Free Cholesterol Affects the Function and Localization of Human Na+/Taurocholate Cotransporting Polypeptide (NTCP) and Organic Cation Transporter 1 (OCT1)

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are associated with obesity. They are accompanied by increased levels of free cholesterol in the liver. Most free cholesterol resides within the plasma membrane. We assessed the impact of adding or removing free cholesterol on the function and localization of two hepatocellular uptake transporters: the Na+/taurocholate cotransporting polypeptide (NTCP) and the organic cation transporter 1 (OCT1). We used a cholesterol-MCD complex (cholesterol) to add cholesterol and methyl-beta-cyclodextrin (MCD) to remove cholesterol. Our results demonstrate that adding cholesterol decreases NTCP capacity from 132 +/- 20 to 69 +/- 37 mu L/mg/min and OCT1 capacity from 209 +/- 66 to 125 +/- 26 mu L/mg/min. Removing cholesterol increased NTCP and OCT1 capacity to 224 +/- 65 and 279 +/- 20 mu L/mg/min, respectively. In addition, adding cholesterol increased the localization of NTCP within lipid rafts, while adding or removing cholesterol increased OCT1 localization in lipid rafts. These results demonstrate that increased cholesterol levels can impair NTCP and OCT1 function, suggesting that the free cholesterol content of the liver can alter bile acid and drug uptake into the liver. This could explain the increased plasma bile acid levels in NAFLD and NASH patients and potentially lead to altered drug disposition.

Automated summary

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), which are associated with obesity, are characterized by increased levels of free cholesterol in the liver. This study found that adding cholesterol impaired the function of two hepatic uptake transporters, while removing cholesterol increased their capacities. Furthermore, adding or removing cholesterol affected the localization of these transporters within lipid rafts. These findings suggest that the free cholesterol content in the liver can affect bile acid and drug uptake, potentially leading to altered drug disposition.