Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice.

TitleEliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice.
Publication TypeJournal Article
Year of Publication2016
AuthorsGariani K, Menzies KJ, Ryu D, Wegner CJ, Wang X, Ropelle ER, Moullan N, Zhang H, Perino A, Lemos V, Kim B, Park Y-K, Piersigilli A, Pham TX, Yang Y, Ku CSiah, Koo SI, Fomitchova A, Cantó C, Schoonjans K, Sauve AA, Lee J-Y, Auwerx J
JournalHepatology
Volume63
Issue4
Pagination1190-204
Date Published2016 Apr
ISSN1527-3350
KeywordsAnalysis of Variance, Animals, Area Under Curve, Biopsy, Needle, Diet, High-Fat, Disease Models, Animal, Fatty Liver, Immunohistochemistry, Lipid Metabolism, Male, Mice, Mice, Inbred C57BL, Mitochondria, NAD, Niacinamide, Pyridinium Compounds, Random Allocation, Sensitivity and Specificity, Treatment Outcome, Unfolded Protein Response
Abstract

UNLABELLED: With no approved pharmacological treatment, nonalcoholic 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 nicotinamide adenine dinucleotide (NAD(+) ) levels driving reductions in hepatic mitochondrial content, function, and adenosine triphosphate (ATP) levels, in conjunction with robust increases in hepatic weight, lipid content, and peroxidation in C57BL/6J mice. To assess the effect of NAD(+) repletion on the development of steatosis in mice, nicotinamide riboside, a precursor of NAD(+) biosynthesis, was added to the HFHS diet, either as a preventive strategy or as a therapeutic intervention. We demonstrate that NR prevents and reverts NAFLD by inducing a sirtuin (SIRT)1- and SIRT3-dependent mitochondrial unfolded protein response, 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 knockout mice (Sirt1(hep-/-) ), whereas apolipoprotein E-deficient mice (Apoe(-/-) ) challenged with a high-fat high-cholesterol diet 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.

DOI10.1002/hep.28245
Alternate JournalHepatology
PubMed ID26404765
PubMed Central IDPMC4805450
Grant ListP30 DK020541 / DK / NIDDK NIH HHS / United States
P30 DK026687 / DK / NIDDK NIH HHS / United States
R01 AG043930 / AG / NIA NIH HHS / United States
R01AG043930 / AG / NIA NIH HHS / United States