Alpha-Amino-Beta-Carboxy-Muconate-Semialdehyde Decarboxylase Controls Dietary Niacin Requirements for NAD + Synthesis

Cell Rep. 2018 Oct 30;25(5):1359-1370.e4. doi: 10.1016/j.celrep.2018.09.091.

Abstract

NAD+ is essential for redox reactions in energy metabolism and necessary for DNA repair and epigenetic modification. Humans require sufficient amounts of dietary niacin (nicotinic acid, nicotinamide, and nicotinamide riboside) for adequate NAD+ synthesis. In contrast, mice easily generate sufficient NAD+ solely from tryptophan through the kynurenine pathway. We show that transgenic mice with inducible expression of human alpha-amino-beta-carboxy-muconate-semialdehyde decarboxylase (ACMSD) become niacin dependent similar to humans when ACMSD expression is high. On niacin-free diets, these acquired niacin dependency (ANDY) mice developed reversible, mild-to-severe NAD+ deficiency, depending on the nutrient composition of the diet. NAD deficiency in mice contributed to behavioral and health changes that are reminiscent of human niacin deficiency. This study shows that ACMSD is a key regulator of mammalian dietary niacin requirements and NAD+ metabolism and that the ANDY mouse represents a versatile platform for investigating pathologies linked to low NAD+ levels in aging and neurodegenerative diseases.

Keywords: ACMSD; NAD; NADP; kynurenine; metabolism; niacin; nicotinamide; nicotinic acid; tryptophan; vitamin B3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl Coenzyme A / metabolism
  • Animals
  • Carboxy-Lyases / metabolism*
  • Diet*
  • Doxycycline / administration & dosage
  • Doxycycline / pharmacology
  • Humans
  • Lactates / metabolism
  • Liver / metabolism
  • Mice, Inbred C57BL
  • NAD / biosynthesis*
  • NADP / metabolism
  • Niacin / metabolism*
  • Oxidation-Reduction
  • Pyruvates / metabolism
  • Weight Loss

Substances

  • Lactates
  • Pyruvates
  • NAD
  • Niacin
  • NADP
  • Acetyl Coenzyme A
  • Carboxy-Lyases
  • aminocarboxymuconate-semialdehyde decarboxylase
  • Doxycycline