Transporter Activity Changes in Nonalcoholic Steatohepatitis: Assessment with Plasma Coproporphyrin I and III.

Expression and functional changes in the organic anion transporting polypeptide (OATP)-multidrug resistance-associated protein (MRP) axis of transporters are well reported in patients with nonalcoholic steatohepatitis (NASH). These changes can impact plasma and tissue disposition of endo- and exogenous compounds. The transporter alterations are often assessed by administration of a xenobiotic or by transporter proteomic analysis from liver biopsies. Using gene expression, proteomics, and endogenous biomarkers, we show that the gene expression and activity of OATP and MRP transporters are associated with disease progression and recovery in humans and in preclinical animal models of NASH. Decreased OATP and increased MRP3/4 gene expression in two cohorts of patients with steatosis and NASH, as well as gene and protein expression in multiple NASH rodent models, have been established. Coproporphyrin I and III (CP I and III) were established as substrates of MRP4. CP I plasma concentration increased significantly in four animal models of NASH, indicating the transporter changes. Up to a 60-fold increase in CP I plasma concentration was observed in the mouse bile duct-ligated model compared with sham controls. In the choline-deficient amino acid-defined high-fat diet (CDAHFD) model, CP I plasma concentrations increased by >3-fold compared with chow diet-fed mice. In contrast, CP III plasma concentrations remain unaltered in the CDAHFD model, although they increased in the other three NASH models. These results suggest that tracking CP I plasma concentrations can provide transporter modulation information at a functional level in NASH animal models and in patients. SIGNIFICANCE STATEMENT: Our analysis demonstrates that multidrug resistance-associated protein 4 (MRP4) transporter gene expression tracks with nonalcoholic steatohepatitis (NASH) progression and intervention in patients. Additionally, we show that coproporphyrin I and III (CP I and III) are substrates of MRP4. CP I plasma and liver concentrations increase in different diet- and surgery-induced rodent NASH models, likely explained by both gene- and protein-level changes in transporters. CP I and III are therefore potential plasma-based biomarkers that can track NASH progression in preclinical models and in humans.

Is aspirin a substrate of MDR1/P-glycoprotein?

Aspirin (acetyl salicylic acid) is widely used co-medication in patients with cardiovascular and cerebrovascular diseases. Given the prevalence of acetyl salicylic acid's use as a co-medication and conflicting reports in the literature on it being a substrate of P-glycoprotein (P-gp). There is a potential risk for its interaction with compounds with P-gp liability, therefore, we have conducted a detailed investigation to determine substrate potential of acetyl salicylic acid towards P-gp. We observed significantly lower cellular uptake of acetyl salicylic acid in MDR1 transfected LLC-PK1 cells compared to LLC-PK1 wild-type (WT) cells, however, the in vitro efflux of acetyl salicylic acid in MDR1 transfected LLC-PK1 cells was not inhibited by known inhibitors under various conditions. Acetyl salicylic acid did not show active asymmetrical transport across MDR1 transfected LLC-PK1 cells compared to LLC-PK1-WT cells in transwell assay. Moreover, no difference in plasma and brain exposure of acetyl salicylic acid and its metabolite salicylic acid was observed between FVB-WT and Mdr1a/b knockout (KO) mice. Taken together, our findings indicate that acetyl salicylic acid is not a substrate of P-gp.

Cardiac Development and Related Clinical Considerations.

The anatomy, physiology, and hemodynamics of the premature heart vary along the range of gestational ages cared for in neonatal intensive care units, from 22 weeks to term gestation. Clinical management of the preterm neonate should account for this heterogenous development. This requires an understanding of the impact of ex utero stressors on immature and disorganized cardiac tissue, the different state of hemodynamics across intracardiac shunts impacting the natural transition from fetal to neonatal life, and the effects of intensive pharmacologic and non-pharmacologic interventions that have systemic consequences influencing cardiac function. This article provides a review of the increasing but still limited body of literature on the anatomy, hemodynamics, and electrophysiology of the preterm heart with relevant clinical considerations.

Does neck circumference predict obstructive sleep apnea in children with obesity?

OBJECTIVES: Obstructive sleep apnea (OSA) affects 10-50% of children with obesity, but its identification is challenging and wait times for testing are long. Previous studies suggest that neck circumference (NC) and neck-to-height ratio (NHR) may predict OSA. Our objectives were to 1) evaluate associations of NC and NHR with OSA; 2) model NHR as a predictor of OSA, adjusting for age, sex, and Tanner stage; and 3) identify thresholds of NHR associated with OSA, in children with obesity. METHODS: Participants were aged 8-17 years, with obesity (BMI >95%ile), undergoing polysomnography. Associations between NC and NHR with OSA were evaluated. NHR, age, sex and self-reported Tanner stage (early/late) were included in a negative binomial multiple regression model to predict obstructive apnea hypopnea index (OAHI). RESULTS: 71 children participated, with median age 14.8 years (IQR 12.6, 16.0), 54% male, median BMI z-score 2.5 (IQR 2.3, 2.7), and 77% late Tanner stage. OSA was severe in 18 children (25.4%), moderate in 12 (16.9%), and mild in 18 (25.4%). In the model, each 0.01 increase in NHR was associated with a 55% increase in OAHI (95% CI: 36%, 80%); boys had a 119% higher OAHI than girls (95% CI: 10%, 337%). Threshold NHR associated with moderate-severe OSA was 0.25 in females and 0.23 in males. CONCLUSIONS: NHR and male sex independently predict OSA severity in children with obesity, adjusting for age and Tanner stage. Children with obesity and NHR above identified thresholds are more likely to have moderate-severe OSA, and may benefit from earlier polysomnography.