title: Effects of small interfering RNA-mediated hepatic glucagon receptor inhibition on lipid metabolism in db/db mice.
abstract: Hepatic glucose overproduction is a major characteristic of type 2 diabetes. Because glucagon is a key regulator for glucose homeostasis, antagonizing the glucagon receptor (GCGR) is a possible therapeutic strategy for the treatment of diabetes mellitus. To study the effect of hepatic GCGR inhibition on the regulation of lipid metabolism, we generated siRNA-mediated GCGR knockdown (si-GCGR) in the db/db mouse. The hepatic knockdown of GCGR markedly reduced plasma glucose levels; however, total plasma cholesterol was increased. The detailed lipid analysis showed an increase in the LDL fraction, and no change in VLDL HDL fractions. Further studies showed that the increase in LDL was the result of over-expression of hepatic lipogenic genes and elevated de novo lipid synthesis. Inhibition of hepatic glucagon signaling via siRNA-mediated GCGR knockdown had an effect on both glucose and lipid metabolism in db/db mice.
authors.affiliation: Division of Cardiovascular Disease, Merck Sharp & Dohme Corp., Whitehouse Station, NJ.
authors.forename: Seongah
authors.initials: S
authors.lastname: Han
authors.forename: Taro E
authors.initials: TE
authors.lastname: Akiyama
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Previs
authors.forename: Kithsiri
authors.initials: K
authors.lastname: Herath
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Roddy
authors.forename: Kristian K
authors.initials: KK
authors.lastname: Jensen
authors.forename: Hong-Ping
authors.initials: HP
authors.lastname: Guan
authors.forename: Beth A
authors.initials: BA
authors.lastname: Murphy
authors.forename: Lesley A
authors.initials: LA
authors.lastname: McNamara
authors.forename: Xun
authors.initials: X
authors.lastname: Shen
authors.forename: Walter
authors.initials: W
authors.lastname: Strapps
authors.forename: Brian K
authors.initials: BK
authors.lastname: Hubbard
authors.forename: Shirly
authors.initials: S
authors.lastname: Pinto
authors.forename: Cai
authors.initials: C
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D001786:Blood Glucose; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000628:therapy; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D050155:Lipogenesis; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018027:Receptors, Glucagon / Q000235:genetics* / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D008077:Lipoproteins, LDL; D034741:RNA, Small Interfering; D018027:Receptors, Glucagon; D014280:Triglycerides; D002784:Cholesterol
keywords: diabetes mellitus; dyslipidemia; glucose