Scientific article
Open access

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

Published inHepatology, vol. 63, no. 4, p. 1190-1204
Publication date2016

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.

  • Analysis of Variance
  • Animals
  • Area Under Curve
  • Biopsy
  • Needle
  • Diet
  • High-Fat/methods
  • Disease Models
  • Animal
  • Fatty Liver/drug therapy/metabolism/pathology
  • Immunohistochemistry
  • Lipid Metabolism/drug effects
  • Male
  • Mice
  • Mice
  • Inbred C57BL
  • Mitochondria/drug effects/metabolism
  • NAD/drug effects/metabolism
  • Niacinamide/analogs & derivatives/pharmacology
  • Random Allocation
  • Sensitivity and Specificity
  • Treatment Outcome
  • Unfolded Protein Response/drug effects
  • Swiss National Science Foundation - 31003A‐140780
  • Autre - SySX.ch 2013/153
Citation (ISO format)
GARIANI, Karim et al. Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. In: Hepatology, 2016, vol. 63, n° 4, p. 1190–1204. doi: 10.1002/hep.28245
Main files (1)
Article (Published version)
ISSN of the journal0270-9139

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