Citrin, encoded by SLC25A13, is a liver-type mitochondrial
aspartate-glutamate carrier (AGC), of which deficiency, in autosomal recessive trait, causes neonatal
intrahepatic cholestasis (
NICCD) and adult-onset type II
citrullinemia (CTLN2).
NICCD patients have
jaundice,
hypoproteinemia,
hypoglycemia,
galactosemia, growth retardation,
fatty liver and multiple aminoacidemia including
citrulline,
methionine,
threonine and
tyrosine. Some of the neonates who have experienced
NICCD suffer from severe CTLN2 more than 10 years or several decades later. In CTLN2, neuropsychotic symptoms such as disorientation, aberrant behavior,
coma and death are observed. Laboratory findings reveal
hyperammonemia,
citrullinemia,
fatty liver and liver-specific decrease in a
urea cycle
enzyme,
argininosuccinate synthetase (ASS). In some cases,
hyperlipidemia,
pancreatitis and
hepatoma are accompanied with CTLN2.
Citrin as a liver-type AGC plays a role in supplying
aspartate to the cytosol for
urea,
protein and
nucleotide synthesis by exchanging mitochondrial
aspartate for cytosolic
glutamate and
proton, and transporting cytosolic
NADH reducing equivalent to mitochondria as a member of
malate aspartate shuttle essential for aerobic glycolysis. AGC is also important for gluconeogenesis from
lactate. Although it is difficult to explain pathogenesis of the symptoms such as
cholestasis in
NICCD and liver-specific decrease of ASS
protein in CTLN2 from the functions of the AGC, some are understandable by the loss of
citrin functions. Many CTLN2 patients have been treated with a low
protein and high
carbohydrate diet and
glycerol at the hyperammonemic
coma. We argue that those treatments may result in
fatty liver,
hyperlipidemia,
hyperammonemia and even death due to loss of the
citrin functions. Loss of
citrin first cause deficiency of
aspartate in the cytosol, which results in an increase in cytosolic
NADH/
NAD(+) ratio and then activation of
fatty acid synthesis pathway to compensate the aberrant ratio. This follows inhibition of
fatty acid oxidation. The peculiar fondness for food of CTLN2 patients who like
protein and dislike
carbohydrate and sweets may be related to their metabolic requirements.