Glucagon receptor antagonism induces increased cholesterol absorption

• DOI: 10.1194/jlr.m060897
• Publication Date: 2015-09-16T01:43:24Z
• Authors: Hong-Ping Guan; Xiaodong Yang; Ku Lu; Sheng-Ping Wang; Jose M. Castro-Perez; Stephen Previs; Michael Wright; Vinit Shah; Kithsiri Herath; Dan Xie; Daphne Szeto; Gail Forrest; Jing Chen Xiao; Oksana Palyha; Li-Ping Sun; Paula J. Andryuk; Samuel S. Engel; Yusheng Xiong; Songnian Lin; David E. Kelley; Mark D. Erion; Harry R. Davis; Liangsu Wang
• Keywords: Male; Hypercholesterolemia; Drug Evaluation, Preclinical; cholesterol/absorption; Mice, Transgenic; QD415-436; Biochemistry; Inhibitory Concentration 50; 03 medical and health sciences; glucagon receptor antagonist; Receptors, Glucagon; Animals; Humans; bile acids; 0303 health sciences; diabetes; hypercholesterolemia; glucagon-like peptide 2; 3. Good health; Mice, Inbred C57BL; Cholesterol; Diabetes Mellitus, Type 2; Intestinal Absorption; beta-Alanine; Pyrazoles

Glucagon and insulin have opposing action in governing glucose homeostasis. In type 2 diabetes mellitus (T2DM), plasma glucagon is characteristically elevated, contributing to increased gluconeogenesis and hyperglycemia. Therefore, glucagon receptor (GCGR) antagonism has been proposed as a pharmacologic approach to treat T2DM. In support of this concept, a potent small-molecule GCGR antagonist (GRA), MK-0893, demonstrated dose-dependent efficacy to reduce hyperglycemia, with an HbA1c reduction of 1.5% at the 80 mg dose for 12 weeks in T2DM. However, GRA treatment was associated with dose-dependent elevation of plasma LDL-cholesterol (LDL-c). The current studies investigated the cause for increased LDL-c. We report findings that link MK-0893 with increased glucagon-like peptide 2 and cholesterol absorption. There was not, however, a GRA-related modulation of cholesterol synthesis. These findings were replicated using structurally diverse GRAs. To examine potential pharmacologic mitigation, coadministration of ezetimibe (a potent inhibitor of cholesterol absorption) in mice abrogated the GRA-associated increase of LDL-c. Although the molecular mechanism is unknown, our results provide a novel finding by which glucagon and, hence, GCGR antagonism govern cholesterol metabolism.