Pantuso G; Blyth K; Montalto G; Pin C; Cervello M; Iovanna J;/titolo:NUPR1 protects liver from lipotoxic injury by improving the endoplasmic reticulum stress response/doi:10.1096%2Ffj.202002413RR/rivista:The FASEB journal (Online)/anno:2021/pagina_da:e21395/pagina_a:/intervallo_pagine:e21395/volume:35
DOI: 10.1096/fj.202002413RR
Popis: Background and AimsNon-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.MethodsWe used patient-derived liver biopsies and in vitro and in vivo NUPR1 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+/+) or Nupr1 knockout mice (Nupr1-/-) fed ad libitum with a high fat diet (HFD) for up to 15 weeks.ResultsNUPR1 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.ObjectiveNon-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.DesignWe used patient-derived liver biopsies and in vitro and in vivo NUPR1 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+/+) or Nupr1 knockout mice (Nupr1-/-) fed ad libitum with a high fat diet (HFD) for up to 15 weeks.ResultsNUPR1 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.ConclusionsAs 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 summaryNUPR1 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 abstractHighlightsNUPR1 protects liver from high caloric intake hepatic damageThe 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.
Databáze: OpenAIRE
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