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

TLDR

Nonalcoholic fatty liver disease is the most common chronic liver disease in Western countries, with no approved pharmacological treatment and a prevalence rising alongside the obesity epidemic. The study aimed to evaluate whether nicotinamide riboside–mediated NAD⁺ repletion could prevent or reverse hepatic steatosis in mice. Nicotinamide riboside was incorporated into a high‑fat high‑sucrose diet as either a preventive or therapeutic intervention. In mice, nicotinamide riboside prevented and reversed NAFLD by activating a SIRT1‑ and SIRT3‑dependent mitochondrial unfolded protein response that increased β‑oxidation and mitochondrial complex activity, a benefit confirmed in liver‑specific Sirt1 knockout and Apoe‑/‑ mouse models, supporting NAD⁺ boosting as a therapeutic strategy. Hepatology 2016;63:1190–1204.

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 ( 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. (H epatology 2016;63:1190–1204)