Gariani 2016 Hepatology
| Gariani K, Menzies KJ, Ryu D, Wegner CJ, Wang X, Ropelle ER, Moullan N, Zhang H, Perino A, Lemos V, Kim B, Park YK, Piersigilli A, Pham TX, Yang Y, Siah Ku C, Koo SI, Fomitchova A, Cantรณ C, Schoonjans K, Sauve AA, Lee JY, Auwerx J (2015) Eliciting the mitochondrial unfolded protein response via NAD+ repletion reverses fatty liver disease. Hepatology [Epub ahead of print]. |
Gariani K, Menzies KJ, Ryu D, Wegner CJ, Wang X, Ropelle ER, Moullan N, Zhang H, Perino A, Lemos V, Kim B, Park YK, Piersigilli A, Pham TX, Yang Y, Siah Ku C, Koo SI, Fomitchova A, Canto C, Schoonjans K, Sauve AA, Lee JY, Auwerx J (2015) Hepatology
Abstract: With no approved pharmacological treatment, non-alcoholic 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 NAD+ levels driving reductions in hepatic mitochondrial content, function and ATP levels, in conjunction with robust increases in hepatic weight, lipid content and peroxidation in C57BL/6J mice. In an effort to assess the effect of NAD+ repletion on the development of steatosis in mice, nicotinamide riboside (NR), a precursor for NAD+ biosynthesis, was given to mice concomitant, as preventive strategy (NR-Prev), and as a therapeutic intervention (NR-Ther), to a HFHS diet. We demonstrate that NR prevents and reverts NAFLD by inducing a SIRT1- and SIRT3-dependent mitochondrial unfolded protein response (UPRmt ), triggering an adaptive mitohormetic pathway to increase hepatic ฮฒ-oxidation and mitochondrial complex content and activity. The cell-autonomous beneficial component of NR treatment was revealed in liver-specific Sirt1 KO mice (Sirt1hep-/-), while Apolipoprotein E-deficient (Apoe-/-) mice challenged with a high-fat high-cholesterol diet (HFC), affirmed the use of NR in other independent models of NAFLD.
Our data warrant the future evaluation of NAD+ boosting strategies to manage the development or progression of NAFLD. โข Keywords: Mitonuclear protein imbalance, Nicotinamide riboside (NR), Non-alcoholic fatty liver disease (NAFLD), Poly(ADP-ribose) polymerases (PARPs), Sirtuins
Labels: MiParea: Respiration, mt-Biogenesis;mt-density, mtDNA;mt-genetics, Genetic knockout;overexpression, Exercise physiology;nutrition;life style, Pharmacology;toxicology
Organism: Mouse
Tissue;cell: Liver
Coupling state: OXPHOS
HRR: Oxygraph-2k
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