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Nonalcoholic Steatohepatitis Modulates Membrane Protein Retrieval and Insertion Processes.

A L Dzierlenga1, J D Clarke1, N J Cherrington2

  • 1Department of Pharmacology & Toxicology, University of Arizona, Tucson, Arizona.

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|September 9, 2016
PubMed
Summary
This summary is machine-generated.

Altered drug transporter localization in nonalcoholic steatohepatitis (NASH) may stem from changes in membrane protein retrieval and insertion. This study identifies specific mediators involved in these processes in NASH rats.

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Area of Science:

  • Hepatology
  • Cell Biology
  • Pharmacology

Background:

  • Interindividual variability in drug response is a challenge in nonalcoholic steatohepatitis (NASH).
  • Mislocalization of the drug transporter multidrug resistance-associated protein 2 (MRP2) from the canalicular membrane contributes to altered drug transport in NASH.
  • The precise mechanisms driving MRP2 mislocalization remain unclear, but enhanced membrane retrieval processes are suspected.

Purpose of the Study:

  • To investigate the activation status of mediators involved in membrane protein retrieval and insertion in a rodent model of NASH.
  • To identify specific cellular processes contributing to the mislocalization of membrane proteins, such as MRP2, in NASH pathogenesis.

Main Methods:

  • Rodent methionine and choline-deficient (MCD) diet-induced NASH model was utilized.
  • Expression, phosphorylation, and membrane translocation of key mediators (protein kinases PKA, PKCα, PKCδ, PKCε; substrates radixin, myristoylated alanine-rich C-kinase substrate, Rab11) were measured.
  • Comparisons were made between control and NASH rat groups.

Main Results:

  • Several mediators showed altered activation in NASH rats compared to controls.
  • NASH rats displayed decreased radixin phosphorylation and increased membrane localization of PKCδ and PKCε, suggesting enhanced membrane retrieval.
  • Altered activation of PKCδ, PKA, and PKCα was observed, potentially impairing Rab11-mediated Mrp2 insertion.

Conclusions:

  • Nonalcoholic steatohepatitis is associated with altered activation of mediators regulating membrane protein dynamics.
  • Changes in membrane retrieval and insertion processes likely contribute to the mislocalization of membrane proteins, including drug transporters, in NASH.
  • These findings provide insights into the mechanisms underlying drug response variability in NASH.