Loss of hepatic Nmnat1 has no impact on diet-induced fatty liver disease

Abstract

Nicotinamide adenine dinucleotide (NAD+), a biological molecule integral to redox reactions involved in multiple cellular processes, has the potential to treat nonalcoholic fatty liver diseases (NAFLDs) and nonalcoholic steatohepatitis (NASH). Nicotinamide mononucleotide adenylyltransferase (Nmnat1), one of the NAD+ biosynthesizing enzymes, plays a central role in all NAD+ metabolic pathways and it is vital to embryonic development. However, the function of Nmnat1 in metabolic pathology and, specifically, in the development and progression of NAFLD and NASH remains unexplored. First, we generated hepatic Nmnat1 knockout (H-Nmnat1−/−) mice to investigate the physiological function of Nmnat1 and found that NAD+ levels were significantly lower in H-Nmnat1−/− mice than control mice. However, H-Nmnat1−/− mice appeared normal with comparable metabolic activity. Next, we used three different diet-induced NASH models to assess the pathophysiological role of Nmant1 in metabolic disorders and discovered that hepatic loos of Nmnat1 decreased 35%–40% of total NAD+ in an obese state. Nevertheless, our analysis of phenotypic variations found comparable body composition, gene expression, and liver histology in all NASH models in H-Nmnat1−/− mice. We also found that aged H-Nmnat1−/− mice exhibited comparable liver phenotypes with control mice. These findings suggest that Nmnat1 has a redundancy to the pathophysiology of obesity-induced hepatic disorders.