ACC2 is expressed at high levels in human white adipose and has an isoform with a novel N-terminus [corrected].
Acetyl-CoA carboxylases ACC1 and ACC2 catalyze the carboxylation of acetyl-CoA to malonyl-CoA, regulating fatty-acid synthesis and oxidation, and are potential targets for treatment of metabolic syndrome. Expression of ACC1 in rodent lipogenic tissues and ACC2 in rodent oxidative tissues, coupled with the predicted localization of ACC2 to the mitochondrial membrane, have suggested separate functional roles for ACC1 in lipogenesis and ACC2 in fatty acid oxidation. We find, however, that human adipose tissue, unlike rodent adipose, expresses more ACC2 mRNA relative to the oxidative tissues muscle and heart. Human adipose, along with human liver, expresses more ACC2 than ACC1. Using RT-PCR, real-time PCR, and immunoprecipitation we report a novel isoform of ACC2 (ACC2.v2) that is expressed at significant levels in human adipose. The protein generated by this isoform has enzymatic activity, is endogenously expressed in adipose, and lacks the N-terminal sequence. Both ACC2 isoforms are capable of de novo lipogenesis, suggesting that ACC2, in addition to ACC1, may play a role in lipogenesis. The results demonstrate a significant difference in ACC expression between human and rodents, which may introduce difficulties for the use of rodent models for development of ACC inhibitors.
Castle
John C
JC
Rosetta Inpharmatics LLC, Seattle, Washington, United States of America. john_castle@merck.com
Hara
Yoshikazu
Y
Raymond
Christopher K
CK
Garrett-Engele
Philip
P
Ohwaki
Kenji
K
Kan
Zhengyan
Z
Kusunoki
Jun
J
Johnson
Jason M
JM
D000103:Acetyl-CoA Carboxylase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000123:Acetyltransferases / Q000378:metabolism; D052436:Adipose Tissue, White / Q000201:enzymology*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats
D007527:Isoenzymes; D012333:RNA, Messenger; D000123:Acetyltransferases; C055210:aminoglycoside N1-acetyltransferase; C520105:ACACB protein, human; D000103:Acetyl-CoA Carboxylase