Insulin acutely decreases hepatic fatty acid synthase activity.
Insulin is viewed as a positive regulator of fatty acid synthesis by increasing fatty acid synthase (FAS) mRNA transcription. We uncover a new mechanism by which insulin acutely reduces hepatic FAS activity by inducing phosphorylation of the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) and its interaction with FAS. Ceacam1 null mice (Cc1(-/-)) show loss of insulin's ability to acutely decrease hepatic FAS activity. Moreover, adenoviral delivery of wild-type, but not the phosphorylation-defective Ceacam1 mutant, restores the acute effect of insulin on FAS activity in Cc1(-/-) primary hepatocytes. Failure of insulin to acutely reduce hepatic FAS activity in hyperinsulinemic mice, including L-SACC1 transgenics with liver inactivation of CEACAM1, and Ob/Ob obese mice, suggests that the acute effect of insulin on FAS activity depends on the prior insulinemic state. We propose that this mechanism acts to reduce hepatic lipogenesis incurred by insulin pulses during refeeding.
Najjar
Sonia M
SM
Department of Pharmacology, Cardiovascular Biology and Metabolic Diseases, The Medical University of Ohio, 3035 Arlington Avenue, HSci Building, Room 270, Toledo, OH 43614, USA. snajjar@meduohio.edu
Yang
Yan
Y
Fernström
Mats A
MA
Lee
Sang-Jun
SJ
Deangelis
Anthony M
AM
Rjaily
George A Abou
GA
Al-Share
Qusai Y
QY
Dai
Tong
T
Miller
Tiffany A
TA
Ratnam
Shobha
S
Ruch
Randall J
RJ
Smith
Stuart
S
Lin
Sue-Hwa
SH
Beauchemin
Nicole
N
Oyarce
Ana Maria
AM
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002272:Carcinoembryonic Antigen; D015815:Cell Adhesion Molecules; D004789:Enzyme Activation; D064429:Fatty Acid Synthases / Q000378:metabolism*; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D011993:Recombinant Fusion Proteins; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; C069847:CD66 antigens; D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D015815:Cell Adhesion Molecules; D007328:Insulin; D011993:Recombinant Fusion Proteins; D064429:Fatty Acid Synthases