Effects of small interfering RNA-mediated hepatic glucagon receptor inhibition on lipid metabolism in db/db mice

• DOI: 10.1194/jlr.m035592
• Publication Date: 2013-07-05T03:39:13Z
• Authors: Seongah Han; Taro E. Akiyama; Stephen F. Previs; Kithsiri Herath; Thomas P. Roddy; Kristian K. Jensen; Hong-Ping Guan; Beth A. Murphy; Lesley A. McNamara; Xun Shen; Walter Strapps; Brian K. Hubbard; Shirly Pinto; Cai Li; Jing Li
• Keywords: Blood Glucose; Male; 0303 health sciences; Lipogenesis; dyslipidemia; Gene Expression; Mice, Obese; QD415-436; Biochemistry; Lipoproteins, LDL; Mice; 03 medical and health sciences; Cholesterol; Diabetes Mellitus, Type 2; Liver; Gene Knockdown Techniques; diabetes mellitus; Receptors, Glucagon; Animals; RNA Interference; glucose; RNA, Small Interfering; Triglycerides

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.