title: Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice.
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.
  
  
  CONCLUSIONS
  Our data warrant the future evaluation of NAD(+) boosting strategies to manage the development or progression of NAFLD.
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Karim
authors.initials: K
authors.lastname: Gariani
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Keir J
authors.initials: KJ
authors.lastname: Menzies
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Dongryeol
authors.initials: D
authors.lastname: Ryu
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, CT.
authors.forename: Casey J
authors.initials: CJ
authors.lastname: Wegner
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Biology of Exercise, School of Applied Science, University of Campinas, Limeira, São Paulo, Brazil.
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Ropelle
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Norman
authors.initials: N
authors.lastname: Moullan
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Metabolic Signaling, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Alessia
authors.initials: A
authors.lastname: Perino
authors.affiliation: School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Vera
authors.initials: V
authors.lastname: Lemos
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, CT.
authors.forename: Bohkyung
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, CT.
authors.forename: Young-Ki
authors.initials: YK
authors.lastname: Park
authors.affiliation: School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Institute of Animal Pathology, University of Bern, Bern, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Piersigilli
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, CT.
authors.forename: Tho X
authors.initials: TX
authors.lastname: Pham
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, CT.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, CT.
authors.forename: Chai Siah
authors.initials: CS
authors.lastname: Ku
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, CT.
authors.forename: Sung I
authors.initials: SI
authors.lastname: Koo
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, CT.
authors.forename: Anna
authors.initials: A
authors.lastname: Fomitchova
authors.affiliation: Nestlé Institute of Health Sciences, Lausanne, Switzerland.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cantó
authors.affiliation: School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.affiliation: Weill Cornell Medical College, New York, NY.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Sauve
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, CT.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D001707:Biopsy, Needle; D059305:Diet, High-Fat / Q000379:methods; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000187:drug effects / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D011726:Pyridinium Compounds; D011897:Random Allocation; D012680:Sensitivity and Specificity; D016896:Treatment Outcome; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: D011726:Pyridinium Compounds; C018613:nicotinamide-beta-riboside; D009243:NAD; D009536:Niacinamide