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Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice
Author(s) -
Gariani Karim,
Menzies Keir J.,
Ryu Dongryeol,
Wegner Casey J.,
Wang Xu,
Ropelle Eduardo R.,
Moullan Norman,
Zhang Hongbo,
Perino Alessia,
Lemos Vera,
Kim Bohkyung,
Park YoungKi,
Piersigilli Alessandra,
Pham Tho X.,
Yang Yue,
Ku Chai Siah,
Koo Sung I.,
Fomitchova Anna,
Cantó Carlos,
Schoonjans Kristina,
Sauve Anthony A.,
Lee JiYoung,
Auwerx Johan
Publication year - 2016
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28245
Subject(s) - nad+ kinase , fatty liver , nicotinamide adenine dinucleotide , nonalcoholic fatty liver disease , medicine , endocrinology , sirtuin , niacin , steatosis , sirt3 , mitochondrion , biology , biochemistry , disease , enzyme
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. (H epatology 2016;63:1190–1204)