Benign recurrent intrahepatic cholestasis type 2 (BRIC2) is caused by mutations in ABCB11, a gene encoding the bile salt export pump (BSEP) that mediates biliary bile salt secretion, and presents with repeated intermittent cholestasis with refractory itching. Currently, no effective medical therapy has been established. We previously provided experimental and clinical evidence suggesting the therapeutic potential of 4-phenylbutyrate (4PB) for the cholestatic attacks of BRIC2.After examining the potential therapeutic use of 4PB treatment by in vitro studies, a patient with BRIC2 was treated p.o. with 4PB at gradually increasing doses (200, 350, and 500 mg/kg per day) for 4 months. Biochemical, histological and clinical data were collected.The patient was diagnosed with BRIC2 because he had non-synonymous mutations (c.1211A>G [p.D404G] and 1331T>C [p.V444A]) in ABCB11, reduced hepatocanalicular expression of BSEP and low biliary bile salt concentrations. In vitro analysis showed that 4PB treatment partially restored the decreased expression of BSEP caused by p.D404G mutation. During the first 2 months of 4PB therapy at 200 and 350 mg/kg per day, the patient had no relief from his symptoms. No beneficial effect was observed after additional treatment with bilirubin absorption and endoscopic nasobiliary drainage. However, after starting treatment at a dose of 500 mg/kg per day, the patient's liver function tests and intractable itching were markedly improved. No apparent side-effects were observed during or after 4PB therapy. The symptoms relapsed within 1.5 months after cessation of 4PB therapy.4PB therapy would have a therapeutic effect on the cholestatic attacks of BRIC2.
A total of 19 patients consisted of 10 cases with hypertrophic cardiomyopathy (HCM), 6 with hypertensive heart disease (HHD) and 3 with professional bicycle racers with myocardial hypertrophy, showing giant negative T waves greater than 10 mm in precordial leads (GNT-group) was examined by catheterization, cineangiography and endomyocardial biopsy. Fourteen patients of myocardial hypertrophy consisted of 5 cases with HCM, 4 with HHD and 4 with professional bicycle racers without giant negative T (non-GNT-group) were selected as the control. The average of mid-ventricular wall thickness (Tm = 17.4 +/- 4.6 mm) and that of apical wall thickness (Ta = 18.5 +/- 3.6 mm) obtained from the left ventriculogram in GNT group were significantly greater than those in non-GNT group. The average of the apical hypertrophic index (Ta/Tm = 1.1 +/- 0.3) was also greater than that in non-GNT group. For the evaluation of hypertrophy of the papillary muscles, pattern of the hypertrophy was divided into 2 types by the feature of the left ventriculogram in systolic phase of right anterior oblique view, i.e., normal to moderate (type I) and severe (type II). In GNT group, 79% of patients belonged to the type II, whereas 71% of patients in non-GNT group belonged to type I. Histopathologically, the hypertrophy of heart muscle cells in GNT group was higher grade than in non-GNT group. Disarray of the muscle cells and myocardial fibrosis was not so prominent in GNT group. It was concluded that the mode of hypertrophy in GNT group was characterized by the existence of papillary muscle hypertrophy and had similarity to the hypertrophy of known etiologies such as mechanically overloaded myocardium which suggested to the secondary heart muscle diseases.
Glycosylation is involved in various pathophysiological conditions. N-Acetylglucosaminyltransferase V (GnT-V), catalyzing β1-6 branching in asparagine-linked oligosaccharides, is one of the most important glycosyltransferases involved in cancer and the immune system. Recent findings indicate that aberrant N-glycan structure can modify lipid metabolism. In this study, we investigated the effects of aberrant glycosylation by GnT-V on high-density lipoprotein cholesterol (HDL) assembly. We used GnT-V transgenic (Tg) mice and GnT-V Hep3B cell (human hepatoma cell line) transfectants. The study also included 96 patients who underwent medical health check-ups. Total serum cholesterol levels, particularly HDL-cholesterol (HDL-C) levels, were significantly increased in Tg vs. wild-type (WT) mice. Hepatic expression of apolipoprotein AI (ApoAI) and ATP-binding cassette subfamily A member 1 (ABCA1), two important factors in HDL assembly, were higher in Tg mice compared with WT mice. ApoAI and ABCA1 were also significantly elevated in GnT-V transfectants compared with mock-transfected cells. Moreover, ApoAI protein in the cultured media of GnT-V transfectants was significantly increased. Finally, we found a strong correlation between serum GnT-V activity and HDL-C concentration in human subjects. Multivariate logistic analyses demonstrated that GnT-V activity was an independent and significant determinant for serum HDL-C levels even adjusted with age and gender differences. Further analyses represented that serum GnT-V activity had strong correlation especially with the large-size HDL particle concentration. These findings indicate that enhanced hepatic GnT-V activity accelerated HDL assembly and could be a novel mechanism for HDL synthesis.
