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

Abstract

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.

• Authors: 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
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 103 Issue 7 Pg. 2488-2497 (07 01 2018) ISSN: 1945-7197 [Electronic] United States
• PMID: 29659898 (Publication Type: Journal Article)

Chemical References

• Bile Acids and Salts
• Biomarkers
• Cholesterol, HDL
• Cholesterol, LDL
• Dehydrocholesterols
• Hydroxycholesterols
• Triglycerides
• 24-hydroxycholesterol
• lathosterol
• Cholesterol
• 7-dehydrocholesterol

Topics

• Adolescent
• Bile Acids and Salts (biosynthesis)
• Biomarkers (blood)
• Brain (metabolism)
• Case-Control Studies
• Child
• Child, Preschool
• Cholesterol (blood)
• Cholesterol, HDL (metabolism)
• Cholesterol, LDL (metabolism)
• Citrullinemia (complications, metabolism)
• Dehydrocholesterols (blood)
• Female
• Humans
• Hydroxycholesterols (blood)
• Hypercholesterolemia (etiology)
• Liver (metabolism)
• Male
• Triglycerides (blood)