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Hepatology. 2016 Apr;63(4):1190-204. doi: 10.1002/hep.28245. Epub 2015 Dec 16.

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

Author information

1
Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
2
Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada.
3
Department of Nutritional Sciences, University of Connecticut, Storrs, CT.
4
Laboratory of Molecular Biology of Exercise, School of Applied Science, University of Campinas, Limeira, São Paulo, Brazil.
5
Metabolic Signaling, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
6
School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
7
Institute of Animal Pathology, University of Bern, Bern, Switzerland.
8
Nestlé Institute of Health Sciences, Lausanne, Switzerland.
9
Weill Cornell Medical College, New York, NY.

Abstract

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.

PMID:
26404765
PMCID:
PMC4805450
DOI:
10.1002/hep.28245
[Indexed for MEDLINE]
Free PMC Article
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