A recent study by Nathan Cherrington, PhD, examined the impact of nonalcoholic steatohepatitis (NASH) on hepatocyte hopping, a critical process in the liver that aids in filtering fluids and waste. His findings revealed that inducing NASH in rodent animal models disrupts the function of transporters involved in this process. This research underscores the significance of understanding the mechanisms underlying NASH and their influence on drug metabolism and disposition. 

What were their key findings? 

This study investigated the impact of nonalcoholic steatohepatitis (NASH) on the three key drug disposition processes involved in hepatocyte hopping. The research focused on three transporters—Mrp3, Oatp, and Mrp2—that play crucial roles in hepatocyte function. The effects of NASH-induced alterations on these transporters were assessed in the context of sorafenib (SFB) filtration, a drug used to treat thyroid and liver cancer. Among the transporters, Oatp was found to be particularly important for the uptake and disposition of SFB into hepatocytes. Both Mrp2 and Mrp3 are also integral to SFB disposition, facilitating its efflux from the cells. The study revealed that NASH-induced changes significantly impair the function of each of these transporters, disrupting their role in SFB processing. 

What is hepatocyte hopping? 

Hepatocytes and sinusoids are essential liver cells that play a key role in its fundamental functions, such as blood purification and the removal of drugs and toxins. Hepatocyte hopping refers to the process by which blood, drugs, or toxins are transferred from a hepatocyte to a sinusoid, and then back to the hepatocyte for detoxification. This process involves several transporters, but nonalcoholic steatohepatitis (NASH) disrupts their function, leading to increased plasma retention in the kidneys. 

What is nonalcoholic steatohepatitis? 

Metabolic syndrome is a condition in which a combination of specific pathologies significantly increases the risk of cardiovascular diseases, such as heart attack or stroke. Nonalcoholic steatohepatitis (NASH) is the liver manifestation of metabolic syndrome, marked by fibrosis, inflammation, and hepatocellular damage. NASH also disrupts gene expression, particularly in genes that regulate absorption, disposition, metabolism, and excretion processes. 

How does this translate to the human body? 

Although this study was conducted using rodent models, the findings are highly relevant to humans, as the rodent model closely mirrors human NASH histology. When NASH was induced in the rodents, the three transporters involved in hepatocyte hopping were significantly impaired. Hepatocyte hopping is the body's mechanism for filtering drugs and waste. Dysfunction in these transporters in humans would hinder the ability to eliminate drugs, leading to prolonged retention and impaired biliary excretion. 

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