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Publication
Deficiency of the Mitochondrial NAD Kinase Causes Stress-Induced Hepatic
Steatosis in Mice.
Authors Zhang K, Kim H, Fu Z, Qiu Y, Yang Z, Wang J, Zhang D, Tong X, Yin L, Li J, Wu J,
Qi NR, Houten SM, Zhang R
Submitted By Submitted Externally on 4/24/2018
Status Published
Journal Gastroenterology
Year 2018
Date Published 1/1/2018
Volume : Pages 154 : 224 - 237
PubMed Reference 28923496
Abstract The mitochondrial nicotinamide adenine dinucleotide (NAD) kinase (NADK2, also
called MNADK) catalyzes phosphorylation of NAD to yield NADP. Little is known
about the functions of mitochondrial NADP and MNADK in liver physiology and
pathology. We investigated the effects of reduced mitochondrial NADP by deleting
MNADK in mice., We generated MNADK knockout (KO) mice on a C57BL/6NTac
background; mice with a wild-type Mnadk gene were used as controls. Some mice
were placed on an atherogenic high-fat diet (16% fat, 41% carbohydrate, and
1.25% cholesterol supplemented with 0.5% sodium cholate) or given methotrexate
intraperitoneally. We measured rates of fatty acid oxidation in primary
hepatocytes using radiolabeled palmitate and in mice using indirect calorimetry.
We measured levels of reactive oxygen species in mouse livers and primary
hepatocytes. Metabolomic analyses were used to quantify serum metabolites, such
as amino acids and acylcarnitines., The KO mice had metabolic features of
MNADK-deficient patients, such as increased serum concentrations of lysine and
C10:2 carnitine. When placed on the atherogenic high-fat diet, the KO mice
developed features of nonalcoholic fatty liver disease and had increased levels
of reactive oxygen species in livers and primary hepatocytes, compared with
control mice. During fasting, the KO mice had a defect in fatty acid oxidation.
MNADK deficiency reduced the activation of cAMP-responsive element binding
protein-hepatocyte specific and peroxisome proliferator-activated receptor
alpha, which are transcriptional activators that mediate the fasting response.
The activity of mitochondrial sirtuins was reduced in livers of the KO mice.
Methotrexate inhibited the catalytic activity of MNADK in hepatocytes and in
livers in mice with methotrexate injection. In mice given injections of
methotrexate, supplementation of a diet with nicotinamide riboside, an NAD
precursor, replenished hepatic NADP and protected the mice from hepatotoxicity,
based on markers such as increased level of serum alanine aminotransferase.,
MNADK facilitates fatty acid oxidation, counteracts oxidative damage, maintains
mitochondrial sirtuin activity, and prevents metabolic stress-induced
non-alcoholic fatty liver disease in mice.




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