Cholesterol Metabolism Is Enhanced in the Liver and Brain of Children with Citrin Deficiency

Satoshi Hirayama, Hironori Nagasaka, Akira Honda, Haruki Komatsu, Takahiro Kodama, Ayano Inui, Ichiro Morioka, Shunsaku Kaji, Tsuyoshi Ueno, Kenji Ihara, Mariko Yagi, Zenro Kizaki, Kazuhiko Bessho, Hiroki Kondou, Tohru Yorifuji, Hirokazu Tsukahara, Kazumoto Iijima, Takashi Miida

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


Context Citrin-deficient infants present neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), which resolves at 12 months. Thereafter, they have normal liver function associated with hypercholesterolemia, and a preference for lipid-rich carbohydrate-restricted diets. However, some develop adult-onset type II citrullinemia, which is associated with metabolic abnormalities. Objectives To identify the causes of hypercholesterolemia in citrin-deficient children post-NICCD. Design and Setting We determined the concentrations of sterol markers of cholesterol synthesis, absorption, and catabolism by liquid chromatography-electrospray ionization-tandem mass spectrometry and evaluated serum lipoprotein profiles. Subjects Twenty citrin-deficient children aged 5 to 13 years and 37 age-matched healthy children. Intervention None. Main Outcome Measures Relationship between serum lipoproteins and sterol markers of cholesterol metabolism. Results The citrin-deficient group had a significantly higher high-density lipoprotein cholesterol (HDL-C) concentration than did the control group (78 ± 11 mg/dL vs 62 ± 14 mg/dL, P < 0.001), whereas the two groups had similar low-density lipoprotein cholesterol and triglyceride concentrations. The concentrations of markers of cholesterol synthesis (lathosterol and 7-dehydrocholesterol) and bile acids synthesis (7α-hydroxycholesterol and 27-hydroxycholesterol) were 1.5- to 2.8-fold and 1.5- to 3.9-fold, respectively, higher in the citrin-deficient group than in the control group. The concentration of 24S-hydroxycholesterol, a marker of cholesterol catabolism in the brain, was 2.5-fold higher in the citrin-deficient group. In both groups, the HDL-C concentration was significantly positively correlated with that of 27-hydroxycholesterol, the first product of the alternative bile acid synthesis pathway. Conclusions HDL-C and sterol marker concentrations are elevated in citrin-deficient children post-NICCD. Moreover, cholesterol synthesis and elimination are markedly enhanced in the liver and brain of citrin-deficient children.

Original languageEnglish
Pages (from-to)2488-2497
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Issue number7
Publication statusPublished - Jul 1 2018

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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