Reply
Authors: Qilin Gu, Zongbin Cui
Journal: Hepatology (2014)

Potential conflict of interest: Nothing to report. Dr. Vinciguerra raised an interesting question about the clinical treatment of nonalcoholic fatty liver disease (NAFLD) with L‐arginine (L‐ARG). A large body of evidence clearly indicates that dietary supplementation or intravenous administration of L‐ARG is beneficial in improving reproductive, cardiovascular, pulmonary, renal, gastrointestinal, liver, and immune functions, as well as facilitating wound healing, enhancing insulin sensitivity, and maintaining tissue integrity.1 Additionally, L‐ARG may provide novel and effective therapies for obesity, diabetes, and metabolic syndrome.1 However, the therapeutic benefits of L‐ARG are often observed during short‐term dosing, but not after long‐term use.2 Moreover, L‐ARG tolerance (and possible toxicity) in endothelial cells exists and is mediated by eNOS down‐regulation, secondary to oxidative stress and glucose accumulation.3 Thus, a better understanding of the biochemical and pharmacological consequences of long‐term L‐ARG supplementation will greatly help to inform the design and evaluation of future clinical trials regarding L‐ARG.2 Functions of nitric oxide (NO) generated in the liver have also attracted the attention of numerous scholars around the world. NO produced from constitutive endogenous nitric oxide synthase (eNOS) is protective for the liver,4 while NO produced from inducible nitric oxide synthase (iNOS) can be either toxic or protective depending on the conditions.6 Under redox stress, induced NO contributes to hepatic damage; however, NO acts as a potent inhibitor of apoptosis in the liver under acute inflammation, a condition associated with cytokine exposure.6 In addition, enhanced oxidant stress is associated with pathological changes in alcoholic liver injury7 and NO can act as an antioxidant.8 Moreover, decreased NO production in nonparenchymal cells of the liver is associated with increased severity of liver injury in alcohol‐fed rats9 and treatment with L‐ARG is able to reverse alcoholic liver injury and markedly attenuated the pathological changes.10 Therefore, both cytoprotective and cytotoxic effects of NO on the liver are noticed under physiological and/or pathological conditions. We recently revealed an NO‐AMPK‐PPARα signaling pathway that is crucial for the control of hepatic fatty acid oxidation in zebrafish and mice under starvation,11 but further investigations are needed to evaluate whether L‐ARG supplements are able to treatment NAFLD through mediation of NO synthesis. NO‐mediated nitration of proteins is induced in patients with chronic viral hepatitis and appears to be associated with the histological severity of viral chronic liver disease.12 Viral hepatitis is essentially different from fasting‐induced hepatic steatosis since no inflammation was found in liver sections of fasted slc7a3a‐null zebrafish mutants,11 so the regulatory mechanisms of NO signaling under starvation may be entirely distinct from those in pathologic fatty liver disease. Consequently, further investigations are needed to fully uncover the roles of NO signaling in pathological and metabolic syndrome‐related NAFLD. Taken together, it will be of great interest to characterize the long‐term therapeutic roles of L‐ARG and other NO donors in NAFLD and other diseases. The dosage of NO donors used in the treatment of liver diseases needs to be carefully titrated. Since multiple signaling pathways are found to be regulated by intracellular NO signaling, downstream molecules of NO‐AMPK signaling pathway may offer the best drug targets for the clinical treatment of NAFLD.