These results suggest that HMGB1 plays a role in virus induced BA pathogenesis and could be a target for therapeutic interventions in a subset of patients with BA and high HMGB1. (Hepatology 2021;74:864-878). B iliary atresia (BA) is a disease of infancy in which a devastating fibroinflammatory cholangiopathy occurs, leading to obstructive jaundice. BA leads to end-stage liver disease (ESLD). (1)(2)(3)(4) In the United States, the incidence of BA is 1 in 15,000 births, (5) and it is the most common indication for pediatric liver transplantation. (6,7) In an effort to restore bile flow, a Kasai hepatoportoenterostomy (HPE) is typically performed soon after diagnosis. (8) However, even if an HPE is performed and cholestasis resolves, bile duct proliferation and fibrosis may progress, (7) resulting in the development of portal hypertension and the complications of ESLD. (9) It is estimated that 60% of the patients who overcome perinatal cholestasis will still need a liver transplantation before the age

Collagen XXII (COL22A1) is a quantitatively minor collagen, which belongs to the family of fibril-associated collagens with interrupted triple helices. Its biological function has been poorly understood. Here, we used a genome-editing approach to generate a loss-of-function mutant in zebrafish col22a1. Homozygous mutant adults exhibit increased incidence of intracranial hemorrhages, which become more prominent with age and after cardiovascular stress. Homozygous col22a1 mutant embryos show higher sensitivity to cardiovascular stress and increased vascular permeability, resulting in a greater percentage of embryos with intracranial hemorrhages. Mutant embryos also exhibit dilations and irregular structure of cranial vessels. To test whether COL22A1 is associated with vascular disease in humans, we analyzed data from a previous study that performed whole-exome sequencing of 45 individuals from seven families with intracranial aneurysms. The rs142175725 single-nucleotide polymorphism was identified, which segregated with the phenotype in all four affected individuals in one of the families, and affects a highly conserved E736 residue in COL22A1 protein, resulting in E736D substitution. Overexpression of human wild-type COL22A1, but not the E736D variant, partially rescued the col22a1 loss-of-function mutant phenotype in zebrafish embryos. Our data further suggest that the E736D mutation interferes with COL22A1 protein secretion, potentially leading to endoplasmic reticulum stress. Altogether, these results argue that COL22A1 is required to maintain vascular integrity. These data further suggest that mutations in COL22A1 could be one of the risk factors for intracranial aneurysms in humans.

Objective Vertical sleeve gastrectomy (VSG) results in weight loss, increased bile acids (BA) and fibroblast growth factor 19 (FGF19) levels. FGF21 shares essential co-factors with FGF19 but its physiology early post-VSG has not been assessed. Methods Ten adolescents (17.4 ± 0.5 years and BMI 51.5 ± 2.5 kg/m2) were enrolled. Fasting and post-meal (100 mL Ensure™) samples (0–120 min) were collected (Pre-VSG [V1], 1 [V2], & 3 months [V3] post-VSG) for analysis of BA, FGF19, and FGF21. Results Post-VSG subjects lost weight (V2 11.8 ± 0.8 kg; V3 21.9 ± 1.7 kg). BA and FGF19 increased by V2; 143.6% at 30 min and 74.9% at 90 min postmeal, respectively. BA hydrophobicity index also improved by V3; 21.1% at 30 min postmeal. Interestingly, fasting and 120 min postmeal FGF21 levels at V2 were increased by 135.7% and 253.9% respectively, but then returned to baseline at V3. BA levels correlated with FGF21 at V2 (P = 0.003, r = 0.89) and body weight lost post-VSG correlated with FGF21 levels (V2; P = 0.012, R = 0.82). Conclusion Expected changes were seen in BA and FGF19 biology after VSG in adolescents, but novel changes were seen in correlation between the early postsurgical increase in FGF21 and weight loss, suggesting that FGF21 may play a role in energy balance postoperatively and further investigation was warranted.

Background and Aims Biliary atresia (BA) is a devastating neonatal cholangiopathy that progresses to fibrosis and end‐stage liver disease by 2 years of age. Portoenterostomy may reestablish biliary drainage, but, despite drainage, virtually all afflicted patients develop fibrosis and progress to end‐stage liver disease requiring liver transplantation for survival. Approach and Results In the murine model of BA, rhesus rotavirus (RRV) infection of newborn pups results in a cholangiopathy paralleling human BA and has been used to study mechanistic aspects of the disease. Unfortunately, nearly all RRV‐infected pups succumb by day of life 14. Thus, in this study we generated an RRV‐TUCH rotavirus reassortant (designated as TR(VP2,VP4)) that when injected into newborn mice causes an obstructive jaundice phenotype with lower mortality rates. Of the mice that survived, 63% developed Ishak stage 3‐5 fibrosis with histopathological signs of inflammation/fibrosis and bile duct obstruction. Conclusions This model of rotavirus‐induced neonatal fibrosis will provide an opportunity to study disease pathogenesis and has potential to be used in preclinical studies with an objective to identify therapeutic targets that may alter the course of BA.

Rotavirus infection is one of the most common causes of diarrheal illness in humans. In neonatal mice, rhesus rotavirus (RRV) can induce biliary atresia (BA), a disease resulting in inflammatory obstruction of the extrahepatic biliary tract and intrahepatic bile ducts. We previously showed that the amino acid arginine (R) within the sequence SRL (amino acids 445 to 447) in the RRV VP4 protein is required for viral binding and entry into biliary epithelial cells. To determine if this single amino acid (R) influences the pathogenicity of the virus, we generated a recombinant virus with a single amino acid mutation at this site through a reverse genetics system. We demonstrated that the RRV mutant (RRV VP4-R446G ) produced less symptomatology and replicated to lower titers both in vivo and in vitro than those seen with wild-type RRV, with reduced binding in cholangiocytes. Our results demonstrate that a single amino acid change in the RRV VP4 gene influences cholangiocyte tropism and reduces pathogenicity in mice.IMPORTANCE Rotavirus is the leading cause of diarrhea in humans. Rhesus rotavirus (RRV) can also lead to biliary atresia (a neonatal human disease) in mice. We developed a reverse genetics system to create a mutant of RRV (RRV VP4-R446G ) with a single amino acid change in the VP4 protein compared to that of wild-type RRV. In vitro, the mutant virus had reduced binding and infectivity in cholangiocytes. In vivo, it produced fewer symptoms and lower mortality in neonatal mice, resulting in an attenuated form of biliary atresia.KEYWORDS RRV, biliary atresia, cholangiocyte, reverse genetics B iliary atresia (BA) is a unique disease of infancy leading to inflammatory obstruction of the extrahepatic biliary tract. It is the most common cause of pathological jaundice in the pediatric population, and it may progress to hepatic cirrhosis and end-stage liver disease, requiring liver transplantation (1, 2). The etiology of BA remains unknown. It has been proposed that a viral agent may be responsible. Several viruses, including rotavirus group C (3), reovirus type 3 (4), Epstein-Barr virus (5), cytomegalovirus (6), and human papillomavirus (7), have been found in explanted livers of infants with BA. In the mouse model of BA, rhesus rotavirus (RRV) infection of newborn BALB/c mice results in an inflammatory cholangiopathy and a pathological phenotype similar to those in human BA (8, 9). This manifests as bilirubinuria, jaundice, acholic stools, growth retardation, and, ultimately, death (9). The morphological and histological