Regulation of putative fatty acid transporters and acyl-CoA synthetase in liver and adipose tissue in ob/ob mice

The hyperlipidemia associated with obesity and type 2 diabetes is caused by an increase in hepatic triglyceride synthesis and secretion that is second ary to an increase in de novo lipogenesis, a decrease in fatty acid (FA) ox idation, and an increase in the flux of peripherally derived FA to the live r The uptake of FA across the plasma membrane may be mediated by three dist inct proteins--FA translocase (FAT), plasma membrane FA binding protein (FA BP-pm), and FA transport protein (FATP)-that have recently been characteriz ed. Acyl-CoA synthetase (ACS) enhances the uptake of FAs by catalyzing thei r activation to acyl-CoA esters for subsequent use in anabolic or catabolic pathways. In this study we examine the nRNA levels of FAT, FABP-pm, FATP, and ACS in the liver and adipose tissue of genetically obese (ob/ob) mice a nd 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. FA TP mRNA levels were not increased in Liver or adipose tissue, ACS mRNA leve ls were higher in adipose tissue but remained unchanged in liver. However, the distribution of ACS activity associated with mitochondria aid microsome s in liver was altered in ob/ob mice, In control Littermates, 61% of ACS ac tivity was associated with mitochondria and 39% with microsomes, whereas in ob/ob mice 34% of ACS activity was associated with mitochondria and 66%, w ith microsomes; this distribution would make more FA available for esterifi cation, rather than oxidation, in ob/ob mouse liver, Taken together, our re sults suggest that the upregulation of FAT and FABP-pm mRNAs may increase t he uptake of FA in adipose tissue and Liver in ob/ob mice, which, coupled w ith an increase in microsomal ACS activity in liver, will enhance the ester ification of FA and support the increased triglyceride synthesis and VLDL p roduction that characterizes obesity and type 3 diabetes.