Protein Phosphatase 1 Regulatory Subunit 3B Genotype at rs4240624 Has a Major Effect on Gallbladder Bile Composition

Abstract

The protein phosphatase 1 regulatory subunit 3B (PPP1R3B) gene is a target of farnesoid X receptor (FXR), which is a major regulator of bile acid metabolism. Both PPP1R3B and FXR have been suggested to take part in glycogen metabolism, which may explain the association of PPP1R3B gene variants with altered hepatic computed tomography attenuation. We analyzed the effect of PPP1R3B 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 2) with PPP1R3B 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 PPP1R3B rs4240624 genotype. However, the concentration of total bile acids (109 ± 55 vs. 35 ± 19 mM; P = 1.0 × 10 −5) 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 (P = 0.011) and phospholipid (P = 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 PPP1R3B, tankyrase (TNKS), Homo sapiens chromosome 8 clone RP11-10A14.5 (AC022784.1 [LOC157273]), Homo sapiens chromosome 8 clone RP11-375N15.1 (AC021242.1), and Homo sapiens chromosome 8, clone RP11-10A14 (AC022784.6) associated with the PPP1R3B genotype. In addition, genes enriched in transmembrane transport and phospholipid binding pathways were associated with the genotype. Conclusion: The rs4240624 variant in PPP1R3B has a major effect on the composition of gallbladder bile. Other transcripts in the same loci may be important mediators of the variant effect. (Hepatology Communications 2020;0:1-14).

Hepatokine ITIH3 protects against hepatic steatosis by downregulating mitochondrial bioenergetics and de novo lipogenesis

“…The study detail and its characteristics have been reported elsewhere 78 , 79 and in Table S3 . The study included a total of 262 participants of the Kuopio Obesity Surgery (KOBS) study who underwent the Roux-en-Y gastric bypass surgery at Kuopio University Hospital, and from whom both detailed liver histology and RNA sequencing data were available.…”

“…RNA sequencing libraries underwent 50-nucleotide long paired-end sequencing on Illumina HiSeq 2500 machine, followed by read alignment, normalization and differential expression analysis considering the technical and confounding factors (namely RIN, uniquely aligned reads %, 3’ bias, age, sex, and BMI) as described previously. 79 The gene level count values were normalized using a trimmed-mean of M values converted to count per million using edgeR 80 and inverse normal transformed. The study protocol was approved by the Ethics Committee of the Northern Savo Hospital District.…”

Indole-3-Propionic Acid, a Gut-Derived Tryptophan Metabolite, Associates with Hepatic Fibrosis

“…Total RNA sequencing was performed for 175 liver samples from the current study population. Briefly, RNA sequencing libraries underwent 50-nucleotide long paired-end sequencing on Illumina HiSeq 2500 machine, followed by read alignment, normalization and differential expression analysis considering the technical and confounding factors (namely RIN, uniquely aligned reads %, 3’ bias, age, sex and BMI) as described previously [ 37 , 39 ].…”

Role of Matrix Gla Protein in Transforming Growth Factor-β Signaling and Nonalcoholic Steatohepatitis in Mice

“…To explore the relevance of our findings to human NASH pathobiology, we analyzed MGP expression in RNAseq data of the Kuopio Obesity Surgery (KOBS) clinical study. 19 Hepatic MGP expression was found to be significantly correlated with fibrosis stage in both female (r ¼ 0.156; P ¼ .036) (Figure 1D) and male patients (r ¼ 0.262; P ¼ .002) (Figure 1D). MGP expression was significantly increased in the livers of patients with NASH compared with non-NASH subjects (healthy or simple steatosis) (P ¼ .021).…”

“…The KOBS study was previously described. 19 The current study included 262 subjects with liver histology (55.7% without and 44.3% with different stages of fibrosis) and RNA sequencing data. Liver biopsies were obtained with ultrasonic scissors during the laparoscopic Roux-en-Y gastric bypass surgery.…”