Abstract 16849: Mice Lacking Cyp8b1 Have Dramatically Improved Cardio-Metabolic Profile Due to Alterations in Bile Acid Profile
Bile acids are important amphoteric biomolecules that can serve in a variety of biological functions including; fat emulsification and molecular signaling via nuclear receptors. Bile acid synthesis mediated via CYP7A1is the primary route for excess cholesterol elimination. The major bile acids in humans are cholic acid (CA) and chenodeoxycholic acids (CDCA). CYP8B1 is part of the family of CYP P450 enzymes. CYP8B1 is expressed in the endoplasmic reticulum as a membrane protein which is responsible for the catalysis of 7α-hydroxy-4cholesten-3-one (7-HCO) into 7-12- α-dihydroxy-4-cholesten-3-one (7-12 diHCO) both being rate-limiting step intermediates of bile acid (BA) synthesis. We hypothesized that CYP8B1 KO mice would have several favorable cardiometabolic changes due to improved BA profile. CYP8B1 KO mice lack CA resulting in a 50% decrease in cholesterol absorption as determined by dual isotope kinetics. These mice also have increased fecal excretion of total-bile acids (~300%) and cholesterol (40%). Examination of liver genes revealed compensatory increased CYP7A1 and cholesterol synthesis (SREB2) pathways. CYP8B1 KO mice, when challenged with a cholesterol diet, have a 66% decrease in LDL-cholesterol while HDL-cholesterol is unchanged (n=10).
Additionally, mice lacking CYP8B1 not only have an improved lipid profile; they have a favorable body weight profile. Under normal chow feed condition CYP8B1 KO mice at 15 weeks of age have 50% less fat, no change in lean mass or food intake (n=25) was observed. When challenged with a high fat diet, CYP8B1 KO mice were protected from weight gain (lean and fat mass were determined by NMR analysis n=12). Mechanistic studies using tracers revealed that CYP8B1 KO mice have increased energy utilization (CO2 production) while gene expression analysis showed a significant up-regulation of brown-fat genes (Ucp1, Cidea and Cpt1b p<0.05) in BAT. These results suggest that inhibition of CYP8B1 is a viable therapeutic target, which can lead to improvements in lipoprotein profile and metabolic endpoints.
Author Disclosures: S. Parathath: Employment; Significant; Merck & Co. R. Rosa: Employment; Significant; Merck & Co. J.N. Gorski: Employment; Significant; Merck & Co. S. Wang: Employment; Significant; Merck & Co. K. Schlessinger: Employment; Significant; Merck & Co. K. Herath: Employment; Significant; Merck & Co. S. Previs: Employment; Significant; Merck & Co. J.M. Castro-Perez: Employment; Significant; Merck & Co. K.K. Wong: Employment; Significant; Merck & Co.
- © 2014 by American Heart Association, Inc.