Impact of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) on the expression and function of hepatobiliary transporters: A comprehensive mechanistic review

The liver plays a central role in the biotransformation and disposition of endogenous molecules and xenobiotics. In addition to drug-metabolizing enzymes, transporter proteins are key determinants of drug hepatic clearance. Hepatic transporters are transmembrane proteins that facilitate the movement of chemicals between sinusoidal blood and hepatocytes. Other drug transporters translocate molecules from hepatocytes into bile canaliculi for biliary excretion. The formers are known as basolateral, while the latter are known as canalicular transporters. Also, these transporters are classified into two super-families, the solute carrier transporter (SLC) and the adenosine triphosphate (ATP)-binding cassette (ABC) transporter. The expression and function of transporters involve complex regulatory mechanisms, which are contributing factors to interindividual variability in drug pharmacokinetics and disposition. A considerable number of liver diseases are known to alter the expression and function of drug transporters. Among them, non-alcoholic fatty liver disease (NAFLD) is a chronic condition with a rapidly increasing incidence worldwide. NAFLD, recently reclassified as metabolic dysfunction-associated steatotic liver disease (MASLD), is a disease continuum that includes steatosis with or without mild inflammation (NASH), and potentially neuroinflammatory pathology. NASH is additionally characterized by the presence of hepatocellular injury. During NAFLD and NASH, drug transporters exhibit altered expression and function, leading to altered drug pharmacokinetics and pharmacodynamics, thus increasing the risk of adverse drug reactions. The purpose of the present review is to provide comprehensive mechanistic information on the expression and function of hepatic transporters under fatty liver conditions and hence, the impact on the pharmacokinetic profiles of certain drugs from the available pre-clinical and clinical literature. •Hepatic transporters are transmembrane proteins that mediate the movement of endogenous and exogenous substances.•Progression of NAFLD and NASH causes significant alterations in the expression of hepatic transporters.•Posttranscriptional modifications of hepatic transcription factors and xenosensors during NASH/NAFLD are in part responsible for altered expression of transporters.•NAFLD- and NASH-related alterations in transporters expression of can impact the pharmacokinetic profile of drugs.