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

Autor: Johan Auwerx, Hongbo Zhang, Anthony A. Sauve, Xu Wang, Casey J. Wegner, Sung I. Koo, Karim Gariani, Young-Ki Park, Dongryeol Ryu, Carlos Cantó, Alessandra Piersigilli, Alessia Perino, Chai Siah Ku, Vera Lemos, Norman Moullan, Yue Yang, Keir J. Menzies, Kristina Schoonjans, Tho X. Pham, Bohkyung Kim, Ji-Young Lee, Eduardo R. Ropelle, Anna Fomitchova
Rok vydání: 2015
Předmět:
Male
0301 basic medicine
NAD/drug effects/metabolism
Biopsy
Mitochondria/drug effects/metabolism
Pyridinium Compounds
Mitochondrion
Nicotinamide adenine dinucleotide
Inbred C57BL
Lipid Metabolism/drug effects
Mice
Random Allocation
Steatohepatitis/Metabolic Liver Disease
chemistry.chemical_compound
Nonalcoholic fatty liver disease
Needle
ddc:616
biology
Biopsy
Needle
Fatty liver
Immunohistochemistry
Mitochondria
3. Good health
Treatment Outcome
Biochemistry
Area Under Curve
Sirtuin
Niacinamide
medicine.medical_specialty
Niacinamide/analogs & derivatives/pharmacology
Diet
High-Fat
Sensitivity and Specificity
03 medical and health sciences
Internal medicine
Mitochondrial unfolded protein response
Unfolded Protein Response/drug effects
medicine
Animals
Fatty Liver/drug therapy/metabolism/pathology
Analysis of Variance
Hepatology
Animal
Lipid Metabolism
High-Fat/methods
NAD
medicine.disease
Diet
Mice
Inbred C57BL
Fatty Liver
Disease Models
Animal
030104 developmental biology
Endocrinology
chemistry
Disease Models
Nicotinamide riboside
Unfolded Protein Response
biology.protein
NAD+ kinase
Zdroj: Hepatology (Baltimore, Md.)
Hepatology, Vol. 63, No 4 (2016) pp. 1190-204
ISSN: 1527-3350
0270-9139
Popis: 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 (Sirt1hep−/−), 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. (Hepatology 2016;63:1190–1204)
Databáze: OpenAIRE
Externí odkaz: