Experimental non-alcoholic fatty liver disease results in decreased hepatic uptake transporter expression and function in rats.
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of diagnoses ranging from simple fatty liver (SFL), to non-alcoholic steatohepatitis (NASH). This study aimed to determine the effect of moderate and severe NAFLD on hepatic transporter expression and function in vivo. Rats were fed a high-fat diet (SFL model) or a methionine-choline-deficient diet (NASH model) for eight weeks. Hepatic uptake transporter function was determined by bromosulfophthalein (BSP) disposition. Transporter expression was determined by branched DNA signal amplification assay and western blotting; inflammation was identified by immunostaining of liver slices for interleukin 1 beta (IL-1beta). MC- rats showed significant retention of BSP in the plasma when compared to control rats. Hepatic NTCP, OATP1a1, 1a4, 1b2 and 2b1; and OAT 2 and 3 mRNA levels were significantly decreased in high-fat and MC- diet rats when compared to control. Protein expression of OATP1a1 was significantly decreased in high-fat animals, while OATP1a1 and OATP1b2 expressions were significantly lower in MC- rats when compared to control. Liver tissue from high-fat and MC- rats stained positive for IL-1beta, a pro-inflammatory cytokine known to decrease expression of NTCP, OATP and OAT transporters, suggesting a plausible mechanism for the observed transporter alterations. These data suggest that different stages of NAFLD result in altered hepatic uptake transporter expression that can lead to a functional impairment of xenobiotic uptake from the blood. Furthermore, NAFLD may alter the plasma retention time of clinically relevant drugs that are reliant on these transporters and may increase the potential drug toxicity.
Fisher
Craig D
CD
Department of Pharmacology and Toxicology, Children's Research Center, University of Arizona, Tucson, AZ 85721, USA
Lickteig
Andrew J
AJ
Augustine
Lisa M
LM
Oude Elferink
Ronald P J
RP
Besselsen
David G
DG
Erickson
Robert P
RP
Cherrington
Nathan J
NJ
D000818:Animals; D001659:Biliary Tract / Q000378:metabolism; D004032:Diet; D005234:Fatty Liver / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013448:Sulfobromophthalein / Q000378:metabolism; D015262:Xenobiotics / Q000493:pharmacokinetics
D053583:Interleukin-1beta; D027361:Organic Anion Transporters; D012333:RNA, Messenger; D015262:Xenobiotics; D013448:Sulfobromophthalein; D005978:Glutathione