title: Regulation of putative fatty acid transporters and Acyl-CoA synthetase in liver and adipose tissue in ob/ob mice.
abstract: The hyperlipidemia associated with obesity and type 2 diabetes is caused by an increase in hepatic triglyceride synthesis and secretion that is secondary to an increase in de novo lipogenesis, a decrease in fatty acid (FA) oxidation, and an increase in the flux of peripherally derived FA to the liver. The uptake of FA across the plasma membrane may be mediated by three distinct proteins--FA translocase (FAT), plasma membrane FA binding protein (FABP-pm), and FA transport protein (FATP)--that have recently been characterized. Acyl-CoA synthetase (ACS) enhances the uptake of FAs by catalyzing their activation to acyl-CoA esters for subsequent use in anabolic or catabolic pathways. In this study, we examine the mRNA levels of FAT, FABP-pm, FATP, and ACS in the liver and adipose tissue of genetically obese (ob/ob) mice and their control littermates. FAT mRNA levels were 15-fold higher in liver and 60-80% higher in adipose tissue of ob/ob mice. FABP-pm mRNA levels were twofold higher in liver and 50% higher in adipose tissue of ob/ob mice. FATP mRNA levels were not increased in liver or adipose tissue. ACS mRNA levels were higher in adipose tissue but remained unchanged in liver. However, the distribution of ACS activity associated with mitochondria and microsomes in liver was altered in ob/ob mice. In control littermates, 61% of ACS activity was associated with mitochondria and 39% with microsomes, whereas in ob/ob mice 34% of ACS activity was associated with mitochondria and 66% with microsomes; this distribution would make more FA available for esterification, rather than oxidation, in ob/ob mouse liver. Taken together, our results suggest that the upregulation of FAT and FABP-pm mRNAs may increase the uptake of FA in adipose tissue and liver in ob/ob mice, which, coupled with an increase in microsomal ACS activity in liver, will enhance the esterification of FA and support the increased triglyceride synthesis and VLDL production that characterizes obesity and type 2 diabetes.
authors.affiliation: Department of Medicine, University of California San Francisco, USA. rmemon@itsa.ucsf.edu
authors.forename: R A
authors.initials: RA
authors.lastname: Memon
authors.forename: J
authors.initials: J
authors.lastname: Fuller
authors.forename: A H
authors.initials: AH
authors.lastname: Moser
authors.forename: P J
authors.initials: PJ
authors.lastname: Smith
authors.forename: C
authors.initials: C
authors.lastname: Grunfeld
authors.forename: K R
authors.initials: KR
authors.lastname: Feingold
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D018955:CD36 Antigens; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism*; D050612:Fatty Acid Transport Proteins; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D018996:Myelin P2 Protein / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D027361:Organic Anion Transporters; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: D018955:CD36 Antigens; D002352:Carrier Proteins; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; D050612:Fatty Acid Transport Proteins; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D018996:Myelin P2 Protein; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D027361:Organic Anion Transporters; D012333:RNA, Messenger; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; C493572:Slc27a4 protein, mouse; D003066:Coenzyme A Ligases; C090799:FAA2 protein, S cerevisiae; D000098859:Long-Chain-Fatty-Acid-CoA Ligase