Effect of caloric restriction and AMPK activation on hepatic nuclear receptor, biotransformation enzyme, and transporter expression in lean and obese mice.
OBJECTIVE
Fatty liver alters liver transporter expression. Caloric restriction (CR), the recommended therapy to reverse fatty liver, increases Sirtuin1 deacetylase activity in liver. This study evaluated whether CR and CR mimetics reversed obesity-induced transporter expression in liver and hepatocytes.


METHODS
mRNA and protein expression was determined in adult lean (lean) and leptin-deficient obese (OB) mice fed ad libitum or placed on 40% (kCal) reduced diet. Hepatocytes were isolated from lean and OB mice, treated with AMP Kinase activators, and gene expression was determined.


RESULTS
CR decreased Oatp1a1, Oatp1b2, and Abcb11 mRNA expression in lean, but not OB mice. CR increased Abcc2 mRNA OB livers, whereas protein expression increased in both genotypes. CR increased Abcc3 protein expression increased in OB livers. CR did not alter Abcc1, 4 and 5 mRNA expression in lean mice but decreased expression in livers of OB mice. CR increased Abcc4 protein in lean, but not OB mice.


CONCLUSIONS
CR restriction reversed the expression of some, but not all transporters in livers of OB mice. Overall, these data indicate a potential for CR to restore some hepatic transporter changes in OB mice, but suggest a functional leptin axis is needed for reversal of expression for some transporters.
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, 7 Greenhouse Road, Kingston, Rhode Island, 02881, USA.
Supriya R
SR
Kulkarni
Jialin
J
Xu
Ajay C
AC
Donepudi
Wei
W
Wei
Angela L
AL
Slitt
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001835:Body Weight; D031204:Caloric Restriction; D002478:Cells, Cultured; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D008055:Lipids / Q000032:analysis; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009765:Obesity / Q000178:diet therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics; D027701:Organic Cation Transport Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics
D055372:AMP-Activated Protein Kinases; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D008055:Lipids; D027381:Liver-Specific Organic Anion Transporter 1; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C490549:Abcb11 protein, mouse; C572127:SLCO1A1 protein, mouse; C498887:Slco1b2 protein, mouse; C114462:multidrug resistance-associated protein 3