Ontogeny of Hepatic Organic Cation Transporter-1 in Rat and Human.

The organic cation transporter (OCT)-1 mediates hepatic uptake of cationic endogenous compounds and xenobiotics. To date, limited information exists on how Oct1/OCT1 functionally develops with age in rat and human livers and how this would affect the pharmacokinetics of OCT substrates in children or juvenile animals. The functional ontogeny of rOct/hOCT was profiled in suspended rat (2-57 days old) and human hepatocytes (pediatric liver tissue donors: age 2-12 months) by determining uptake clearance of 4-[4-(dimethylamino)styryl]-N-methylpyridinium iodide (ASP+) as a known rOct/hOCT probe substrate.

Brown Adipose Tissue Heterogeneity, Energy Metabolism, and Beyond.

Brown adipocyte in brown adipose tissue (BAT) specializes in expending energy through non-shivering thermogenesis, a process that produces heat either by uncoupling protein 1 (UCP1) dependent uncoupling of mitochondrial respiration or by UCP1 independent mechanisms. Apart from this, there is ample evidence suggesting that BAT has an endocrine function. Studies in rodents point toward its vital roles in glucose and lipid homeostasis, making it an important therapeutic target for treating metabolic disorders related to morbidities such as obesity and type 2 diabetes.

Liver disease predominates in a mouse model for mild human Zellweger spectrum disorder.

Zellweger spectrum disorders (ZSDs) are autosomal recessive diseases caused by defective peroxisome assembly. They constitute a clinical continuum from severe early lethal to relatively milder presentations in adulthood. Liver disease is a prevalent symptom in ZSD patients.

Functional peroxisomes are required for β-cell integrity in mice.

Objectives: Peroxisomes play a crucial role in lipid and reactive oxygen species metabolism, but their importance for pancreatic β-cell functioning is presently unknown. To examine the contribution of peroxisomal metabolism to β-cell homeostasis in mice, we inactivated PEX5, the import receptor for peroxisomal matrix proteins, in an inducible and β-cell restricted manner (Rip-Pex5 mice).

Methods: After tamoxifen-induced recombination of the Pex5 gene at the age of 6 weeks, mice were fed either normal chow or a high-fat diet for 12 weeks and were subsequently phenotyped.

Mitochondrial disruption in peroxisome deficient cells is hepatocyte selective but is not mediated by common hepatic peroxisomal metabolites.

The structural disruption of the mitochondrial inner membrane in hepatocytes lacking functional peroxisomes along with selective impairment of respiratory complexes and depletion of mitochondrial DNA was previously reported. In search for the molecular origin of these mitochondrial alterations, we here show that these are tissue selective as they do neither occur in peroxisome deficient brain nor in peroxisome deficient striated muscle. Given the hepatocyte selectivity, we investigated the potential involvement of metabolites that are primarily handled by hepatic peroxisomes.

Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in Drosophila and mouse.

Peroxisome biogenesis disorders (PBD) are a group of multi-system human diseases due to mutations in the PEX genes that are responsible for peroxisome assembly and function. These disorders lead to global defects in peroxisomal function and result in severe brain, liver, bone and kidney disease. In order to study their pathogenesis we undertook a systematic genetic and biochemical study of Drosophila pex16 and pex2 mutants.

Inter-Subject Variability in OCT1 Activity in 27 Batches of Cryopreserved Human Hepatocytes and Association with OCT1 mRNA Expression and Genotype.

Purpose: OCT1/3 (Organic Cation Transporter-1 and -3; SLC22A1/3) are transmembrane proteins localized at the basolateral membrane of hepatocytes. They mediate the uptake of cationic endogenous compounds and/or xenobiotics. The present study was set up to verify whether the previously observed variability in OCT activity in hepatocytes may be explained by inter-individual differences in OCT1/3 mRNA levels or OCT1 genotype.

Abl1 inhibitory contaminants leach from plastic tubes.

Plastic materials are widely used in research laboratories. Disposable plasticware facilitates life science research in the storage, transportation and manipulation of biological samples. However, recent findings have shown that some disposable plasticwares release bioactive contaminants.

Mitochondria in peroxisome-deficient hepatocytes exhibit impaired respiration, depleted DNA, and PGC-1α independent proliferation.

The tight interrelationship between peroxisomes and mitochondria is illustrated by their cooperation in lipid metabolism, antiviral innate immunity and shared use of proteins executing organellar fission. In addition, we previously reported that disruption of peroxisome biogenesis in hepatocytes severely impacts on mitochondrial integrity, primarily damaging the inner membrane. Here we investigated the molecular impairments of the dysfunctional mitochondria in hepatocyte selective Pex5 knockout mice.