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Abstract
Recent studies have demonstrated significant metabolic changes in different strains of mice fed a high-fat diet (HFD). Pharmacological doses of niacin can improve nonalcoholic fatty liver disease (NAFLD) in HFD-fed rodents. However, previous study from our lab demonstrated that niacin increases the hepatic triglyceride content and histological score in HFD-fed B6129SF2/J (B6129) mice but has no effect in C57BL/6J (B6) mice. Therefore, the aim of this study was to identify the mechanism responsible for niacin-induced fatty liver in B6129 mice using targeted liver metabolomic analysis. Livers were collected from B6 and B6129 mice, which were fed either a chow (10% fat) or HFD (60% fat) for 20 weeks with niacin (360 mg/kg/day) or vehicle supplementation from week 5 to week 20. Two hundred polar metabolites were identified in these livers. A total of 21 and 26 metabolites identified as different between chow and HFD group in B6 and B6129 mice, respectively. In B6 mice, only 6 metabolites were identified as different with niacin treatment and no specific pathways appeared to be impacted. In contrast to B6 mice, 16 metabolites and 5 pathways were impacted by niacin in HFD-fed B6129 mice. Of the metabolites that were changed in these pathways, only hydroxyphenylpyruvate (also known as 4-Hydroxyphenylpyruvate, 4-HPP) did not change with HFD feeding but significantly decreased with niacin treatment. 4-HPP is an intermediate in the metabolism of phenylalanine/tyrosine and improves mitochondrial oxidation in rats subjected to hemorrhagic shock. Therefore, decreased 4-HPP by niacin may lead to decreased beta-oxidation in the liver and subsequent lipid accumulation and liver damage in B6129 mice. Further lipidomic analysis suggested different hepatic lipid profiles with HFD and niacin treatment in B6129 mice, which may explain the increased NAFLD development in these mice with niacin treatment. Disclosure H. Fang: None. Z. Li: None. E. Graff: Research Support; Self; Elanco Animal Health. K.J. McCafferty: None. R.L. Judd: None. Funding Boshell Diabetes and Metabolic Diseases Research Program
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