Department of MedicineUniversity of Eastern Finland and Kuopio University HospitalKuopioFinland.
Department of Experimental Vascular MedicineAmsterdam UMC, University of AmsterdamAmsterdamthe Netherlands.
Hepatol Commun. 2020 Nov 25;5(2):244-257. doi: 10.1002/hep4.1630. eCollection 2021 Feb.
The protein phosphatase 1 regulatory subunit 3B () gene is a target of farnesoid X receptor (), which is a major regulator of bile acid metabolism. Both and have been suggested to take part in glycogen metabolism, which may explain the association of gene variants with altered hepatic computed tomography attenuation. We analyzed the effect of rs4240624 variant on bile acid composition in individuals with obesity. The study cohort consisted of 242 individuals from the Kuopio Obesity Surgery Study (73 men, 169 women, age 47.6 ± 9.0 years, body mass index 43.2 ± 5.4 kg/m) with genotype and liver RNA sequencing (RNA-seq) data available. Fasting plasma and gallbladder bile samples were collected from 50 individuals. Bile acids in plasma did not differ based on the rs4240624 genotype. However, the concentration of total bile acids (109 ± 55 vs. 35 ± 19 mM; = 1.0 × 10) and all individual bile acids (also 7α-hydroxy-4-cholesten-3-one [C4]) measured from bile were significantly lower in those with the AG genotype compared to those with the AA genotype. In addition, total cholesterol ( = 0.011) and phospholipid ( = 0.001) levels were lower in individuals with the AG genotype, but cholesterol saturation index did not differ, indicating that the decrease in cholesterol and phospholipid levels was secondary to the change in bile acids. Liver RNA-seq data demonstrated that expression of , tankyrase (), chromosome 8 clone RP11-10A14.5 ( []), chromosome 8 clone RP11-375N15.1 (), and chromosome 8, clone RP11-10A14 () associated with the genotype. In addition, genes enriched in transmembrane transport and phospholipid binding pathways were associated with the genotype. The rs4240624 variant in has a major effect on the composition of gallbladder bile. Other transcripts in the same loci may be important mediators of the variant effect.
蛋白磷酸酶 1 调节亚基 3B()基因是法尼醇 X 受体()的靶标，是胆汁酸代谢的主要调节剂。和都被认为参与了糖原代谢，这也许可以解释基因变异与肝 CT 衰减改变的相关性。我们分析了 rs4240624 变异对肥胖个体中胆汁酸组成的影响。研究队列由 242 名来自库奥皮奥肥胖手术研究的个体组成（73 名男性，169 名女性，年龄 47.6±9.0 岁，体重指数 43.2±5.4kg/m），他们具有基因型和肝 RNA 测序（RNA-seq）数据。从 50 名个体中采集空腹血浆和胆囊胆汁样本。根据 rs4240624 基因型，血浆胆汁酸没有差异。然而，与 AA 基因型个体相比，AG 基因型个体的总胆汁酸（109±55 与 35±19mM；=1.0×10）和所有个体胆汁酸（也为 7α-羟基-4-胆甾烯-3-酮[C4]）浓度显著降低。此外，AG 基因型个体的总胆固醇（=0.011）和磷脂（=0.001）水平较低，但胆固醇饱和度指数没有差异，表明胆固醇和磷脂水平的降低是胆汁酸变化的次要原因。肝 RNA-seq 数据表明，与基因型相关的基因包括()、 Tankyrase()、8 号染色体 8 克隆 RP11-10A14.5()、8 号染色体 8 克隆 RP11-375N15.1()、8 号染色体 RP11-10A14 克隆()，此外，与基因型相关的基因还包括富含跨膜转运和磷脂结合途径的基因。位于中的 rs4240624 变异对胆囊胆汁的组成有重要影响。同一基因座的其他转录本可能是变异效应的重要介导者。
