Circulating bile acids concentration is predictive of coronary artery disease in human

Synthetized by the liver and metabolized by the gut microbiota, BA are involved in metabolic liver diseases that are associated with cardiovascular disorders. Animal models of atheroma documented a powerful anti-atherosclerotic effect of bile acids (BA). This prospective study examined whether variations in circulating BA are predictive of coronary artery disease (CAD) in human. Consecutive patients undergoing coronary angiography were enrolled. Circulating and fecal BA were measured by high pressure liquid chromatography and tandem mass spectrometry. Of 406 screened patients, 80 were prospectively included and divided in two groups with (n = 45) and without (n = 35) CAD. The mean serum concentration of total BA was twice lower in patients with, versus without CAD (P = 0.005). Adjusted for gender and age, this decrease was an independent predictor of CAD. In a subgroup of 17 patients, statin therapy doubled the serum BA concentration. Decreased serum concentrations of BA were predictors of CAD in humans. A subgroup analysis showed a possible correction by statins. With respect to the anti-atherosclerotic effect of BA in animal models, and their role in human lipid metabolism, this study describe a new metabolic disturbance associated to CAD in human.

Treatment of a metabolic liver disease by in vivo prime editing in mice

Prime editing is a highly versatile CRISPR-based genome editing technology with the potential to correct the vast majority of pathogenic mutations. However, correction of a disease phenotype in vivo in somatic tissues has not been demonstrated thus far. Here, we establish proof-of-concept for in vivo prime editing and repair the metabolic liver disease phenylketonuria (PKU) in mice. We first developed a size-reduced SpCas9 prime editor (PE) lacking the RNaseH domain of the reverse transcriptase (PE2-deltaRnH), and a linker- and NLS-optimized intein-split PE construct (PE2 p.1153) for delivery by adeno-associated virus (AAV) vectors. Systemic dual AAV-mediated delivery of this variant into the liver of neonatal mice enabled installation of a transversion mutation at the Dnmt1 locus with an average efficiency of 15%, and delivery of unsplit PE2-deltaRnH using human adenoviral vector 5 (AdV5) further increased editing rates to 58%. PE2-deltaRnH-encoding AdV5 was also used to correct the disease-causing mutation of the phenylalanine hydroxylase (Pah)enu2 allele in phenylketonuria (PKU) mice with an average efficiency of 8% (up to 17.3%), leading to therapeutic reduction of blood phenylalanine (L-Phe) levels. Our study demonstrates in vivo prime editing in the liver with high precision and editing rates sufficient to treat a number of metabolic liver diseases, emphasizing the potential of prime editing for future therapeutic applications.

Role of bile acids in inflammatory liver diseases

Bile acids and their signaling pathways are increasingly recognized as potential therapeutic targets for cholestatic and metabolic liver diseases. This review summarizes new insights in bile acid physiology, focusing on regulatory roles of bile acids in the control of immune regulation and on effects of pharmacological modulators of bile acid signaling pathways in human liver disease. Recent mouse studies have highlighted the importance of the interactions between bile acids and gut microbiome. Interfering with microbiome composition may be beneficial for cholestatic and metabolic liver diseases by modulating formation of secondary bile acids, as different bile acid species have different signaling functions. Bile acid receptors such as FXR, VDR, and TGR5 are expressed in a variety of cells involved in innate as well as adaptive immunity, and specific microbial bile acid metabolites positively modulate immune responses of the host. Identification of Cyp2c70 as the enzyme responsible for the generation of hydrophilic mouse/rat-specific muricholic acids has allowed the generation of murine models with a human-like bile acid composition. These novel mouse models will aid to accelerate translational research on the (patho)physiological roles of bile acids in human liver diseases .

Correlation of Genotype and Phenotype in 32 Patients with Hereditary Hemochromatosis in China

Background: Hereditary hemochromatosis (HH) is widely recognized and clinical manifestations of HFE-related HH is well studied in European populations. Less is known about the clinical and laboratory characteristics of non-HFE related HH in Asian population. We aimed to explore the relationship between genotype and clinical phenotype in Chinese patients with non-HFE related hereditary hemochromatosis.Methods: Peripheral blood samples and clinical data of patients with primary iron overload were collected from the China Registry of Genetic/Metabolic Liver Diseases. Sanger sequencing was performed in cases with primary iron overload, for 5 known HH related genes (HFE, HJV, HAMP, TFR2 and SLC40A1) and 2 novel iron homeostasis-related genes (DENND3 and SUGP2). The correlation of genotype and clinical phenotype in these patients was analyzed.Results: Of the 32 patients with primary iron overload (23 were males and 9 were females), non-HFE variants were detected in 31 (31/32, 97%), including 8 pathogenic variants in HJV, 7 pathogenic variants in SLC40A1, 8 likely pathogenic variants in SUGP2 and 5 likely pathogenic variants in DENND3 cases. Among these 31 cases, 4 cases harbored homozygous variants, 2 cases harbored homozygous+ heterozygous variants, 19 cases harbored heterozygous or combined heterozygous variants, and 6 cases harbored no any damaging variants. None of investigated cases carried damaging HAMP and TFR2 variants were found. 8 cases were classified as type 2A HH and 6 cases as type 4 HH, 10 cases as non-classical genotype, and 6 cases had no pathogenic variants from 31 cases. During the statistical analysis, we excluded one case (SLC40A1 IVS3+10delGTT+SUGP2 p. R639Q(homo)) with difficulty in grouping due to combined damaging variants. Cases with type 2A HH have an earlier age at diagnosis. The iron index of cases in type 2A HH and type 4 HH was higher than that in other groups. Arthropathy was relatively rare in all groups. None of cases with type 2A HH developed cirrhosis. Cirrhosis and diabetes are more prevalent in type 4 HH.Conclusions: This is the first comprehensive analysis about the gene variant spectrum and phenotypic aspects of non-HFE HH in China. The results will be useful to the identification, diagnosis and management of HH in China.