Eliciting the mitochondrial unfolded protein response via NAD(+) repletion reverses fatty liver disease

Gariani, Karim; Menzies, Keir J; Ryu, Dongryeol; Wegner, Casey J; Wang, Xu; Ropelle, Eduardo R; Moullan, Norman; Zhang, Hongbo; Perino, Alessia; Lemos, Vera; Kim, Bohkyung; Park, Young-Ki; Piersigilli, Alessandra; Pham, Tho X; Yang, Yue; Siah Ku, Chai; Koo, Sung I; Fomitchova, Anna; Cantó, Carlos; Schoonjans, Kristina; ... (2015). Eliciting the mitochondrial unfolded protein response via NAD(+) repletion reverses fatty liver disease. Hepatology, 63(4), pp. 1190-1204. Wiley Interscience 10.1002/hep.28245

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With no approved pharmacological treatment, non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease in western countries and its worldwide prevalence continues to increase along with the growing obesity epidemic. Here we show that a high-fat high-sucrose (HFHS) diet, eliciting chronic hepatosteatosis resembling human fatty liver, lowers hepatic NAD(+) levels driving reductions in hepatic mitochondrial content, function and ATP levels, in conjunction with robust increases in hepatic weight, lipid content and peroxidation in C57BL/6J mice. In an effort to assess the effect of NAD(+) repletion on the development of steatosis in mice, nicotinamide riboside (NR), a precursor for NAD(+) biosynthesis, was given to mice concomitant, as preventive strategy (NR-Prev), and as a therapeutic intervention (NR-Ther), to a HFHS diet. We demonstrate that NR prevents and reverts NAFLD by inducing a SIRT1- and SIRT3-dependent mitochondrial unfolded protein response (UPR(mt) ), triggering an adaptive mitohormetic pathway to increase hepatic β-oxidation and mitochondrial complex content and activity. The cell-autonomous beneficial component of NR treatment was revealed in liver-specific Sirt1 KO mice (Sirt1(hep-/-) ), while Apolipoprotein E-deficient (Apoe(-/-) ) mice challenged with a high-fat high-cholesterol diet (HFC), affirmed the use of NR in other independent models of NAFLD. CONCLUSION Our data warrant the future evaluation of NAD(+) boosting strategies to manage the development or progression of NAFLD. This article is protected by copyright. All rights reserved.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Piersigilli, Alessandra

Subjects:

600 Technology > 630 Agriculture

ISSN:

0270-9139

Publisher:

Wiley Interscience

Language:

English

Submitter:

Barbara Gautschi-Steffen

Date Deposited:

18 Feb 2016 10:26

Last Modified:

26 Jun 2016 02:11

Publisher DOI:

10.1002/hep.28245

PubMed ID:

26404765

Uncontrolled Keywords:

mitonuclear protein imbalance nicotinamide riboside (NR), non-alcoholic fatty liver disease (NAFLD), poly(ADP-ribose) polymerases (PARPs) sirtuins

BORIS DOI:

10.7892/boris.75642

URI:

https://boris.unibe.ch/id/eprint/75642

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