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. 2021;11(3):831-839.
doi: 10.1016/j.jcmgh.2020.09.001. Epub 2020 Sep 9.

NTCP Deficiency Causes Gallbladder Abnormalities in Mice and Human Beings

Fengfeng Mao  1 , Meng-Xuan Wang  2 , Xinfeng Hou  3 , Zhongmin Zhou  1 , Yan-Yan Yan  4 , Ling-Juan Fang  5 , Zexi Tan  6 , Wei-Yuan Fang  4 , Teng Liu  4 , Wenhui He  6 , Cong Li  3 , Xin-Bao Xie  4 , Shi-Qi Lu  4 , Jianhua Sui  7 , Fengchao Wang  8 , Jun Han  9 , Jian-She Wang  10 , Wenhui Li  11
Affiliations

NTCP Deficiency Causes Gallbladder Abnormalities in Mice and Human Beings

Fengfeng Mao et al. Cell Mol Gastroenterol Hepatol. 2021.
No abstract available

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Figures

Figure 1
Figure 1
No obvious pathologic changes in 4-week-old and aged Slc10a1-/- mice. Representative H&E staining of liver, small intestine (SI), large intestine (LI), kidney, pancreas, and spleen in (A) 4-week-old and (B) aged WT and Slc10a1-/- mice. Slc10a1-/- mice with extremely high serum TBA levels (>1 mmol/L) showed mild liver injury and inflammation (not shown).
Figure 2
Figure 2
NTCP deficiency causes gallbladder abnormalities in mice. Representative photographs of gallbladders from fasted 4-week-old (A) male WT and (B–D) Slc10a1-/- mice. Scale bar: 1 mm. Representative gallbladder H&E staining of (E and I) WT mice related to panel A, and (F-H and J-L) Slc10a1-/- mice related to panels B-D, respectively. The arrow indicates elongated epithelial folds, arrowheads indicate stromal granulocyte infiltration, closed triangles indicate submucosal vasodilation, and open triangles indicate the presence of lipids in the gallbladder walls. (M) Gallbladder (GB) weights in WT (n = 20) and Slc10a1-/- mice (n = 19) at 4 weeks of age. (N) Representative photos of bile from WT and Slc10a1-/- mice. (O) BA profiling in bile from WT and Slc10a1-/- mice (WT, n = 5; Slc10a1-/-, n = 9) at 4 weeks of age. Inset: the significant decrease of taurine-conjugated β MCA (TβMCA). All mice were male. Values are shown as medians. Each symbol represents an individual mouse. Two-tailed Student t tests were used.
Figure 3
Figure 3
Slc10a1-/- mice did not develop cholesterol gallstone disease. Demonstrations of gallbladder abnormalities in 4-week-old (A) male and (B) female Slc10a1-/- mice. (C) Ileal Fgf15 expression in male WT (n = 8) and Slc10a1-/- mice (n = 10) at 4 weeks of age. (D) Correlation of ileal Fgf15 expression and TBA level in male Slc10a1-/- mice (n = 17). (E) Correlation of ileal Fgf15 expression and gallbladder weight in male Slc10a1-/- mice (n = 10). Concentrations of (F) bile acids, (G) cholesterol, and (H) phospholipids in GB bile, and (I) values of cholesterol saturation index in WT (n = 7) and Slc10a1-/- mice (n = 11) at 4 weeks of age. Values are given as medians. Each symbol represents an individual mouse. Two-tailed Student t tests and Spearman rank correlation analysis were used. mRNA, messenger RNA.
Figure 4
Figure 4
Gallbladder abnormalities in aged Slc10a1-/- mice. BA profiling in bile from old (A) male and (B) female WT and Slc10a1-/- mice (n = 4–5). (C) Representative photographs and H&E staining of gallbladder abnormalities in old male and female Slc10a1-/- mice. (D) Bile flow and (E) biliary BA secretion during the 10-minute collection period for WT and Slc10a1-/- mice (n = 5). Values are shown as mean ± SD. Each symbol represents an individual mouse. Two-tailed Student t tests were used.
Figure 5
Figure 5
Infant and teenage human beings with the NTCP p.Ser267Phe variant present with gallbladder abnormalities. Abdominal ultrasound indicated the following: (A) multiple polyps in the gallbladder (maximal diameter, approximately 5 mm), male, age 15 years; (B) a polyp in the gallbladder (diameter, approximately 2 mm), male, age 14 years; (C) a gallstone in the gallbladder (size, 1.1 cm ◊ 0.6 cm), male, age 6 months; and (D) a rough gallbladder wall and multiple sand-like gallstones in the gallbladder (diameters, 0.6–1.3 mm), male, age 7 months. Arrows indicate the sites of gallbladder abnormality. (E) Major primary and secondary BAs in plasma from healthy controls (HCs, shown with a mean level of each BA species, n = 43), patient 1 and patient 8 by UPLC/multiple-reaction monitoring-MS. (F) Sera levels of FGF19 in HCs (n = 15) and NTCP p.Ser267Phe variants (n = 15). (G) Correlation of FGF19 levels and TBA levels in NTCP p.Ser267Phe variants. Values are shown as medians. Each symbol represents a HC individual with the NTCP p.Ser267Phe variant. Two-tailed Student t test and Spearman rank correlation analysis were used.
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