Hepatic NAD + levels and NAMPT abundance are unaffected during prolonged high-fat diet consumption in C57BL/6JBomTac mice

Mol Cell Endocrinol. 2018 Sep 15;473:245-256. doi: 10.1016/j.mce.2018.01.025. Epub 2018 Feb 2.

Abstract

Dietary supplementation of nicotinamide adenine dinucleotide (NAD+) precursors has been suggested as a treatment for non-alcoholic fatty liver disease and obesity. In the liver, NAD+ is primarily generated by nicotinamide phosphoribosyltransferase (NAMPT), and hepatic levels of NAMPT and NAD+ have been reported to be dependent on age and body composition. The aim of the present study was to identify time course-dependent changes in hepatic NAD content and NAD+ salvage capacity in mice challenged with a high-fat diet (HFD). We fed 7-week-old C57BL/6JBomTac male mice either regular chow or a 60% HFD for 6, 12, 24, and 48 weeks, and we evaluated time course-dependent changes in whole body metabolism, liver steatosis, and abundance of hepatic NAD-associated metabolites and enzymes. Mice fed a 60% HFD rapidly accumulated fat and hepatic triglycerides with associated changes in respiratory exchange ratio (RER) and a disruption of the circadian feeding pattern. The HFD did not alter hepatic NAD+ levels, but caused a decrease in NADP+ and NADPH levels. Decreased NADP+ content was not accompanied by alterations in NAD kinase (NADK) abundance in HFD-fed mice, but NADK levels increased with age regardless of diet. NAMPT protein abundance did not change with age or diet. HFD consumption caused a severe decrease in protein lysine malonylation after six weeks, which persisted throughout the experiment. This decrease was not associated with changes in SIRT5 abundance. In conclusion, hepatic NAD+ salvage capacity is resistant to long-term HFD feeding, and hepatic lipid accumulation does not compromise the hepatic NAD+ pool in HFD-challenged C57BL/6JBomTac male mice.

Keywords: C57BL/6JBomTac; High-fat diet; NAD(+) salvage pathways; NAFLD; SIRT5; lysine malonylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiposity
  • Animals
  • Diet, High-Fat*
  • Feeding Behavior
  • Liver / metabolism*
  • Lysine / metabolism
  • Male
  • Mice, Inbred C57BL
  • NAD / metabolism*
  • NADP / metabolism
  • Nicotinamide Phosphoribosyltransferase / metabolism*
  • Respiration
  • Triglycerides / metabolism

Substances

  • Triglycerides
  • NAD
  • NADP
  • Nicotinamide Phosphoribosyltransferase
  • Lysine